Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)=O.[CH3:20][O:21][CH2:22][CH2:23][NH2:24].C([BH3-])#N.[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(O)(=O)C>[CH3:20][O:21][CH2:22][CH2:23][NH:24][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: COCCN
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: COCCNCc1ccc(SC(C)(C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
7.9 g of 1,1-dimethylethyl 2-[(4-formylphenyl)thio]-2-methyl-propanoate and 4.23 g of methoxyethylamine are initially charged in 100 ml of methanol and admixed with 19 ml of acetic acid. The mixture is stirred at RT for 15 min, boiled briefly and then, at 0° C., admixed a little at a time with 8.9 g of sodium cyanoborohydride. The mixture is stirred at room temperature overnight and then admixed with 1 N HCl and stirred for 30 min. The mixture is then made basic using sodium carbonate solution and extracted 2× with ethyl acetate. The organic phase is washed with sat. sodium chloride solution and dried over magnesium sulphate. Concentration and chromatographic purification give 5.6 g (58%) of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[Cl:25][C:26]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Cl.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:28][C:27]2[CH:30]=[CH:31][C:32]([Cl:34])=[CH:33][C:26]=2[Cl:25])[CH2:12]1)=[O:9])=[O:5]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: ClCc1ccc(Cl)cc1Cl
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2Cl)C1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A mixture of (R)-3-[{N-(2-amino-5-(trifluoromethoxy)benzoyl)glycyl}amino]pyrrolidine (0.050 mmol), 2,4-dichlorobenzyl chloride (0.060 mmol), piperidinomethylpolystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) was stirred at 60° C. for 12 h. The reaction mixture was cooled, loaded onto Varian™ SCX column and washed with 50% CHCl3/CH3OH (10 mL) and CH3OH (10 mL). Product was eluted using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material was added 4 N HCl in 1,4-dioxane (2 mL), and the solution was stirred overnight at room temperature. Concentration and preparative TLC afforded (R)-3-[{N-(2-amino-5-(trifluoromethoxy)benzoyl)glycyl}amino]-1-(2,4-dichlorobenzyl)pyrrolidine (Compound No. 1905) (17.6 mg, 70%): The purity was determined by RPLC/MS (93%); ESI/MS m/e 505 (M++H, C21H21Cl2F3N4O3).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][C:24]4[S:25][C:26]5[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=5[N:28]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+].Cl.C(Cl)Cl>C(O)(C)C.O>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(CCc2c[nH]c3ccc(Oc4nc5ccccc5s4)cc23)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: O=C(O)C1CCN(CCc2c[nH]c3ccc(Oc4nc5ccccc5s4)cc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.1 %

Procedure:
To a solution of 1-{2-[5-(benzothiazol-2-yloxy)-1H-indol-3-yl]-ethyl}-piperidine-4-carboxylic acid ethyl ester (44 mg, 0.098 mmol) in isopropanol (2.5 mL) was added H2O (1.1 mL) followed by KOH (11 mg, 0.19 mmol) in H2O (2.5 mL) and the resulting reaction mixture was stirred (rt, 16 h). The reaction mixture was acidified with 6 N HCl to pH 6 and treated with DCM (10 mL). The layers were separated and the aqueous layer was extracted with 25% isopropanol/DCM (2×10 mL). The combined organic layers were dried, filtered and concentrated in vacuo to afford the title compound as a white solid (43 mg, 100%). MS (ESI): mass calcd. for, C23H23N3O3S, 421.5; m/z found, 422.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.76 (d, J=8.0, 1H), 7.66 (m, 2H), 7.51 (d, J=8.7, 1H), 7.43 (m, 1H), 7.36 (s, 1H), 7.31 (m, 1H), 7.16 (dd, J=8.7, 2.3, 1H), 5.20 (s, 2H), 3.94 (m, 1H), 3.30-3.14 (m, 2H), 2.54-2.30 (m, 1H), 2.23-2.04 (m, 2H), 1.30 (s, 2H), 1.17 (d, J=6.2, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[N:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].OO.[OH-].[K+].S([O-])([O-])(=O)=[O:22].[Mg+2]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[N:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]([NH2:9])=[O:22]
Reactant: N#Cc1cccnc1Oc1cccc(Cl)c1
Reactant: O=S(=O)([O-])[O-]
Agent: OO
Agent: [K+]
Agent: [Mg+2]
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)c1cccnc1Oc1cccc(Cl)c1
Temperature: 0 °C

Procedure:
A solution of 2-(3-Chloro-phenoxy)-nicotinonitrile (7.81 grams, 33.9 mmole), 3% hydrogen peroxide (190 ml, 169 mmole) and 50% potassium hydroxide (380 ml, 3.39 mmole) in ethanol (100 ml) was stirred at 70° C. over night. The mixture was concentrated to 250 ml and cooled to 0° C. A solid was isolated by filtration, dissolved in ethyl acetate, dired over magnesium sulfate and concentrated to a white solid (6.51 g). M.P. 225-228° C.; MW 248.67; MS (m/e) 250 (M++1).
Reaction SMILES: ClC1C=CC=C(C(OO)=O)C=1.[CH2:12]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[N:18][C:19](SC)=[N:20][CH:21]=2)[N:16]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH:13]=[CH2:14].C(N(CC)C(C)C)(C)C.[NH2:42][C:43]1[CH:44]=[CH:45][C:46]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[C:47]([CH2:49][OH:50])[CH:48]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:12]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[N:18][C:19]([NH:42][C:43]3[CH:44]=[CH:45][C:46]([N:51]4[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]4)=[C:47]([CH2:49][OH:50])[CH:48]=3)=[N:20][CH:21]=2)[N:16]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH:13]=[CH2:14]
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1ccccn1
Reactant: CN1CCN(c2ccc(N)cc2CO)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)c(CO)c3)nc2n1-c1ccccn1
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
M-chloroperbenzoic acid (>65%) (796 mg) was added to a toluene (20 mL) solution of 2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one (898 mg), and stirred for 30 minutes. N,N-diisopropylethylamine (1.60 mL), [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol (800 mg) and tetrahydrofuran (10 mL) were added to the reaction liquid, and stirred overnight. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with a chloroform/isopropanol (80/20) mixed solution. This was dried with anhydrous magnesium sulfate, the solvent was evaporated away, and the residue was purified through basic silica gel chromatography (hexane/ethyl acetate=50/50 to 0/100). The resulting crystal was recrystallized with ethanol to give the entitled compound as a white crystal (941 mg).
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:3][CH2:2]1.[I:15]I.S(=O)(=O)(O)O.O>CC(O)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[C:13]([I:15])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: II
Reactant: COC(=O)c1ccc(C2CC2)cc1C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(I)c(C2CC2)cc1C
Temperature: 110 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
To a solution of methyl 4-cyclopropyl-2-methylbenzoate (compound 142.1, 2.68 g, 13.4 mmol, 1.00 equiv, 95%) in AcOH (50 mL) were added NaIO4 (1.51 g, 7.08 mmol, 0.50 equiv), I2 (3.58 g, 14.1 mmol, 1.00 equiv), and sulfuric acid (201 mg, 2.01 mmol, 0.15 equiv, 98%). The reaction mixture was stirred at 110° C. overnight. After cooling to ambient temperature, 100 mL of water was added. The resulting mixture was diluted with 100 mL of ethyl acetate, then washed with 3×30 mL of Na2S2O3 (aq., sat.) and 1×30 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified via silica gel column chromatography with ethyl acetate/petroleum ether (1/50) as eluent to yield 2.00 g (45%) of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:18]=[C:19]2[C@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=3)[O:23][C:20]2=[N:21][CH:22]=1.O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:16][C:17]1[CH:18]=[C:19]2[C@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:28]=3)[O:23][C:20]2=[N:21][CH:22]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Temperature: 80 °C

Procedure:
A vial charged with pyridin-3-ylboronic acid (0.295 g, 2.401 mmol), palladiumtetrakis (0.126 g, 0.109 mmol), potassium carbonate (1.509 g, 10.92 mmol), and (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (1.000 g, 2.183 mmol) was treated with 11 mL dioxane followed by 4.5 mL water. The vial was flushed with argon and was heated to 80° C. for 4 hours. The reaction mixture was diluted with EtOAc and dried over MgSO4. The organics were then concentrated, and the crude residue was purified by column chromatography yielding (S)-3-bromo-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine
Reaction SMILES: [CH3:1][N:2]=[S:3]([CH:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=1)[CH3:12])([C:5]1[S:6][CH:7]=[C:8](Br)[N:9]=1)=[O:4].[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]=[S:3]([CH:11]([C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=1)[CH3:12])([C:5]1[S:6][CH:7]=[C:8]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)[N:9]=1)=[O:4]
Reactant: CN=S(=O)(c1nc(Br)cs1)C(C)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN=S(=O)(c1nc(-c2ccc(C)cc2)cs1)C(C)c1ccc(C(F)(F)F)nc1
Yield: 68.9 %

Procedure:
A suspension of 5-{1-[methyl(4-bromo-1,3-thiazol-2-yl)sulfonimidoyl]ethyl}-2-(trifluoromethyl)pyridine (13) (0.055 g, 0.133 mmol), 4-methylphenyl boronic acid (0.027 g, 0.199 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.006 g, 0.005 mmol) in dioxane (0.9 ml) and 2M Na2CO3 (0.070 g, in 0.33 ml of water) was heated at reflux for 2 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo and the residue was dissolved in EtOAc, and subsequently washed with water and brine. The combined organic layers were dried (MgSO4), filtered and concentrated to dryness. The crude product was purified by column chromatography (SiO2, with a gradient of 50% EtOAc/hexanes) to give 5-{1-[methyl(4-(4-methylphenyl)-1,3-thiazol-2-yl)sulfonimidoyl]ethyl}-2-(trifluoromethyl)pyridine (19) as a dark yellow semi-solid (0.039 g, 70%). 1:1 mixture of two diastereomers 1H NMR (300 MHz, CDCl3) δ 8.85 (d, 1H), 8.75 (d, 1H), 8.1 (m, 2H), 7.7 (m, 6H), 7.2 (m, 4H), 6.9 (d, 2H), 5.4 (m, 1H), 5.2 (m, 1H), 3.3 (s, 3H), 3.1 (s, 3H), 2.4 (d, 6H), 2.0 (d, 3H), 1.9 (d, 3H); LC-MS (ESI): Mass calcd for C19H18F3N3OS2 [M+H]+, 426. Found 426.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH2:21][N:22]1[C:28](=[O:29])[C@@H:27]([NH:30][C:31](=[O:43])[C@@H:32]([N:34]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH3:35])[CH3:33])[CH2:26][O:25][C:24]3[C:44]([C:48](O)=[O:49])=[CH:45][CH:46]=[CH:47][C:23]1=3)=[C:16]([O:51][CH3:52])[CH:15]=[CH:14]2.Cl.[NH2:54][CH2:55][CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C.CCOC(C)=O>[C:60]([O:59][C:57](=[O:58])[CH2:56][CH2:55][NH:54][C:48]([C:44]1[C:24]2[O:25][CH2:26][C@H:27]([NH:30][C:31](=[O:43])[C@@H:32]([N:34]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH3:35])[CH3:33])[C:28](=[O:29])[N:22]([CH2:21][C:17]3[C:18]4[C:13](=[CH:12][C:11]([Br:10])=[CH:20][CH:19]=4)[CH:14]=[CH:15][C:16]=3[O:51][CH3:52])[C:23]=2[CH:47]=[CH:46][CH:45]=1)=[O:49])([CH3:63])([CH3:62])[CH3:61]
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2c(C(=O)O)cccc21
Reactant: CC(C)(C)OC(=O)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)COc2c(C(=O)NCCC(=O)OC(C)(C)C)cccc21
Yield: 69.9 %

Procedure:
DIEA (177 mg, 242 μl, 1.37 mmol, Eq: 5.00) was added to a mixture of (S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-9-carboxylic acid (180 mg, 274 μmol, Eq: 1.00), tert-butyl 3-aminopropanoate hydrochloride (49.8 mg, 274 μmol, Eq: 1.00), HBTU (104 mg, 274 μmol, Eq: 1.0) and HOBT.H2O (37.0 mg, 274 μmol, Eq: 1.0) in DMF (3.41 mL) at 0° C. and the mixture was warmed to RT. After 45 min. the mixture was diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography to afford 3-({(S)-9-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-7-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carbonyl}-amino)-propionic acid tert-butyl ester (150 mg, 69%) as an off-white foam.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:14].ClN1C(=O)CCC1=O>CCOC(C)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:14][CH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccon2)cn1
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: ClCc1ccc(-c2ccon2)cn1
Reaction time: 4 h
Yield: 34 %

Procedure:
To a stirring mixture of 3-(6-methylpyridin-3-yl)isoxazole (76 mg, 0.474 mmol) and 6 mL carbon tetrachloride, was added N-chlorosuccinimide (69.7 mg, 0.52 mmol), followed by 3 mg benzoyl peroxide. The reaction mixture was refluxed. Additional N-chlorosuccinimide (40 mg, 0.30 mmol) was added in two portions after stirring 2 h and 4 h. After refluxing for a total of 13 h the reaction mixture was diluted with EtOAc, then washed sequentially with 1 N aq. NaOH solution, water and saturated aqueous NaCl. The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to isolate 31 mg (34%) of the title compound as a white solid. HPLC/MS: retention time=1.77 min, [M+H]+=195.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[N:6]=1.CN(C(ON1N=NC2[CH:27]=[CH:28][CH:29]=[N:30]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:30][CH:29]3[CH2:27][CH2:28]3)=[O:13])=[CH:14][CH:15]=2)[N:6]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
4-(2-Amino-thiazol-4-yl)-benzoic acid (4.4 g, 20 mmol) was dissolved in DMF (100 mL) and treated with HATU (1.1 eq. 8.4 g) and DIEA (2.1 eq, 7.5 mL) and stirred for 15 minutes. Then cyclopropyl amine (1.1 eq, 1.5 mL) was added and the mixture stirred at ambient temperature for 1 hr. The reaction was diluted with 100 mL of water, extracted with EtOAc (3×100 mL) dried with brine (100 mL) and then Na2SO4 and the solvents removed. The resulting solid was triturated with ether to give the product >95% purity by HPLC. MS: 260.3 (M+H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[CH2:25]([N:27]1[CH:32]=[C:31]([C:33]([OH:35])=O)[C:30](=[O:36])[N:29]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:28]1=[O:44])[CH3:26].C(N(CC)C(C)C)(C)C.[CH3:54][O:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][C:65]=1[O:66][CH3:67])[N:62]=[CH:61][CH:60]=[C:59]2[O:68][C:69]1[CH:74]=[CH:73][C:72]([NH2:75])=[CH:71][C:70]=1[F:76]>CN(C)C=O.CCOC(C)=O>[CH3:54][O:55][C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][C:65]=1[O:66][CH3:67])[N:62]=[CH:61][CH:60]=[C:59]2[O:68][C:69]1[CH:74]=[CH:73][C:72]([NH:75][C:33]([C:31]2[C:30](=[O:36])[N:29]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:28](=[O:44])[N:27]([CH2:25][CH3:26])[CH:32]=2)=[O:35])=[CH:71][C:70]=1[F:76]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)c(=O)n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) (0.072 g, 0.19 mmol) and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.053 g, 0.19 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.055 mL, 0.32 mmol). After 15 min stirring at rt, 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylamine (0.05 g, 0.2 mmol) was added. The reaction was stirred at rt for 12 h, diluted with EtOAc (25 mL), then washed with 1N Na2CO3, water and brine and then dried over MgSO4. The product was crystallized from MeOH to give 75 mg (68%) as a white solid. mp=151-4° C.; LCMS m/z=575 (M+1); 1H NMR (DMSO) δ: 11.04 (s, 1H), 8.89 (s, 1H), 8.47 (d, 1H, J=5.4 Hz), 7.98, 8.01 (dd, 1H, J=2.3, 12.6 Hz), 7.52-7.56 (m, 2H), 7.33-7.46 (m, 6H), 6.47 (d, 1H, J=5.4 Hz), 4.01 (q, 2H, J=7 Hz), 3.98 (d, 6H), 13.0 (t, 3H, J=7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: CCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCOc1ccc(Br)c(C)c1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
In DMF (120 ml) was dissolved 4-bromo-3-methylphenol (12 g). To the mixture were added potassium carbonate (11.5 g) and sodium iodide (9.6 g) and then added dropwise 2-chloroethylpropylether (9.7 ml), and the mixture was stirred at 90° C. for 10 hours and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 4-bromo-3-methyl-1-(2-propoxyethoxy)benzene (11.0 g). 1H-NMR (200 MHz, CDCl3) δ 0.93 (3H, t, J=7.2 Hz), 1.54-1.71 (2H, m), 2.25 (3H, s), 3.48 (2H, t, J=6.6 Hz), 3.73-3.79 (2H, m), 4.05-4.10 (2H, m), 6.63 (1H, dd, J=8.8, 2.8 Hz), 6.82 (1H, d, J=2.8 Hz), 7.38 (1H, d, J=8.8 Hz).
Reaction SMILES: B#B.CSC.[CH3:6][C:7]1([CH3:40])[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:23])[C:20](O)=[O:21])=[CH:15][CH:14]=2)[C:9](=[O:25])[N:8]1[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[CH:28]=1.O.[OH-].[Na+]>O1CCCC1.CO.Cl.C(OCC)(=O)C>[OH:21][CH2:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([N:10]2[C:11](=[O:12])[C:7]([CH3:40])([CH3:6])[N:8]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[CH:28]=3)[C:9]2=[O:25])=[CH:14][CH:15]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C(=O)O)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccnc4)c3)C(C)(C)C2=O)cc1
Agent: B#B
Agent: Cl
Agent: [Na+]
Solvent: CSC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CO)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccnc4)c3)C(C)(C)C2=O)cc1
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 0.29 mL of diborane-dimethyl sulphide (2M in tetrahydrofuran) in 5 mL of tetrahydrofuran, under argon, at room temperature, is added 0.11 g of 2-(4-{4,4-dimethyl-2,5-dioxo-3-[2-(pyridin-3-ylamino)pyridin-4-ylmethyl]imidazolidin-1-yl}-phenyl)-2-methylpropionic acid obtained in stage f) below. The reaction medium is stirred at this same temperature for one hour and concentrated under reduced pressure. The residue obtained is taken up in 10 mL of methanol and 2 mL of 1N hydrochloric acid. The solution is concentrated under reduced pressure. The residue obtained is purified by Preparative LC/MS (gradient: acetonitrile/water/TFA 0.07%). The product obtained is taken up in 10 mL of ethyl acetate, 2 mL of water and 1 mL of 1N sodium hydroxide. The organic phase is dried over magnesium sulphate, filtered and then concentrated under reduced pressure to give 0.048 g of 3-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-5,5-dimethyl-1-{[2-(pyridin-3-ylamino)-pyridin-4-yl]methyl}imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:11]([CH:13]=[N+]=[N-])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[BrH:23].CCOCC>O1CCCC1.C(OCC)(=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:11]([CH2:13][Br:23])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: Br
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)CBr
Reaction time: 0.08 h

Procedure:
Boc-TyrCHN2 (0.40 g, 1.32 mmoles) was dissolved in 20 mL of tetrahydrofuran, and the resulting solution was cooled to about -10°. Anhydrous HBr: ether (2.3M, 0.58 mL, 1.3 mmoles) was added, and after about 5 minutes, solvent was evaporated, leaving a residue. The residue was dissolved in ethyl acetate, and the resulting solution was washed with water and saturated aqueous sodium chloride. The solution was then dried over anhydrous sodium sulfate and ethyl acetate was evaporated, yielding an oil. The oil was applied to a 2 cm column containing 10 g of silica gel, and the column eluted with chloroform. Eluate solvent was evaporated, and the remaining residue was triturated with hexane to yield crystalline Boc-TyrCH2Br (0.22 g, mp 109.5°-111°).