Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:36]=[C:37]([O:44][CH3:45])[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN1C(=O)N(C)CC1>[CH3:45][O:44][C:37]1[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=[C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:36]=1
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCC2
Solvent: CN1CCN(C)C1=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCC2
Temperature: 85 °C
Reaction time: 8 h

Procedure:
After adding 27 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine to a solution of 128 mg of [2-(7-methoxy-2,3-dihydrobenzofuran-5-yl) -2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMI, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(7-methoxy-2,3-dihydrobenzofuran-5-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH2:10]([CH:17]1[CH2:20][CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)Cl>[N+](C1C=CC=CC=1)([O-])=O>[N+:1]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:17]2[CH2:20][CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18]2)=[CH:12][CH:13]=1)([O-:4])=[O:2]
Reactant: CCOC(=O)C1CC(Cc2ccccc2)C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)C1CC(Cc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of concentrated nitric acid (0.5 mL) and concentrated sulphuric acid (0.8 mL) was added slowly with stirring to an ice-cooled solution of ethyl 3-benzylcyclobutanecarboxylate (German Patent DE 2626287) (876 mmol, 4.02 mmol) in nitrobenzene (2 mL). The reaction mixture was warmed to ambient temperature and stirred for 1.5 h then poured onto ice/water. DCM (5 mL) was added and the mixture was stirred before passing through a phase separation cartridge. Solvent was removed by evaporation to give the title compound that was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].OO.S([O-])([O-])(=[O:29])=S.[Na+].[Na+].C(O)C.O>C(O)C.[O-][V](=O)=O.[Na+]>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:29])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: O=S([O-])([O-])=S
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=[V](=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 8 h
Yield: 385.3 %

Procedure:
2-[[3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio]benzimidazole (monohydrate) (10.0 g) was dissolved in ethanol (75 ml), to which was added a solution of sodium metavanadate (15 mg) in 35% aqueous solution of hydrogen peroxide (3.07 g), and allowed to react by stirring at 20°-25° for about 8 hours. After completion of the reaction an aqueous solution of sodium thiosulfate (1 g/5 ml) was added to the reaction mixture, which was stirred vigorously for about 10 minutes. The crystals were collected by filtration and washed with an ice-cooled mixture of ethanol-water (1:1). The crystals thus obtained were treated with a mixture of ethanol-water (9:1, 50 ml), heated (65°-70° C.) and stirred so that the crystals were dissolved, then the insoluble matters were removed by hot filtration. The filtrate was ice-cooled for crystallization, and the crystals were collected by filtration, washed with ice-cooled ethanol-water mixture (8:2) and dried in vacuo, to give white needles of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylsulfinyl]benzimidazole (9.0 g). (yield: 90.5%).
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.S(Cl)([Cl:15])=O>CN(C)C=O>[Cl:15][C:9]1[C:4]2[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=c1[nH]cnc2cnc(F)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1cc2c(Cl)ncnc2cn1
Reaction time: 0.5 h

Procedure:
A suspension of 6-fluoropyrido[3,4-d]pyrimidine-4(3H)-one (U.S. patent application Ser. No. 08/358,352, 1994) (1.65 g) in 50 mL thionyl chloride and several drops of dimethyl formamide was heated under reflux until a clear solution was obtained (20 minutes), and then for a further 30 minutes. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with aqueous Na2CO3. The solvent was dried and removed to give crude 4-chloro-6-fluoropyrido[3,4-d]pyrimidine which was dissolved in 2-propanol (50 mL) containing 3-bromoaniline (2.1 g). The mixture was heated under reflux for 15 minutes to give a precipitate, which was redissolved by the addition of triethylamine. After the addition of water, the solution was concentrated and cooled to give 4-[(3-bromophenyl)amino]-6-fluoropyrido[3,4-d]-pyrimidine, (2.29 g), mp (MeOH) 219.5-221° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][O:31]CC4C=CC(OC)=CC=4)[N:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:17])[F:18])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(COCCCNc2nccc(-c3c(-c4ccc(F)cc4)nn4cc(C(F)(F)F)ccc34)n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: OCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3cc(C(F)(F)F)ccc23)n1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(3-(4-methoxybenzyloxy)propyl)-2-pyrimidinamine (2.1 g, 3.8 mmol) in 4N HCl/dioxane (5 mL) was stirred at room temperature for 4.5 h, then heated to reflux for 1 h. The mixture was cooled to room temperature, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc. The EtOAc extracts were dried (MgSO4), filtered, and the solvent was evaporated. The residue was triturated with 2% EtOAc/hexanes to afford a solid which was collected by filtration and dried to give the title compound as a white solid, 1.31 g (80% yield). 1H NMR (acetone-d6) δ 9.20 (s, 1H), 8.73 (d, 1H, J=9.3 Hz), 8.15 (d, 1H, J=5.1 Hz), 7.77 (m, 2H), 7.64 (d, 1H, J=9.9 Hz), 7.34 (m, 2H), 6.50 (s, 1H), 6.40 (d, 1H, J=5.1 Hz), 3.60–3.70 (m, 4H), 1.88 (m, 2H). MS (+ve ion electrospray) 432 (95), (MH+).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[N:3]=1.[CH:29]([NH:31][NH2:32])=[O:30]>C(Cl)(Cl)Cl>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:4]2[N:3]=[C:2]([NH:32][NH:31][CH:29]=[O:30])[N:7]([CH3:8])[C:6](=[N:9][C:10]3[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[CH3:18])[CH:5]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: NNC=O
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(Cl)n2)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(NNC=O)n2)cc1OC
Temperature: 25 °C
Yield: 26.4 %

Procedure:
To a suspension of 2-chloro-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (3.0 g) in chloroform (15 ml) was added formylhydrazine (1.36 g). The mixture was refluxed for 6 hours and cooled to ambient temperature. The resulting precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel using chloroform to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-(2-formylhydrazino)-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (0.84 g).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)(=[O:27])=[O:26])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(C2=CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418 mmol), benzenesulfonyl chloride (20 mg, 0.113 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[O:11])[S:7][CH:8]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].CCN(CC)CC>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][NH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[C:20]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])=[O:11])[S:7][CH:8]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(NC(=O)Nc2nc(CCN)cs2)c(C(=O)C2CCCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNCCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To 1-[4-(amino-ethyl)-thiazol-2-yl]-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (0.03 g, 0.08 mmol) in 10 mL DCM was added methyl bromoacetate (0.01 g, 0.08 mmol) followed by Et3N (0.008 g, 0.08 mmol). After stirring at room temperature overnight, reation was concentrated and purified by flash chromatography on silica gel with 5% MeOH/EtOAc to obtain the product in 50% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.O>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Nc4ccc(F)cc4)nc(Cl)nc32)cc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 76.2 %

Procedure:
A mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (260 mg, 0.556 mmol), 4-fluoroaniline (0.055 mL, 0.581 mmol) and DIEA (0.300 mL, 1.72 mmol) in dioxane (4 mL) was stirred at 110° C. for 20 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2-chloro-N-(4-fluorophenyl)-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (230 mg).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[F:48][C:49]([F:59])([F:58])[C:50]1[CH:57]=[CH:56][C:53](C=O)=[CH:52][CH:51]=1.[B-]C#N.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:53]4[CH:56]=[CH:57][C:50]([C:49]([F:59])([F:58])[F:48])=[CH:51][CH:52]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: O=C([O-])O
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]1(COc2ccc(N3CCN(Cc4ccc(C(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 7 h
Yield: 74.1 %

Procedure:
A mixture of tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)-phenyl]piperazine-1-carboxylate prepared in Example 148 (800 mg, 1.74 mmol) and trifluoroacetic acid (3 ml) was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). To the solution, triethylamine (3 ml, 21.52 mmol) was added followed by stirring at room temperature for 5 minutes. The mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml). To the solution, 4-trifluoromethylbenzaldehyde (910 mg, 5.23 mmol), sodium cyanotrihydroborate (328 mg, 5.23 mmol) and acetic acid (0.33 ml, 5.23 mmol) were added followed by stirring at room temperature overnight. To the reaction mixture, a saturated sodium hydrogencarbonate solution and methylene chloride were added, and the solution was stirred and then extracted with methylene chloride. The organic phase was dried over magnesium sulfate and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) to afford (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (667 mg, yield 74%) as a light yellow powder.
Reaction SMILES: [NH3:1].[C:2]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][C:31]=1[OH:32])[O:8][CH2:9][CH:10]([NH:12][CH2:13][CH:14]([OH:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](OC)=[O:24])=[C:19]([OH:27])[CH:18]=1)[CH3:11])(=[O:4])[NH2:3]>O1CCOCC1>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH:14]([OH:28])[CH2:13][NH:12][CH:10]([CH3:11])[CH2:9][O:8][C:7]2[CH:29]=[CH:30][C:31]([OH:32])=[C:5]([C:2](=[O:4])[NH2:3])[CH:6]=2)=[CH:18][C:19]=1[OH:27])(=[O:24])[NH2:1]
Reactant: N
Reactant: COC(=O)c1ccc(OCC(O)CNC(C)COc2ccc(O)c(C(N)=O)c2)cc1O
Solvent: C1COCCO1
Product: CC(COc1ccc(O)c(C(N)=O)c1)NCC(O)COc1ccc(C(N)=O)c(O)c1
Reaction time: 1.5 h

Procedure:
A mixture of 50 ml of dioxan and 500 ml of concentrated ammonia solution is added to 21.5 g of 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]-3-(3-hydroxy-4-methoxycarbonylphenoxy)propan-2-ol. The reaction mixture is stirred for 1-2 hours, and as soon as it is homogeneous, left to stand for 3 days at 20°-30°. By concentration by evaporation, 20 g of crude, crystalline 1-(4-carbamoyl-3-hydroxyphenoxy)-3-[2-(3-carbamoyl-4-hydroxyphenoxy)-1-methylethylamino]propan-2-ol is obtained as a diastereoisomeric mixture having a melting point of 180°-190°. A hydrochloride is formed which melts at 238°-243° (from ethanol/methanol).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25]N1C(=O)CCC1=O>C1COCC1>[Br:25][C:24]1[N:10]2[C:11]3[CH:23]=[CH:22][CH:21]=[N:20][C:12]=3[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:9]2=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cn3c(n2)-c2ccccc2Nc2ncccc2-3)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.7 g, 1 eq.) in THF (20 mL) was added N-bromosuccinimide (0.4 g, 1 eq.). The reaction was stirred at room temperature for 1 hour, poured onto water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic extracts were combined, washed with saturated sodium bicarbonate (1×100 mL), water (1×50 mL), brine (1×50 mL) and dried over sodium sulfate. After filtration and concentration under reduced pressure 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.85 g, 97%) was obtained which was used with no further purification. 1H NMR (DMSO-d6) 400 MHz δ 8.64 (s, 1H), 8.28 (dd, JA=4.8 Hz, JB=1.6 Hz, 1H), 8.05 (dd, JA=8 Hz, JB=1.6 Hz, 1H), 8.02-7.98 (m, 1H), 7.85 (dd, JA=8 Hz, JB=1.6 Hz, 1H), 7.53-7.48 (m, J=8 Hz, 2H), 7.42-7.34 (m, 2H), 7.30-7.22 (m, 2H), 7.14-7.09 (m, 1H); LCMS: 388 [M+H].
Reaction SMILES: CN1CC[O:5][CH2:4]C1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([C:24]([F:27])([F:26])[F:25])=[N:16]2)=[CH:11][CH:10]=1.C(Cl)(Cl)=O>C(Cl)Cl>[N:8]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:17]([C:24]([F:27])([F:26])[F:25])=[N:16]2)=[CH:13][CH:14]=1)=[C:4]=[O:5]
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Reactant: CN1CCOCC1
Agent: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C=Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
To morpholinomethyl polystyrene (Novabiochem, substitution=3.55 mmol/g, 1.02 g, 3.62 mmol) in methylene chloride (18.5 mL) under argon was added 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.555 g, 1.88 mmol). The mixture was cooled to 0° C. and phosgene (1.93M in toluene, Fluka, 1.95 mL, 3.76 mmol) was added. After thirty minutes the reaction mixture was filtered, washed with methylene chloride (2×30 mL) and concentrated to give 1-(4′-isocyanatophenyl)-3,5-bis(trifluoromethyl)pyrazole.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][CH2:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][C@@H:21]([OH:25])[C:22]([OH:24])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]([F:42])([F:41])[O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN1CCCC1=O.ClCC(Cl)C>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][C@@H:21]([OH:25])[C:22]([OH:24])=[O:23])=[O:18])=[CH:26][CH:27]=2)[C:38](=[O:39])[CH2:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][C:29]([F:41])([F:28])[F:42])=[CH:32][CH:33]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)C1CCC(NCc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)C1CCC(N(Cc2ccc(C(=O)NC[C@@H](O)C(=O)O)cc2)C(=O)Cc2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The above resin bound (R)-3-{4-[(4-tert-butylcyclohexylamino)methyl]benzoylamino}-2-hydroxypropionic acid was added 1,2-dichloropropane (500 μL) and BSA (100 μL) and the mixture was vortexed at 25° C. for 1 hour followed by filtration. To the resin was added a solution of 4-(trifluoromethoxy)phenylacetic acid (400 umol) in a mixture of N-methyl-2-pyrrolidinone, 1,2-dichloropropane and diisopropylethylamine (4.5:4.5:1, 1 mL) was added followed by a solution of bromo-tris(pyrrolidino)phosphonium hexafluorophosphate (400 μmol) in 1,2-dichloropropane (500 μL). The mixture was allowed to react for 3 hours at 50° C. and the resin was allowed to cool to 25° C. while washed with N-methyl-2-pyrrolidinone (4×1 mL), and DCM (10×1 mL) afforded the resin bound title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19](OC)=[N:18][S:17](=[O:22])[N:16]=2)=[CH:7][CH:6]=1)[CH3:3].[CH3:23][NH2:24]>>[CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:19]([NH:24][CH3:23])=[N:18][S:17](=[O:22])[N:16]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN
Reactant: COC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Product: CNC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To the methanolic solution of the product of Step A that was cooled to 5° in an ice-water bath was added anhydrous methylamine for 8 minutes. The reaction mixture was stirred at ambient temperature for 17 hours, then evaporated under reduced pressure to give the product as a yellow oil that was placed on 55 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fraction was evaporated, dissolved in methanol and diluted with diethyl ether to yield the title compound (2.32 g) as a solid that was dried in vacuo at ambient temperature over P2O5 for 3 hours, mp 86°-92°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][N:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[C:12]([C:14]([F:16])([F:17])[F:15])=[N:11][N:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2n[nH]c(C(F)(F)F)n2)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(-c2nnc(C(F)(F)F)n2COCC[Si](C)(C)C)c1
Reaction time: 0.5 h

Procedure:
A stirred solution of the product from step (ix) (17.46 g) in dry N,N-dimethylformamide (300 ml) was treated with 60% dispersion of sodium hydride (3.22 g) in portions at room temperature under nitrogen. After the initial effervescence had subsided the resultant orange oil was stirred for a further 30 min before being treated with 2-(trimethylsilyl)ethoxymethyl chloride (14.3 ml) dropwise giving a pale yellow suspension which was further stirred for 30 min. The mixture was carefully poured onto water (700 ml) and extracted with ethyl acetate (3×250 ml). The combined organic extracts were further washed with water (3×250 ml) and saturated brine (250 ml) before collecting, drying over magnesium sulphate and evapoaration of the solvent under reduced pressure to give the subtitle product as a yellow oil. Yield: 26.1 g. This was not purified but used directly in the next step.