Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:20][C:21]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24]>C(Cl)Cl.CN1CCOCC1.ClC(OCC(C)C)=O>[C:11]1([CH2:10][C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:17]2[O:19][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([F:31])([F:32])[F:33])[C:21]=3[N:20]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Yield: 44.5 %

Procedure:
Using the procedure of Step A of Example 7, a solution of 19.9 g of BOC-L-phenylalanine in 150 ml of methylene chloride and 20.6 ml of N-methyl-morpholine, 19.5 ml of isobutyl chloroformate in 75 ml of methylene chloride and 15.4 g of 2-amino-3-trifluoromethyl benzoic acid in 150 ml of methylene chloride and 8.3 ml of N-methyl-morpholine were reacted to obtain 14.5 g of 1,1-dimethylethyl N-[(S) 2-phenyl-1-[4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl]-ethyl]-carbamate melting at 145° C. and having a specific rotation of [α]D =-33.5°±2° (c=0.5% in CH3COOH).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH2:33][CH2:34][F:35])[C:15]3[CH:32]=[CH:31][C:18]([C:19]([NH:21][C@H:22]([C:28]([O-:30])=[O:29])[CH2:23][CH2:24][C:25]([O-:27])=[O:26])=[O:20])=[CH:17][CH:16]=3)[CH:8]=2)[N:3]=1.[OH-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH2:33][CH2:34][F:35])[C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:21][C@H:22]([C:28]([OH:30])=[O:29])[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:20])=[CH:31][CH:32]=3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(O)c2cc(CN(CCF)c3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(O)c2cc(CN(CCF)c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)ccc2n1
Reaction time: 2 h
Yield: 60.1 %

Procedure:
N-(4-(N-((2-amino-4-hydroxy-6-quinazolinyl)methyl)2-fluoroethylamino)benzoyl)-L-glutamate (0.206 g) was suspended in a mixture of water (4.5 ml) and ethanol (1 ml) and treated with 1 N NaOH aq. (5 mol eq.). Vigorous shaking gave a solution within 5 min. After 2 hr. the solution was clarified by filtration and the pH brought to 4.0 using 1 N HCl aq. A gelatinous precipitate of the product resulted. It was freed from inorganic ions by three cycles of suspension-centrifugation-decantation. The amorphous white solid was dried at 70° C. in vacuo, (m.p.>350° C. with some darkening and slow decomposition from 245° C.) giving N-(4-(N-((2-amino-4-hydroxy-6-quinazolinyl)methyl)2-fluoroethylamino)benzoyl)-L-glutamic acid (CB 3731). Yield 60.1%. The structure was confirmed by elemental analysis (C,H,N and F) and by uv spectroscopy (spectrum determined in 0.1 N NaOH aq.). uv λ(nm) (ε) maxima: 307 (29,200), 275 (19,500), 227.5 (49,700 ); minima: 279 (19,200), 250 (9,100).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=1>C(#N)C>[I:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][N:3]2[CH2:4][CH2:5][CH2:6][C@H:2]2[CH3:1])=[CH:20][CH:21]=1
Reactant: C[C@@H]1CCCN1
Reactant: ClCCCCOc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCCOc1ccc(I)cc1
Temperature: 100 °C
Reaction time: 9 h
Yield: 89 %

Procedure:
To a suspension of (2R)-2-methylpyrrolidine (0.8 g) and cesium carbonate (1.7 g) in acetonitrile (5 mL), 1-(4-chlorobutoxy)-4-iodobenzene obtained in Example 61-(1) (1.4 g) was added and the mixture was heated to 100° C., at which it was stirred for 9 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1) to give the titled compound (1.4 g, 89%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][C:14]1[CH:41]=[CH:40][C:17]([CH2:18][N:19]([CH2:30][C:31]2[NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[N:32]=2)[CH:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CCN(CC)CC>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[CH2:30][N:19]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[N:10][C:2]=2[CH3:1])=[CH:41][CH:40]=1)[CH:20]1[C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccnc(C)c1C(=O)NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A solution of 2,4-dimethyl-nicotinic acid (54 mg, 0.35 mmol) in SOCl2 (˜2 mL, excess) was heated to 80° C. for 4 hours. The condenser was removed and the mixture was flushed with N2 at 80° C. for ˜5 minutes and then dried in vacuo for 10 minutes. The resulting syrup was dissolved in CH2Cl2 (2.4 mL) and added to a stirring mixture of (4-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (187 mg, 0.47 mmol), Et3N (0.33 mL, 2.35 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight at room temperature. Purification of the crude yellow foam (240 mg) by radial chromatography on silica gel (2 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) followed by radial chromatography on silica gel (1 mm plate, EtOAc/MeOH/NH4OH, 400:3:3) afforded the desired amide (61 mg, 33%) as a white foam.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16].[F:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1>>[F:26][C:27]1[CH:32]=[C:31]([C:9]2[CH:10]=[C:11]3[C:6](=[N:7][CH:8]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])=[C:2]3[OH:1])[CH:30]=[CH:29][N:28]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Cn1c(=O)c(C(=O)NCC(=O)OC(C)(C)C)c(O)c2cc(I)cnc21
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cc(-c3ccnc(F)c3)cnc21

Procedure:
The title compound was prepared similarly to the procedures described for Example 64 (a, b) from tert-butyl 2-(4-hydroxy-6-iodo-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate (Example 26 (g)) and 2-fluoro-4-pyridinylboronic acid. MS (ESI, pos. ion) m/z: 373 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm: 12.99 (s, 1 H), 10.34-10.48 (m, 1 H), 9.31 (s, 1 H), 8.80 (s, 1 H), 8.30-8.41 (m, 1 H), 7.84-7.96 (m, 1 H), 7.78 (s, 1 H), 4.04-4.25 (m, 2 H), 3.72 (s, 3 H).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([OH:21])([C:17]([F:20])([F:19])[F:18])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)([CH3:9])[CH3:8])C.[CH3:23][N:24](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:23]([C:13]1[CH:14]=[CH:15][C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([OH:21])([C:17]([F:18])([F:19])[F:20])[C:4]([OH:3])=[O:22])=[CH:11][CH:12]=1)#[N:24]
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(Br)cc1)C(F)(F)F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(CC(O)(C(=O)O)C(F)(F)F)c1ccc(C#N)cc1

Procedure:
From 4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, zinc cyanide and tetrakis-triphenylphosphine-palladium in dimethylformamide at 140° C. After saponification, the title acid is obtained as a foam.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[CH:17]([CH3:19])[CH3:18].F[C:21]1[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[CH:23][C:22]=1[CH3:31].O>CS(C)=O>[CH3:27][C:26]1[CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=[C:22]([CH3:31])[C:21]=1[O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1F
Reactant: CC(C)c1n[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc2[nH]nc(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
86 mg (0.624 mmol) of potassium carbonate are added to a solution of 110 mg (0.624 mmol) of 5-hydroxy-3-isopropyl-1H-indazole in 5 ml of DMSO and the mixture is stirred for 1 h. After addition of 106 mg (0.624 mmol) of 4-fluoro-3,5-dimethylnitrobenzene in portions, the mixture is then firstly stirred at room temperature for 2 h, then at 100° C. for 3 h. After cooling to room temperature, the mixture is added to 10 ml of water and the aqueous phase is extracted 3× with ethyl acetate. The combined organic extracts are washed with water and satd NaCl soln, dried over sodium sulphate and concentrated in vacuo. By purification of the resulting residue on silica gel (cyclohexane/ethyl acetate 3:1), 84 mg (41%) of 5-(2,6-dimethyl-4-nitrophenoxy)-3-isopropyl-1H-indazole are obtained.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]Br.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:21][C:14]1[C:15]2[C:20]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: BrBr
Reactant: c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Reaction time: 1 h
Yield: 89 %

Procedure:
6.0 g (23.7 mmol) of 9-phenylanthracene was dissolved in 80 ml of carbon tetrachloride, and a solution in which 3.80 g (21.1 mmol) of bromine was dissolved in 10 ml of carbon tetrachloride was dropped into the reaction solution by a dropping funnel. After the dropping, stirring was conducted for 1 hour at room temperature. After reaction, a sodium thiosulfate water solution was added and the reaction was stopped. An organic layer was washed with an NaOH water solution and a saturated saline and dried with magnesium sulfate. After the natural filtration, it was concentrated, dissolved in toluene, and filtered through florisil, Celite (registered trademark), and alumina. The filtrate was concentrated and recrystallized by dichloromethane and hexane. Then, 7.0 g of a light-yellow solid of 9-bromo-10-phenylanthracene, which was the intended object, was obtained with a yield of 89% (synthetic scheme of (b-4)).
Reaction SMILES: O[CH:2]([C:7]1[O:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)[CH2:3][CH2:4][CH2:5]O.CS(Cl)(=O)=O.C([N:31]([CH2:34][CH3:35])CC)C>O1CCCC1.C(OCC)(=O)C>[CH2:34]([N:31]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:7]1[O:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1)[C:35]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:7]=1
Reactant: OCCCC(O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(1,4-dihydroxybutyl)-4,5-diphenyloxazole (1 g) in tetrahydrofuran (10 ml) were added methanesulfonyl chloride (1.6 g) and triethylamine (1.5 ml) at 0° C. The solution was diluted with ethyl acetate and washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated. The residue was dissolved in benzylamine (10 ml). After being stirred for 2 hours at 80° C., the mixture was partitioned between ether and water. The organic layer was washed with water and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to afford 1-benzyl-2-(4,5-diphenyloxazol-2-yl)pyrrolidine (1.3 g). MS (m/z): 381 (M+ +1) IR (Neat): 1600 cm-1NMR (CDCl3, δ): 1.8-2.6 (5H, m), 3.0-3.2 (1H, m), 3.60 (1H, d, J=13 Hz), 3.85 (1H, t, J=7.8 Hz), 3.89 (1H, d, J=13 Hz), 7.0-7.8 (15H, m)
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C@H:6]1[O:11][C@H:10](Br)[C@H:9]([O:13][C:14]([CH3:16])=[O:15])[C@@H:8]([O:17][C:18]([CH3:20])=[O:19])[C@@H:7]1[O:21][C:22]([CH3:24])=[O:23])=[O:3].[CH3:25][O:26][C:27](=[O:30])[CH2:28][OH:29]>[Hg]=O.[Hg](Br)Br>[CH3:25][O:26][C:27]([CH2:28][O:29][CH:10]1[O:11][C@H:6]([CH2:5][O:4][C:2](=[O:3])[CH3:1])[C@@H:7]([O:21][C:22](=[O:23])[CH3:24])[C@H:8]([O:17][C:18](=[O:19])[CH3:20])[C@H:9]1[O:13][C:14](=[O:15])[CH3:16])=[O:30]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(=O)CO
Agent: Br[Hg]Br
Agent: O=[Hg]
Product: COC(=O)COC1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 60 %

Procedure:
The yields of the compounds of general formula I, which can be achieved with the process according to the invention, are good. For known compounds in which a comparison with the prior art is possible, they exceed the yields of the prior art. Thus, for example, (WO 96/35700), in the reaction of acetobromoglucose with glycolic acid methyl ester under the influence of mercury oxide and mercury(II) bromide according to Koenigs-Knorr, the 1-O-methyloxycarbonylmethyl-2,3,4,6-tetra-O-acetyl-glucopyranose is obtained with a yield of 60%. The saponification to the free acid would be connected with a further loss in yield. EP 882733 also describes the production of this compound, but without yield information. According to the process of the invention, the acid is also obtained in a two-stage process. Here, the yield is 78%, however (Example 24 of this application).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:32][CH2:33][CH3:34]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:32][CH2:33][CH3:34])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.5 %

Procedure:
A solution of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)acetate (2.5 g; 8.60 mmol) in dry DMF (40 mL) was cooled to −78° C. LHMDS (9.46 mL; 9.46 mmol; 1M in THF) was added dropwise and the mixture was stirred at −78° C. for 15 min followed by the dropwise addition of iodopropane (1.260 ml; 12.90 mmol). After stirring for 2 h at −15° C. the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-10%) in heptane to give 1.131 g (37%) of the title compound as a yellow oil. ESI/APCI(+): 333 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].CN.[CH2:39]([N:41](CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([NH:41][CH3:39])=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: CCN(CC)CC
Reactant: Cc1c(F)cc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc(F)c(C)c(-c2nc(NCCN(C)C)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Yield: 54.5 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoic acid (25 mg, 0.05 mmol) in CH2Cl2 (2 mL) were added methylamine (2.0 M soln. in THF, 0.13 mL, 0.26 mmol), triethylamine (0.05 mL, 0.36 mmol) and HBTU (20 mg, 0.053 mmol). The reaction mixture was stirred over night. The reaction mixture was concentrated. Separation via a HPLC with TFA followed by treatment with t-amino SPE cartridge then provided the title compound as a white solid (14 mg, 54%). LC-MS m/z 514 (M+H)+; 1H-NMR (MeOD) δ 2.24 (s, 3H), 2.78 (s, 6H), 2.94 (s, 3H), 3.15 (m, 2H), 3.55 (m, 2H), 4.22 (s, 2H), 7.18 (m, 2H), 7.56 (m, 2H), 7.39 (m, 1H).
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1>C(N(CC)CC)C.[Cu](I)I>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: Brc1ccncn1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccncn2)CCN(C)C1
Temperature: 40 °C
Yield: 17.7 %

Procedure:
5-Ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.466 mmol) and 4-bromopyrimidine (126 mg, 0.797 mmol) were dissolved in triethylamine (1.5 mL), and the solution was purged with nitrogen. Dichlorobis (triphenylphosphine) palladium (12.5 mg, 0.017 mmol) and copper iodide (6.7 mg, 0.035 mmol) were added and the reaction mixture was purged again with nitrogen. The reaction mixture was heated by microwave at 40° C. for 90 min. The reaction mixture was quenched with 30 mL water and extracted with EtOAc (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude product was purified with column chromatography (silica gel: 100-200 mesh, eluent 0-10% MeOH in DCM) to obtain 25 mg product. 1H NMR (CDCl3, freebase) δ (ppm): 9.17 (s, 1H), 8.76 (d, 1H), 7.57 (d, 1H), 7.40 (d, 1H), 7.18 (m, 2H), 3.64 (s, 2H), 3.06 (d, 2H), 2.98 (d, 2H), 2.61 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19][CH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][C@H:23]([CH2:27][O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:22]1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19][CH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][C@H:23]([CH2:27][O:28][C:29]([CH3:37])([CH3:38])[C:30]([OH:32])=[O:31])[CH2:22]1)[CH3:2]
Reactant: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COC[C@@H]1CCC[C@H](COC(C)(C)C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COC[C@@H]1CCC[C@H](COC(C)(C)C(=O)O)C1

Procedure:
270 mg of tert-butyl 2-{(1S,3R)-3-[5-ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxymethyl]cyclohexylmethoxy}-2-methylpropionate are dissolved in 5 ml of dichloromethane and 2.5 ml of trifluoroacetic acid and stirred overnight. The solution is then completely evaporated, and the residue is purified by preparative HPLC, resulting in 127 mg of 2-{(1S,3R)-3-[5-ethyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxymethyl]cyclohexylmethoxy}-2-methylpropionic acid as yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][NH2:14])=[O:12])[N:2]=1.[N:15]([O-])=O.[Na+]>Cl.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([N:13]=[N+:14]=[N-:15])=[O:12])[N:2]=1
Reactant: O=N[O-]
Reactant: NNC(=O)c1cc2ccccc2cn1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc2ccccc2cn1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
To a suspension of isoquinoline-3-carbohydrazide (43 g, 0.23 mol) in aqueous HCl (1 N, 230 mL) and water (1 L) was added a solution of NaNO2 (23.8 g, 0.34 mol) in water (200 mL) dropwise at 0-5° C. The mixture was stirred at 0-5° C. for 4 h. LC-MS indicated the reaction was not completed. Another solution of NaNO2 (11.9 g, 0.115 mol) in water (60 mL) was added and the reaction mixture was stirred at 0-5° C. until LC-MS indicated the completion of the reaction. The precipitate was filtered, washed with cold water, and dried under high vacuum to give isoquinoline-3-carbonyl azide (42.7 g, 93.8%) as a white solid. LRMS (M+H+) m/z 199.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][CH3:22])[C:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.CC(C)N=C=NC(C)C.C1(N)CC1>CN(C=O)C>[CH:27]1([NH:29][C:11](=[O:13])[C:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:20][CH2:21][CH3:22])[CH2:28][CH2:26]1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(OCC)(OCC)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(OCC)(OCC)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.6 %

Procedure:
(S)-3-(tert-butoxycarbonylamino)-2,2-diethoxyhexanoic acid (8.03 g, 25.1 mmol) was dissolved under nitrogen in 400 mL DMF and HOBt (4.10 g, 30.3 mmol), DIC (7.7 mL, 49.7 mmol) and cyclopropylamine (3.5 mL, 50.0 mmol) were added to the reaction mixture. After stirring for 24 hours at room temperature, the mixture was quenched with 400 mL 5% NaCl and 800 mL EtOAc and the phases were separated. The aqueous phase was extracted with 100 mL EtOAc, the combined organic phases were dried over Na2SO4 and the solvent was removed in vacuo. Purification by column chromatography on silica gel (CHX:EE 10:1→3:1) yielded 3.2 g (S)-tert-butyl 1-(cyclopropylamino)-2,2-diethoxy-1-oxohexan-3-ylcarbamate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:22][CH2:21][C@H:20](OS(C)(=O)=O)[CH2:19]2)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:22][CH2:21][CH:20]([N:30]3[CH2:31][CH2:32][CH2:33][C@@H:29]3[CH3:28])[CH2:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@H]1CCC(c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Reactant: C[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Reaction time: 16 h
Yield: 82.7 %

Procedure:
Methanesulfonic acid (S)-3-(4-benzyloxycarbonylamino-phenyl)cyclopentyl ester (Intermediate 12) (510 mg, 1.31 mmol, 1 equiv.) was dissolved in 8 mL of anhydrous acetonitrile. This solution was transferred into a flask containing (S)-2-methyl-pyrrolidine (445 mg, 5.24 mmol, 4 equiv.) and K2CO3 (800 mg, 5.76 mmol, 4.4 equiv.). The suspension was de-gassed by vacuum/nitrogen exchange 3 times, and then, heated on an oil bath set at 80° C. under nitrogen with stirring for 16 h. TLC (5% MeOH in DCM for SM) showed the reaction was complete. Acetonitrile was removed in vacuo. The residue was taken in water (5 mL) and DCM (20 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL), and dried (K2CO3). The solution was filtered. The filtrate was concentrated in vacuo to obtain a crude product which was purified on a silica gel column eluting with 5% 7N ammonia methanolic solution in DCM to afford 410 mg (84%) of the title compound.