Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H](C)[C@H](NC([C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)=[CH:13][CH:12]=1)=O)C(OC)=O.CCN=C=NCCCN(C)C.[CH:37]1[CH:38]=[CH:39][C:40]2N(O)N=N[C:41]=2[CH:42]=1.COC(=O)[CH:50]([NH:60][C:61](=[O:79])[C:62]1[CH:67]=[CH:66][C:65]([C:68]#[C:69]C#CC2C=CC(N)=CC=2)=[CH:64][CH:63]=1)[CH2:51][NH:52]C(OC(C)(C)C)=O.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:17]([CH:51]([NH2:52])[CH2:50][NH:60][C:61](=[O:79])[C:62]1[CH:67]=[CH:66][C:65]([C:68]#[CH:69])=[CH:64][CH:63]=1)([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:15]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:42]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)NC(=O)c1ccc(C#CC#Cc2ccc(N)cc2)cc1
Reactant: On1nnc2ccccc21
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(C(=O)c2ccccc2)cc1)[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1ccc(C(=O)NCC(N)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h
Yield: 97.1 %

Procedure:
To a solution of 4-ethynylbenzoic acid 1 (292 mg, 2.00 mmol), EDCI (382 mg, 2.00 mmol), and HOBt (270 mg, 2.00 mmol) in DMF (10 mL) was added N-trityl ethylenediamine 2 (810 mg, 2.67 mmol) and DIEA (1.4 mL, 8.0 mmol). The reaction mixture was stirred 24 h, diluted with EtOAc (200 mL), washed with 0.5 M HCl (60 mL), saturated NaHCO3 (2×60 mL), H2O (4×60 mL), dried over MgSO4 and concentrated to give 836 mg (97% yield) of N-(2-trityl-amino-ethyl)-4-ethynyl-benzamide 3 as a white solid, mp 50-51° C. Rf=0.40 (1:1 Hexanes/EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(Cl)(=O)C(Cl)=O.[CH2:20]([O:22][C:23](=[O:37])[C:24]([C:27]1[CH:28]=[N:29][C:30]([NH2:36])=[C:31]([O:33][CH2:34][CH3:35])[CH:32]=1)([CH3:26])[CH3:25])[CH3:21]>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1>[CH2:20]([O:22][C:23](=[O:37])[C:24]([C:27]1[CH:28]=[N:29][C:30]([NH:36][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:13])=[C:31]([O:33][CH2:34][CH3:35])[CH:32]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)C(C)(C)c1cnc(N)c(OCC)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)c1cnc(NC(=O)c2cc3cc(Cl)ccc3[nH]2)c(OCC)c1
Reaction time: 0.75 h
Yield: 7 %

Procedure:
To a slurry of 0.31 mmol of 5-chloro-1H-indole-2-carboxylic acid in methylene chloride (1.5 mL) was added 0.4 mL of 1M oxalyl chloride solution in methylene chloride. A solution of DMF (0.031 mL) in methylene chloride (1 mL) was then added dropwise to the slurry. After shaking for 45 min., the acid chloride solution was added dropwise to a solution of 2-(6-amino-5-ethoxy-pyridin-3-yl)-2-methyl-propionic acid ethyl ester in DMF (0.5 mL) and pyridine (0.25 mL). The reaction mixture was then shaken overnight. The reaction mixture was partitioned between EtOAc and 1N aqueous hydrochloric acid, and the phases were separated. The organic phase was washed with 1N aqueous sodium hydroxide, brine, and dried over sodium sulfate. After filtration and evaporation, the residue was further purified on a 2 mm silica gel preparative plate, developing with 9:1 methylene chloride/methanol. The product band was extracted and evaporated to afford 22 mg (7% yield) of the title compound as an amorphous solid. AP/MS+=430, AP/MS−=428.
Reaction SMILES: [F:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:26](=[O:27])[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:19])=[C:13]([CH3:28])[CH:12]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:26](=[O:27])[C:25]3[C:20](=[N+:21]([O-:37])[CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:19])=[C:13]([CH3:28])[CH:12]=1)([C:7]([F:9])([F:8])[F:10])[C:3]([F:6])([F:5])[F:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N1C(=O)c2cccnc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N1C(=O)c2ccc[n+]([O-])c2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
In 25 ml of chloroform was dissolved 3.1 g of N-[4-(heptafluoro-2-propyl)-2-methylphenyl]pyridine-2,3-dicarboximide, and 5.0 g of m-chloroperbenzoic acid was added thereto at room temperature. After the resulting mixture was stirred at room temperature for 3 hours, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography using ethyl acetate/n-hexane as an eluent, to obtain 820 mg (yield: 84%) of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:6]=2[N:7]=1
Reactant: BrC1CCCC1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCCC1
Yield: 34.5 %

Procedure:
Ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (3 g, 11.15 mmol) was dissolved in acetonitrile (30 mL) and K2CO3 (1.85 g, 13.38 mmol) and cyclopentyl bromide (3.35 g, 22.30 mmol) was added to it. The reaction mixture was refluxed for 3 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (1.3 g, 50%).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C@H:18]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:33][CH2:34][CH2:35][CH2:36][N:37]=2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C@H:18]([C:39]([OH:41])=[O:40])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:33][CH2:34][CH2:35][CH2:36][N:37]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(CCCOc1ccc(C[C@H](Nc2nc3ccccc3o2)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h
Yield: 98 %

Procedure:
3 ml of trifluoroacetic acid is added to 200 mg of ester 6-2 in 10 ml of dichloromethane, agitation is carried out for 2 hours at ambient temperature then 10 ml of toluene is added. After evaporating under reduced pressure, taking up in dichloromethane and crystallizing by adding an Et2O/pentane mixture, 175 mg of 6-3 is obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: OP(O)CCCCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CP(=O)(O)CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (1.0 g, 0.005 mole) in chloroform (20 ml) was added triethylamine (1.6 ml, 0.011 mole) and the solution was cooled in an ice bath to 0° C. Trimethyl silyl chloride (1.4 ml, 0.011 mole) was added to the above solution dropwise, followed by ethyl bromoacetate (0.84 g, 0.56 ml, 0.011 mole). The ice bath was removed and the mixture stirred at room temperature overnight. The mixture was poured into 10% aqueous HCl (10 ml) and crushed ice HCl (10 ml) and crushed ice (10 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil (1.42 g) was vacuum dried to get 1.42 g (99%) of title compound in the form of an oil. TLC: silica gel, CH2Cl2 :MeOH:HOAc shows one main spot, but elongated, Rf =0.29.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.CNC(C1C2C=CC(O)=CC=2SC=1C)=O>>[OH:2][C:3]1[CH:12]=[CH:11][C:6]2[CH:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2cc(C)oc2c1
Agent: BrB(Br)Br
Agent: CNC(=O)c1c(C)sc2cc(O)ccc12
Product: Cc1cc2ccc(O)cc2o1
Yield: 75.5 %

Procedure:
This material was prepared from 6-methoxy-2-methylbenzofuran (1.00 g, 6.17 mmole) by treatment with BBr3 in a manner as previously described for 1d to give a colorless oil (690 mg, 75%) which solidified on standing. 1H NMR (DMSO-d6) δ 9.32 (1H, s), 7.23 (1H, d, J=8.3 Hz), 6.80 (1H, s),6.64 (1H, d, J=8.3 Hz), 6.37 (1H, s), 2.35 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5](=[O:13])[N:6]([CH2:9][CH2:10][CH2:11][CH3:12])[C:7]=1N.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40](O)=[O:41])=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl>CN(C)C=O.O>[CH2:9]([N:6]1[CH:7]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]2[CH:35]=[CH:34][C:33]([S:30](=[O:31])(=[O:32])[NH:29][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)=[CH:38][CH:37]=2)[C:3](=[O:22])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:5]1=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: O=C(O)Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reactant: CCCCn1c(N)c(N)c(=O)n(Cc2ccccc2F)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCn1cc(NC(=O)Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)c(=O)n(Cc2ccccc2F)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A solution of 5,6-diamino-1-butyl-3-(2-fluoro-benzyl)-1H-pyrimidine-2,4-dione (30.6 mg, 0.1 mmol) and [4-(pyridin-2-ylsulfamoyl)-phenyl]-acetic acid (29.2 mg, 0.1 mmol) in dry N,N-dimethylformamide (1 mL) was treated with N,N-diisopropylethylamine (61 mL, 0.35 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (37.9 mg, 0.1 mmol). The mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water and acidified to pH=5.0 with a 0.01M aqueous hydrochloric acid solution. The reaction mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford N-[1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[4-(pyridin-2-ylsulfamoyl)-phenyl]-acetamide (86%); 1H NMR(CDCl3, 300 MHz) δH 8.20–6.65 (m, 13H), 5.21 (broad s, 2H), 5.02 (s, 2H), 3.79 (t, J=7 Hz, 2H), 3.60 (s, 2H), 1.65–1.20 (m, 4H), 0.85 (t, J=7 Hz, 3H); LRMS for C28H29FN6O5S (M+H)+ at m/z=581.
Reaction SMILES: C[Mg]Br.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13])(=[O:6])[CH3:5].OS(O)(=O)=O.[C:35]([O-])(O)=O.[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:6][C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13])([CH3:35])[CH3:5]
Reactant: O=C([O-])O
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Agent: C[Mg]Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reaction time: 0.75 h

Procedure:
3M Methylmagnesium bromide (0.10 ml, 0.29 mmol) was added to a solution of 5-acetyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 72; 100 mg, 0.29 mmol) in tetrahydrofuran (3 ml) at 0° C. The solution was stirred for 45 minutes. Another 3 equivalents of 3M methylmagnesium bromide (300 ul) were added at 0° C. and solution was stirred for 18 hours. 1N H2SO4 (5 ml) was then added, the mixture was stirred for 3 minutes, then ethyl acetate (10 ml) was added. The acid layer was basified to pH 9 using saturated NaHCO3 solution. The organic layer was washed with saturated NaHCO3 solution (5 ml), dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by MDAP to give the title compound as a white solid. 61 mg.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:34])([F:33])[CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH2:23][C:22]([F:21])([F:33])[F:34])=[CH:26][CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(OCC(F)(F)F)cc1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OCC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 4-(2,2,2-trifluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.89 min.; [M+H]+: 424.45 g/mol.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:16][C:17](=[O:19])[CH3:18])[CH:11]=[N:10][C:9]=3[NH:8][C:6]2=[O:7])[CH2:3][CH2:2]1.[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:16][C:17](=[O:19])[CH3:18])[CH:11]=[N:10][C:9]=3[N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:6]2=[O:7])[CH2:2][CH2:3]1
Reactant: CC(=O)Cn1cnc2[nH]c(=O)n(CC3CC3)c(=O)c21
Reactant: BrC1CCCC1
Product: CC(=O)Cn1cnc2c1c(=O)n(CC1CC1)c(=O)n2C1CCCC1

Procedure:
The title compound was prepared from 1-cyclopropylmethyl-7-(2-oxopropyl)xanthine and cyclopentylbromide in an analogous procedure to that of Example 19. The product was obtained as a crystalline solid; m.p. 155° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[CH2:25][N:24]([C:22]([C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[O:14][C@H:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1)C3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCCNC1)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
A mixture of (S)-3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (288 mg; 0.53 mmol; 1 eq.) and TFA (3 mL) in DCM (3 mL) was stirred at room temperature for 1 hour then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH extracted with DCM (2×). The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting solid was triturated in water and filtered off to afford the title compound (82 mg, 35%) as an off-white solid. 1H NMR (CDCl3) δ 7.36-7.29 (m, 1H), 6.78-6.68 (m, 2H), 5.01-4.99 (m, 2H), 4.66 (s, 2H), 4.29-0.23 (m, 1H), 3.13-3.06 (m, 1H), 2.91 (s, 2H), 2.86 (s, 1H), 2.84-2.75 (m, 2H), 2.71-2.65 (m, 2H), 2.62 (s, 2H), 2.03-1.91 (m, 1H), 1.78-1.56 (m, 3H), 1.51-1.36 (m, 1H). HPLC (max plot) 98.7%, Rt 2.82 min. UPLC/MS: (MS+) 444.4 ([M+H]+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][C@:5]([CH:12]([CH3:14])[CH3:13])([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:12]([C@:5]1([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7][C@@H:3]([NH:2][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[CH2:4]1)([CH3:14])[CH3:13]
Reactant: COC(=O)[C@@]1(C(C)C)CC[C@@H](N)C1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@]1(C(C)C)CC[C@@H](NC2CCOCC2)C1
Reaction time: 0.17 h

Procedure:
Methyl (1S,3R)-3-amino-1-isopropylcyclopentanecarboxylate hydrochloride (prepared in the same way as the intermediate from Step F, Procedure A, INTERMEDIATE 2, except with the modification that the methyl ester was employed instead of the benzyl ester, 1.4 g, 6.1 mmol) was combined with tetrahydro-4H-pyran-4-one (730 mg, 7.3 mmol), and triethylamine (1 mL, 7 mmol) in 50 mL of DCM. After 10 min, 4 Å powdered molecular sieves (1 g), and sodium triacetoxyborohydride (5.1 g, 24 mmol) were added and the resulting mixture was permitted to stir overnight. The reaction mixture was filtered through celite, and the filtrate was washed with saturated NaHCO3 solution twice, then once with brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to afford 1 g of methyl (1S,3R)-1-isopropyl-3-(tetrahydro-2H-pyran-4-ylamino)cyclopentanecarboxylate.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([Cl:23])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12](OC)[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(OP(CC1C=CC(N)=CC=1)(=O)OCC)C>>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[N:22]=[C:21]([Cl:23])[C:20]([C:24]([F:25])([F:27])[F:26])=[CH:19][N:18]=2)=[CH:14][CH:15]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccc(N)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC

Procedure:
Prepared in a manner analogous to that for diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate using commercially available diethyl(4-aminobenzyl)phosphonate in place of diethyl(4-amino-3-methoxybenzyl)phosphonate. Following chromatography, the semi-pure product was crystallized from ethyl acetate to afford the title compound. 1H NMR (400 MHz, METHANOL-d4) d ppm 1.22-1.32 (m, 6H), 3.17-3.28 (m, 2H), 3.98-4.10 (m, 4H), 7.30 (dd, J=8.72, 2.65 Hz, 2H), 7.65 (d, J=7.83 Hz, 2H), 8.63 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:13]=[C:12]2[N:4]([C:5](=[O:19])[N:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]3[N:8]=[CH:9][NH:10][C:11]=32)[N:3]=1.[Br:20]N1C(=O)CCC1=O.C1(O)C=CC=CC=1>C1COCC1>[Br:20][C:9]1[NH:10][C:11]2[C:12]3=[N:13][C:2]([CH3:1])=[N:3][N:4]3[C:5](=[O:19])[N:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]=2[N:8]=1
Reactant: CCCCCn1c(=O)n2nc(C)nc2c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CCCCCn1c(=O)n2nc(C)nc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of 8-methyl-4-pentyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (20 mg, 0.078 mmol) in THF (5 mL) was added N-Bromosuccinimide (19 mg, 0.11 mmol). After stirring at room temperature for 1 hour, phenol was added to quench the reaction. The reaction mixture was concentrated at reduced pressure, and the residue was purified by preparative LCMS (method B) to yield the desired product as white powder. LCMS calculated for C12H16BrN6O (M+H): 339.1. found: 339.0, 341.0.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:16]2[C:7](=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=3)[CH:6]=[C:5]([OH:18])[CH:4]=1.[Cl:19][CH2:20][CH2:21][CH2:22][CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[ClH:19].[Cl:19][CH2:20][CH2:21][CH2:22][CH2:23][O:18][C:5]1[CH:4]=[CH:3][C:16]2[C:7]([CH:6]=1)=[N:8][C:9]1[C:14](=[CH:13][CH:12]=[C:11]([O:17][CH2:23][CH2:22][CH2:21][CH2:20][Cl:19])[CH:10]=1)[CH:15]=2
Reactant: Cc1ccc(S(=O)(=O)OCCCCCl)cc1
Reactant: Oc1ccc2cc3ccc(O)cc3nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: ClCCCCOc1ccc2cc3ccc(OCCCCCl)cc3nc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 11.8 g. of sodium hydride (61.1% dispersion in oil) and 26.0 g. of 3,6-acridinediol is added 250 ml. of dimethylformamide. The mixture is stirred at room temperature for 1.5 hours, then 52.5 g. of 4-chlorobutyl-p-toluenesulfonate are added. This mixture is stirred at room temperature for 3 hours and 20 minutes and then at 50° C. for 2 hours. The volatile materials are removed under reduced pressure at 35°-40° C. The residue is quenched with 1200 ml. of ice-cold saturated aqueous sodium bicarbonate. The resulting tan crystals are collected and dissolved in 500 ml. of chloroform, 30 ml. of 6 N hydrochloric acid in isopropanol are added and the mixture is diluted with ether, giving the desired product as the hydrochloride salt.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([O-:15])=[O:14].[Na+].C1N=C(N)C2N=CN([C@@H]3[O:30][C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>P([O-])([O-])([O-])=O>[C:1]1([C@@:7]([CH3:8])([OH:30])[C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: O=C[O-]
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: C[C@](O)(C(=O)O)c1ccccc1
Reaction time: 48 h

Procedure:
100 mg of the lyophilized, surface expressing E. coli was suspended with 100 mg of phenylpyruvic acid, 7 mg of sodium formate and 1.32 mg of NAD in 10 mL of 0.1 M phosphate buffer (pH 7.0) solution and stirred for 48 hours for reaction. After completion of the reaction, the solution was centrifuged at 12,000 rpm for 3 minutes to remove cells and obtain the supernatant. The obtained solution was adjusted to pH 2.0, extracted 5 times with 5 mL of ethyl acetate and subjected to liquid chromatography (column: Chiralcel OD-H; flow rate: 0.5 mL/min; solvent: Hexane/iso-propanol/tri-fluoroacetic acid=80:20:1 (volume); detection: UV 210 nm). As a result, (R)-phenyl lactic acid with an optical purity of 90% or better was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.C[O:16][B:17](OC)[O:18]C.Cl>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[B:17]([OH:18])[OH:16]
Reactant: Cc1ccc(Br)cc1I
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(Br)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 2-methyl-5-bromo-iodobenzene (12 g, 40.4 mmol) in tetrahydrofuran (75 ml), cooled to −78° C., was added a solution of isopropylmagnesium chloride (4.6 g, 44.5 mmol) in tetrahydrofuran (22.2 ml) dropwise over 20 minutes. After stirring at −78° C. for 30 minutes, the mixture was warmed slowly to −20° C. and stirred for 1 hour. After cooling again to −78° C., trimethylborate (8.4 g, 80.8 mmol) was added dropwise. After warming to 0° C., the mixture was stirred for 2 hours, treated with 1 M hydrochloric acid (35 ml), and extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water (50 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residual solid was suspended in hexane (50 ml), filtered, washed with hexane (30 ml) and dried under reduced pressure to provide 2-methyl-5-bromo-phenylboronic acid (7.32 g, 84% yield) as a white solid. 1H NMR (DMSO-d6) δ 7.92 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 2.59 (s, 3H).