Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].CO.[C:5]([C:7]1[C:15]2[S:14][C:13]([NH:16][C:17]([CH:19]3[CH2:21][CH2:20]3)=[O:18])=[N:12][C:11]=2[CH:10]=[CH:9][C:8]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([NH:30]C(=O)C(F)(F)F)[CH:24]=1)#[N:6]>C(O)C>[NH2:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[F:29])[O:22][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21]3)=[O:18])[S:14][C:15]=2[C:7]=1[C:5]#[N:6]
Reactant: N#Cc1c(Oc2ccc(F)c(NC(=O)C(F)(F)F)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: N#Cc1c(Oc2ccc(F)c(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of sodium borohydride (586 mg, 15.5 mmol) in ethanol (7 mL) was added dropwise methanol (3 ml). To this suspension was added N-(7-cyano-6-{4-fluoro-3-[(trifluoroacetyl)amino]phenoxy}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (360 mg, 0.775 mmol). The reaction mixture was stirred at 60° C. for 1 hr, cooled to room temperature, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (100 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=80/20→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (194 mg, 68%) as a white powder.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:54])[CH2:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:41])[N:33]1[C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[N:45][C:46]([O:52][CH3:53])=[CH:47][CH:48]=2)[N:43]=1)(C(C)(C)C)(C)C.O>O1CCCC1>[OH:26][CH2:27][CH2:28][CH2:29][C:30](=[O:54])[CH2:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:41])[N:33]1[C:42]1[CH:51]=[CH:50][C:49]2[C:44](=[N:45][C:46]([O:52][CH3:53])=[CH:47][CH:48]=2)[N:43]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCCO[Si](C)(C)C(C)(C)C)nc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCCO)nc2n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
Tetrabutylammonium fluoride (11.5 g) is added in small portions at a temperature in the region of 0° C. to a solution of 3-(5-tert-butyldimethylsilyloxy-2-oxopentyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (9.2 g) in anhydrous tetrahydrofuran (185 cc), and the solution obtained is stirred for 5 minutes at a temperature in the region of 0° C. The reaction mixture is then stirred for 1 hour 30 minutes at a temperature in the region of 20° C. and then poured into a mixture of ice (200 g) and water (600 cc). The insoluble product is separated by filtration, washed successively with water (5×25 cc) and diisopropyl ether (2×10 cc) and dried in the air. After recrystallization in acetonitrile, 3-(5-hydroxy-2-oxopentyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (5.6 g), m.p. 152° C., is obtained.
Reaction SMILES: [CH2:1]1[CH2:15][O:14][C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:4][CH2:5][CH2:6][NH2:7])[O:2]1.[CH:16]([C:18]1[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=1)[O:21][CH:22]([CH2:30][CH3:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:15]1[CH2:1][O:2][C:3]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([CH2:4][CH2:5][CH2:6][NH:7][CH2:16][C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[O:21][CH:22]([CH2:30][CH3:31])[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[O:14]1
Reactant: NCCCC1(c2ccccc2)OCCO1
Reactant: CCC(Oc1cccc(C=O)c1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(Oc1cccc(CNCCCC2(c3ccccc3)OCCO2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 65 %

Procedure:
4,4-Ethylenedioxy-4-phenylbutylamine (27.0 mg, 0.13 mmol) was dissolved in chloroform (3 ml) at room temperature, and thereto were added tert-butyl 2-(3-formylphenoxy)butyrate (34.4 g, 0.13 mmol) in a chloroform solution (2 ml) and sodium triacetoxyborohydride (41.4 mg, 0.20 mmol) in sequential order at the same temperature, and thereafter, the mixture was stirred at room temperature for 12 hours. The reaction solution was added to a saturated aqueous sodium hydrogencarbonate solution and thereafter extracted by chloroform. The extracted organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant substance was purified by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained as a colorless oil (38.5 mg, 64.9%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[C:5]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>>[CH3:13][C:10]1[S:9][C:7]2=[N:8][C:3]([CH2:2][N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[C:4]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:5]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)=[C:6]2[C:11]=1[CH3:12]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc2c(c1)OCO2
Product: CCOC(=O)c1c(Cn2cncn2)nc2sc(C)c(C)c2c1-c1ccc2c(c1)OCO2

Procedure:
In substantially the same manner as in Example 2, ethyl 6-chloromethyl-4-(3,4-methylenedioxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate was allowed to react with 1H-1,2,4-triazole to produce ethyl 2,3-dimethyl-4-(3,4-methylenedioxyphenyl)-6-(1,2,4-triazol-1-ylmethyl)thieno[2,3-b]pyridine-5-carboxylate. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.109°-110° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH:14]([OH:16])[CH3:15])[CH2:13][CH2:12][CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[OH:8][CH2:9][C:10]1([CH:14]([OH:16])[CH3:15])[CH2:13][CH2:12][CH2:11]1
Reactant: CC(O)C1(CO[Si](C)(C)C(C)(C)C)CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)C1(CO)CCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-[1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]ethanol (3.2 g) was dissolved in tetrahydrofuran (30 mL), tetrabutylammonium fluoride (32 mL, 1.0 M tetrahydrofuran solution) was added dropwise, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate/2-propanol (3/1). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as an oily compound (1.3 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ccccc1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccccc3)c1)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (54 mg, 0.20 mmol), aniline (0.027 mL, 0.30 mmol), and N,N-diisopropylethylamine (0.174 mL, 1.0 mmol) in 1.5 mL DMF at room temperature was added HBTU (83 mg, 0.22 mmol). After 1 hour at room temperature, the reaction was briefly warmed to approx. 60° C. and then continued at room temperature. At 2 hours the reaction was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with EtOAc to give the title compound as an off-white solid (52 mg, 75%). 1H NMR (DMSO-d6) δ: 10.15 (s, 1H), 8.13 (s, 1H), 7.74-7.79 (m, 2H), 7.49-7.52 (m, 1H), 7.31-7.41 (m, 4H), 7.22 (dt, J=7.5, 2.3 Hz, 1H), 7.06-7.13 (m, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].B1([O-])O[O:17]1.O.O.O.O.[Na+]>C(O)(=O)C>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[O:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])[C:1]([OH:17])=[O:2])#[N:9]
Reactant: [O-]B1OO1
Reactant: CC[C@H](C)Oc1ccc(C=O)cc1C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC[C@H](C)Oc1ccc(C(=O)O)cc1C#N
Temperature: 50 °C
Yield: 103.5 %

Procedure:
To a solution of 5-formyl-2-{[(1S)-1-methylpropyl]oxy}benzonitrile (D35) (220 mg, 1.08 mmol) in acetic acid (20 ml) was added sodium perborate tetrahydrate (334 mg, 2.17 mmol), the reaction mixture was heated at 50° C. over the weekend. The reaction mixture was concentrated in-vacuo. Water (˜50 ml) was added, EtOAc (˜30 ml) was added and the layers partitioned, the aq layer was extracted twice more with EtOAc (˜30 ml) and the combined organics were evaporated to dryness under reduced pressure to give the title compound (245 mg) as an off white solid. δH (d6-DMSO, 400 MHz): 8.17 (2H, apparent d), 7.39 (1H, s), 4.68-4.74 (1H, m), 1.55-1.76 (2H, m), 1.31 (3H, d), 0.95 (3H, t). MS (ES): C12H13NO2 requires 219; found 220 (MH+).
Reaction SMILES: [Si]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[C:19]1([Li])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.CO>[C:19]1([C:15]2[CH:14]=[CH:13][C:12]3[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=3)[N:16]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cccnc2c1
Reactant: [Li]c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(tert-butyldimethylsilyloxy)quinoline (3.992 g, 15.39 mmol) in dry THF (35 mL), cooled by ice/water, was added phenyllithium (1.8 M in cyclohexane:ether 70:30, 10 mL, 18 mmol). The solution slowly warmed up to ambient temperature and was stirred overnight. More phenyllithium (1.0 mL, 1.8 mmol) was added, and stirring was continued for 4 h. The reaction was quenched by adding saturated NH4Cl solution and water. Most of the THF was evaporated, the residue was extracted with EtOAc (4×30 mL) and the combined EtOAc layers were washed with water (2×) and brine and dried over MgSO4. LC/MS indicated that a significant amount of the TBDMS ether had been cleaved during the workup, the ratio of quinolines to dihydroquinolines was about 1:1. Air was bubbled into the solution overnight, the MgSO4 was filtered off, the filtrate was concentrated, dissolved in MeOH, aq. HCl (2 M, 2 mL, 4 mmol) was added, and the solution was stirred at ambient temperature overnight. Sat. NaHCO3 solution was added, most of the MeOH was evaporated, water (≈100 mL) was added, and the dark brown precipitate was filtered off and washed with more water. The combined filtrate and washings were extracted with EtOAc (4×60 mL), the combined EtOAc extracts were washed with water and brine and dried over MgSO4. The dark brown precipitate was dissolved in MeOH (≈100 mL), the solution was filtered, and the filtrate was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2→5% EtOAc in CH2Cl2→10% EtOAc→15% EtOAc]. The mixed fractions were combined with the crude material from the EtOAc extracts and chromatographed on silica gel [Jones Flashmaster, material adsorbed onto Hydromatrix, 10 g/70 mL cartridge, eluting with CH2Cl2→5% EtOAc in CH2Cl2→7.5% EtOAc]. Combination of pure fractions of both columns gave the title compound as light beige solid; 1H NMR (DMSO-d6, 400 MHz) δ 7.15 (dd, J=8.8, 2.4 Hz, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.45-7.51 (m, 1H), 7.51-7.57 (m, 2H), 7.83 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 8.20-8.25 (m, 2H), 8.29 (d, J=8.8 Hz, 1H), 10.19 (s, 1H); MS (ES+): m/z 222.1 (100) [MH+]; HPLC: tR=2.2 min (OpenLynx, polar—5 min).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:51])[N:29]([CH2:31][CH2:32][O:33][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:30])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:51])[N:29]([CH2:31][CH2:32][OH:33])[CH3:30])[N:27]=2)[CH2:20]1
Reactant: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 106.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-{N-[2-(t-butyldiphenylsilyloxy)ethyl]-N-methyl-carbamoyl}-1,3-thiazol-2-yl)azetidine (2.24 g, 3.05 mmol) (obtained as described in Reference Example 40(2)) in anhydrous tetrahydrofuran (70 ml) was added a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (7.32 ml, 7.32 mmol) in an ice bath, and the mixture was stirred in the ice bath for 1 hour. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (20:1)→ethyl acetate:methanol (15:1) as the eluant to afford 3-hydroxy-1-{4-[N-(2-hydroxyethyl)-N-methyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (833 mg, yield 94%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[C:30]([CH3:41])[CH:29]=2)[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[C:30]([CH3:41])[CH:29]=2)=[N:26][C:21]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: CNC(=O)CN1CCc2cc(N)c(OC)cc2CC1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)ccc1N1CCN(C)CC1
Product: CNC(=O)CN1CCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCN(C)CC5)c(C)c4)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N-methyl-acetamide and (2,5-Dichloro-pyrimidin-4-yl)-[3-methyl-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.008 g, 8%). MP: 179-185° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.05 (s, 1H), 8.03 (s, 1H), 7.58-7.53 (m, 1H), 7.48 (s, 1H), 7.39-7.31 (m, 1H), 7.21-7.18 (m, 1H), 7.04 (d, 1H, J=8.8 Hz), 6.91 (s, 1H), 6.61 (s, 1H), 3.85 (s, 3H), 3.09 (s, 2H), 2.97-2.92 (m, 4H), 2.90 (d, 3H, J=4.8 Hz), 2.86-2.81 (m, 2H), 2.75-2.53 (m, 9H), 2.38 (s, 3H), 2.30 (s, 3H). MS: 579.29 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[C:13]([CH:15]=[N:16][OH:17])[N:12]=[C:11]([CH3:18])[N:10]=1)=[O:8].[CH3:23][N:24]1[CH:29]=[C:28]([CH:30]=[CH2:31])[CH:27]=[CH:26][C:25]1=[O:32].Cl[O-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][NH:6][C:7]([C:9]1[CH:14]=[C:13]([C:15]2[CH2:31][CH:30]([C:28]3[CH:27]=[CH:26][C:25](=[O:32])[N:24]([CH3:23])[CH:29]=3)[O:17][N:16]=2)[N:12]=[C:11]([CH3:18])[N:10]=1)=[O:8]
Reactant: Cc1nc(C=NO)cc(C(=O)NCc2ccc(F)c(F)c2)n1
Reactant: C=Cc1ccc(=O)n(C)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Product: Cc1nc(C(=O)NCc2ccc(F)c(F)c2)cc(C2=NOC(c3ccc(=O)n(C)c3)C2)n1
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
To a solution of N-(3,4-difluorobenzyl)-6-((hydroxyimino)methyl)-2-methylpyrimidine-4-carboxamide (13.60 g, 44.4 mmol, Preparation #A.1.2) and 1-methyl-5-vinylpyridin-2(1H)-one (6 g, 44.4 mmol, Preparation #F.1.13) in DCM (150 mL) was added 9% aqueous sodium hypochlorite solution (80 mL, 1296 mmol, Avra labs) drop wise at 10-15° C. for about 30 min. Reaction mixture was allowed to stir for another 15-30 min, diluted the reaction mixture with water (100 mL) and the product extracted with DCM (2×100 mL). The combined organic layers was dried over sodiumsulphate and evaporated to dryness. The resulting crude material was purified by silica gel column chromatography by eluting with 2% methanol in DCM. Relevant fractions containing product were combined and evaporated under reduced pressure to afford N-(3,4-difluorobenzyl)-2-methyl-6-(5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide 3 g (15.38%) as pale yellow solid; 1H NMR (400 MHz, DMSO): δ 9.606-9.574 (m, 1H), 8.179 (s, 1H), 7.872-7.866 (d, J=2.4 Hz, 1H), 7.527-7.497 (dd, J=9.6 Hz, 1H), 7.421-7.353 (m, 2H), 7.205-7.173 (m, 1H), 6.436-6.412 (d, J=9.6 Hz, 1H), 5.688-5.637 (m, 1H), 4.504-4.488 (d, J=6.4 Hz, 2H), 3.836-3.764 (m, 1H), 3.463-3.440 (m, 1H), 3.425 (s, 3H), 2.767 (s, 3H); MS m/z: 440.2 (M+H)+.
Reaction SMILES: Cl.Cl.[C:3](O)(=[O:24])[C:4]1[CH:23]=[CH:22][C:7]([NH:8][CH2:9][C:10]2[N:21]=[C:20]3[C:13]([N:14]=[C:15]([NH:17][C:18]3=[O:19])[NH2:16])=[N:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[NH2:33][C@H:34]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:35][CH2:36][C:37](=[O:58])[NH:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54]>CN(C)C=O.C(OCC)C>[NH2:16][C:15]1[N:17]=[C:18]([OH:19])[C:20]2[C:13](=[N:12][CH:11]=[C:10]([CH2:9][NH:8][C:7]3[CH:22]=[CH:23][C:4]([C:3]([NH:33][C@H:34]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:35][CH2:36][C:37](=[O:58])[NH:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][NH:50][C:51](=[O:57])[O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:24])=[CH:5][CH:6]=3)[N:21]=2)[N:14]=1
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)O)cc3)nc2c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCNC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCOCCOCCOCCNC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc3nc(N)nc(O)c3n2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To pteroic acid dihydrochloride (424 mg, 1.10 mmol) and triethylamine (0.75 mL, 5.50 mmol) in N,N-dimethylformamide (10 mL), propanephosphonic anhydride 50% solution in N,N-dimethylformamide (1.30 mL, 2.23 mmol) was added. After the reaction stirred for 45 minutes at ambient temperature, (5)-tert-butyl 21-amino-2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazadocosan-22-oate (802 mg, 1.68 mmol) in N,N-dimethylformamide (5 mL) was added, and the reaction was stirred for 16 h at ambient temperature. After this time, the reaction was diluted with diethyl ether (150 mL) and the filtered to give (S)-tert-butyl 21-(4-((2-amino-4-hydroxypteridin-6-yl)methylamino)benzamido)-2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazadocosan-22-oate (849 mg, obtained as a 1:1 mixture with pteroic acid, 50%) as a brown solid that was used in the next step without further purification: MM-APCI MS m/z=794 [M+Na]+.
Reaction SMILES: [SH:1][CH:2](C)[C:3]([OH:5])=[O:4].[SH:7][CH:8](C)[C:9]([OH:11])=[O:10].SC(C)[C:15]([OH:17])=[O:16].[CH2:19]([C:21]([CH2:26][OH:27])([CH2:24][OH:25])[CH2:22][CH3:23])[OH:20].ClN1C(=O)CCC1=O.[C:36]([Cl:40])(Cl)(Cl)Cl>>[S:7]=[CH:8][CH:36]([Cl:40])[C:3]([OH:5])=[O:4].[S:1]=[CH:2][CH:36]([Cl:40])[C:9]([OH:11])=[O:10].[S:1]=[CH:2][CH:36]([Cl:40])[C:15]([OH:17])=[O:16].[CH2:19]([C:21]([CH2:26][OH:27])([CH2:24][OH:25])[CH2:22][CH3:23])[OH:20]
Reactant: CC(S)C(=O)O
Reactant: ClC(Cl)(Cl)Cl
Agent: CCC(CO)(CO)CO
Agent: O=C1CCC(=O)N1Cl
Product: O=C(O)C(Cl)C=S
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of trimethylolpropane tris(mercaptopropionate) (4.0 grams, 0.010 mol.) in carbon tetrachloride (10 milliliters) was added dropwise to a slurry of N-chlorosuccinimide (4.15 grams, 0.031 mol.) and carbon tetrachloride (30 milliliters) in a 3-neck round bottom flask equipped with a magnetic stir-bar, nitrogen inlet, pressure-equalizing dropping funnel and a thermocouple. The exothermic reaction was controlled to less than 27° C. using an ice-bath. The mixture was allowed to stir at ambient temperature for an additional 5 hours. The reaction mixture was filtered to remove succinimide by-product to give a yellow solution of trimethylolpropane tris(3-sulfenylchloropropionate). 1H NMR (CDCl3) δ: 4.09 (s, 6H), 3.37 (m, 6H), 2.89 (t, J=6.5 Hz, 6H); 1.52 (q, J=6.5 Hz, 2H); 0.96 (t, J=7.4 Hz, 3H). 13C NMR (CDCl3): 170.8, 64.2, 41.4, 36.7, 33.7, 23.3, 7.8 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH2:7][CH2:6]2.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(c1)CCOC2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(=O)occc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 6-methoxyisochroman-1-one (15.1 g), NBS (27 g) and benzoyl peroxide (500 mg) in tetrachloromethane (250 mL) was heated to reflux while irradiating with light for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in triethylamine (100 mL) and stirred at room temperature for 48 h. The reaction mixture was partitioned between water and ethyl acetate and brought to pH 1 with concentrated hydrochloric acid. The organic phase was separated off, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel. The product with the molecular weight of 176.17 (C10H8O3) was obtained in this way; MS (ESI): 177 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[CH:12]=2)[NH:7][CH:6]=1.[BH4-].[Na+]>CO>[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH:23]([OH:24])[C:22]4[C:21](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]3=[O:29])[CH:12]=2)[NH:7][CH:6]=1
Reactant: NCCc1c[nH]c2ccc(OCCCCN3C(=O)c4ccccc4C3=O)cc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCCc1c[nH]c2ccc(OCCCCN3C(=O)c4ccccc4C3O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a solution of 3-(2-aminoethyl)-5-(4-phthalimidobutyloxy)-1H-indole hydrochloride (0.057 g, 0.14 mmol) in methanol (10 mL) was added sodium borohydride (0.057 g, 1.36 mmol) and the resulting mixture was stirred at room temperature for 4 hours. The solution was then poured onto a silica gel column and the product eluted with methanol/ammonium hydroxide (19:1) to give the title compound as a syrup (0.052 g, 100%).