Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][NH:6][C:7](=[O:33])[C@H:8]([C:10]([S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:12])[CH3:11])[NH2:9])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][NH:6][C:7](=[O:33])[C@H:8]([C:10]([S:13][C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([CH3:12])[CH3:11])[NH:9][C:35](=[O:37])[CH3:36])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CNC(=O)[C@@H](N)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)[C@@H](NC(C)=O)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To the solution of S-trityl-L-penicillamylglycine ethyl ester (C-2) (3.7 g) in dichloromethane (50 ml) were added acetyl chloride (0.66 ml) and triethylamine (0.88 ml) at 0° C. The mixture was stirred at the same temperature for 15 minutes and then ice water was added. The organic layer was washed with an aqueous potassium hydrogensulfate solution, water, an aqueous sodium hydrogencarbonate solution, water and saturated saline, in this order, and dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was subjected to silica gel column chromatography, to give N-acetyl-S-trityl-L-penicillamylglycine ethyl ester (3.5 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([CH2:10][C:11]#[N:12])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.Br[CH:15](Br)[CH3:16]>C1COCC1>[Cl:3][C:4]1[C:9]([C:10]2([C:11]#[N:12])[CH2:16][CH2:15]2)=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1
Reactant: N#CCc1ccc(Cl)nc1Cl
Reactant: CC(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Cl)nc2Cl)CC1
Temperature: 0 °C
Yield: 60.7 %

Procedure:
5.92 g of sodium hydride (60% in oil) was suspended in 200 ml of dry THF and 10.13 g of (2,6-dichloro-pyridin-3-yl)-acetonitrile in 25 mL of dry THF was added dropwise at 0° C. The reaction mixture was stirred at 0° C. until the end of gas formation. Then 37.4 g of dibromoethane was added at 0° C. and the reaction mixture was stirred at ambient temperature for 14 h. Subsequently, the reaction mixture was quenched with 60 ml of aqueous saturated ammonium chloride. The reaction mixture was extracted with two 500 ml portions of ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate, filtered and concentrated. 19 g of crude material was obtained as a dark solid which was purified by flash chromatography on silica gel with cyclohexane/ethyl acetate (4:1) as a solvent. Thus, 7 g of 1-(2,6-dichloro-pyridin-3-yl)-cyclopropanecarbonitrile was obtained as an orange solid. 1H-NMR (CDCl3): 7.64 ppm (d, 1H), 7.30 ppm (d, 1H), 1.83 ppm (m, 2H), 1.36 ppm (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:16]=[C:15]([C:17](O)=[O:18])[O:14][N:13]=2)=[N:10][CH:11]=1.[NH4+].[Cl-].Cl.C[N:28](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:16]=[C:15]([C:17]([NH2:28])=[O:18])[O:14][N:13]=2)=[N:10][CH:11]=1
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3Cl)cn2)no1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccc(OCc3ccccc3Cl)cn2)no1
Reaction time: 8 h
Yield: 53.2 %

Procedure:
3-[5-(2-Chloro-benzyloxy)-pyridin-2-yl]-isoxazole-5-carboxylic acid (which may be prepared as described in Preparation of Intermediate 10; 220 mg, 0.67 mmol), NH4Cl (71 mg, 1.33 mmol), N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (258 mg, 1.33 mmol), and 1-hydroxybenzotriazole (183 mg, 1.33 mmol) were taken up in THF (8 mL). Diisopropylethylamine (235 μL, 1.33 mmol) was added and the mixture was stirred overnight under nitrogen. The solvent was evaporated and the residue was purified by flash chromatography on silica, eluting with 50% EtOAc/hexanes, to give 3-[5-(2-chloro-benzyloxy)-pyridin-2-yl]-isoxazole-5-carboxylic acid amide (117.5 mg, 53%) as off-white flakes. HRMS Calcd. for C16H13ClN3O3 (M+H)+, 330.0640. Found: 330.0638.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O.[C:15](O)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:17])[CH3:16].[C:1]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)O
Agent: CCCCOC(=O)c1cccnc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1ccccn1
Reaction time: 63 h

Procedure:
An electrically heated tubular reactor with an i. d. of 12 mm was filled with 15 ml (≈15 g) of catalyst prepared according to EP-A-0 352 674, example 1. Over a period of 63 h, a mixture of butyl nicotinate (104 g), water (162 g) and acetic acid (606 g) was metered using a precision pump to the reactor operating at 405° C. From the reaction mixture, 30 g of acetyl pyridine, 3 g of pyridine and 26 g of butyl nicotinate were obtained. This corresponded to a yield of 43% 3-acetylpyridine at a butyl nicotinate conversion of 75% (selectivity 58%). The selectivity of pyridine formation was 5%.
Reaction SMILES: C(O)(=O)C.CN.C([O:9][C:10](=O)[CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[C:13]1[CH:23]=O)C.[C:26]([BH3-])#[N:27].[Na+]>O1CCCC1>[CH3:26][N:27]1[C:10](=[O:9])[CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[C:13]2[CH2:23]1
Reactant: [BH3-]C#N
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)cc1C=O
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1Cc2cc(-c3ccccc3)cn2CC1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30 %

Procedure:
Acetic acid was added to a solution of methylamine (0.45 mL, 5.30 mmol, 40% in water) in tetrahydrofuran (8 mL) to adjust the pH to 6. A solution of (2-formyl-4-phenyl-pyrrol-1-yl)-acetic acid ethyl ester (680 mg, 2.65 mmol) in tetrahydrofuran (4 mL) was added and the reaction mixture stirred at ambient temperature for 45 min. Sodium cyanoborohydride (0.33 g, 5.30 mmol) was added and the reaction mixture heated at 75 C for 18 h. Concentration in vacuo yielded a residue which was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude product. Purification by column chromatography over silica gel (100-200 mesh) using 30% ethyl acetate in petroleum ether afforded 2-methyl-7-phenyl-1,2-dihydropyrrolo[1,2-a]pyrazin-3-one (180 mg, 30%) as a solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11](=[S:12](=[O:14])=[O:13])[C:10]([O:15][CH3:16])=[C:9]([CH3:17])[CH:8]=[C:4]1[C:5](O)=[O:6].S(Cl)([Cl:20])=O>CN(C)C=O>[CH3:1][O:2][CH:3]1[C:11](=[S:12](=[O:14])=[O:13])[C:10]([O:15][CH3:16])=[C:9]([CH3:17])[CH:8]=[C:4]1[C:5]([Cl:20])=[O:6]
Reactant: COC1=C(C)C=C(C(=O)O)C(OC)C1=S(=O)=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC1=C(C)C=C(C(=O)Cl)C(OC)C1=S(=O)=O
Reaction time: 0.33 h

Procedure:
161 g of 2,4-dimethoxy-5-methyl sulphonyl-benzoic acid is reacted. 590 g of thionyl chloride, 5 drops of dimethylformamide and about half of the organic acid are placed in a 2 liter flask fitted with a reflux condenser. The resultant suspension is heated in a water bath at 55° C. for about 5 minutes. The second half of the organic acid is added and heating is continued for 20 minutes at 60°-65° C. then for 45 minutes at 70°-75° C. The medium becomes fluid and turns yellow. The acid dissolves gradually, while the acid chloride begins to crystallize. When the reaction is over the excess thionyl chloride is distilled to constant weight, finishing up under vacuum.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:22])[C:4]([C:7]2[CH:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:9](=[O:21])[CH:8]=2)=[N:5][N:6]=1.[OH-].[Na+].[CH2:25](O)C.IC>O>[CH3:22][N:3]1[C:2]([S:1][CH3:25])=[N:6][N:5]=[C:4]1[C:7]1[CH:12]=[CH:11][N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[C:9](=[O:21])[CH:8]=1
Reactant: Cn1c(S)nnc1-c1ccn(COCC[Si](C)(C)C)c(=O)c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nnc(-c2ccn(COCC[Si](C)(C)C)c(=O)c2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
The title compound of example 21.1 (21.6 g, 63.8 mmol) was dissolved in a solution of NaOH (5.36 g, 134 mmol) in water (134 mL). When a clear solution was observed, ethanol (40 mL) was added followed by iodomethane (6.37 mL, 102 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then extracted four times with chloroform and the combined organic layer was dried over sodium sulfate and concentrated to give the title product (22.0 g, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.C(OCC)(=[O:18])C.CCCCCC>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:15][C:14](=[O:18])[O:13][C:11](=[O:12])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C=Cc1ccc(OC)cc1
Solvent: CCCCCC
Product: COc1ccc(C2CC(=O)OC(=O)C2)cc1
Yield: 38 %

Procedure:
Using ethyl 3-(4-methoxyphenyl)-2-propenoate, the title compound was synthesized in the same manner as in Reference Example 5. Yield 38%. mp. 144–149° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].C(N(CC)CC)C.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1.Cl>O1CCCC1>[F:34][C:35]([F:45])([F:46])[C:36]1[CH:44]=[CH:43][C:39]([C:40]([O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=2[Cl:26])[CH3:13])=[O:41])=[CH:38][CH:37]=1
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime, 0.12 g of triethylamine, and 10 ml of tetrahydrofuran were placed in a reaction vessel, to which 0.25 g of 4-trifluoromethylbenzoyl chloride was slowly added dropwise with stirring at room temperature. After completion of the addition, the reaction mixture was further stirred at room temperature for 30 minutes, poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.59 g (yield, 96%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-(4-trifluoromethylbenzoyl)oxime, nD25.6 1.5300.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13]C(=O)[N:11](C)[N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].BrC1C=C(C2OC(=O)NN=2)C=CC=1C.CI.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[C:9]([NH:10][NH2:11])=[O:13]
Reactant: Cc1ccc(-c2nn(C)c(=O)o2)cc1Br
Agent: Cc1ccc(-c2n[nH]c(=O)o2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NN)cc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Step-3: 5-(3-Bromo-4-methylphenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one: A mixture of 5-(3-bromo-4-methylphenyl)-1,3,4-oxadiazol-2(3H)-one (400 mg, 1.57 mmol, 1.0 eq), methyl iodide (0.2 mL, 3.15 mmol, 2.0 eq) and potassium carbonate (210 mg, 3.15 mmol, 2.0 eq) in DMF (10 mL) was stirred at room temperature for 24 h. Water (50 mL) was added to the reaction mixture followed by ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (2×25 mL), brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to afford 400 mg of the desired product as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 7.90 (d, J=2.0 Hz, 1H), 7.70 (dd, J=8.0, 2.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 3.40 (s, 3H), 2.41 (s, 3H); ESI-MS (m/z) 269, 271 [(MH)+, Br79,81].
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1)=O)[CH3:2].[BH4-].[Na+].C(O)(=O)C.N#N>C1COCC1>[CH2:1]([NH:3][CH2:4][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCNC(=O)[C@H]1CC[C@H](C(=O)OC)CC1
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNC[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 25 °C

Procedure:
A stirred suspension of methyl trans-4-[(ethylamino)carbonyl]cyclohexanecarboxylate (Intermediate 5, 430 mg, 2.01 mmol) and NaBH4 in THF (10 mL) was treated with acetic acid (1.6 mL) and heated at reflux for 16 h an atmosphere of N2. The reaction was cooled to room temperature, quenched with H2O (1 mL) and diluted with 1N NaOH (15 mL). The mixture was extracted with EtOAc (3×40 mL) and the combined extracts were washed with brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford methyl trans-4-[(ethylamino)methyl]cyclohexanecarboxylate as a clear oil. LCMS=200.2 (M+)+. 1H NMR (CDCl3, 500 MHz): δ 3.67 (s, 3H), 2.67-2.64 (q, J=7.1 Hz, 2H), 2.49-2.46 (m, 2H), 2.28-2.24 (m, 1H), 2.16-1.86 (m, 4H), 1.49-1.41 (m, 2H), 1.12 (t, J=5.5 Hz, 3H), 1.03 (m, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[N:11]([OH:21])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][N:14]=1.C(N(CC)CC)C.Cl.[NH2:30][CH2:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[OH:33]>CN(C)C=O>[Cl:40][C:36]1[CH:35]=[C:34]([CH:32]([OH:33])[CH2:31][NH:30][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:10]2[N:11]([OH:21])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: COc1nccc(I)c1-c1ncc(-c2ccccc2)n1O
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1[nH]ccc(NCC(O)c2cccc(Cl)c2)c1-c1ncc(-c2ccccc2)n1O
Temperature: 65 °C
Yield: 26.8 %

Procedure:
2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol (0.020 g, 0.053 mmol) was dissolved in N,N-dimethylformamide (4 mL) and treated with triethylamine (20 μL, 0.159 mmol) and the hydrochloric acid salt of (S)-2-amino-1-[3-chlorophenyl]ethanol (0.017 g, 0.0795 mmol). This mixture was heated at 65° C. for 3 hours, then the solvent was evaporated. The residue was purified by Prep HPLC (ammonium acetate/water/acetonitrile) to give the title material (0.006 g, 27%) as a beige solid. HPLC 87.9% (220 nm), LCMS (+ESI, M+H+) m/z 423; IR ν (cm−1): 2923, 2853, 1637; HRMS calcd for C22H20N4O3Cl (M+H)+=423.1224, found: 423.1221; 1H NMR (400 MHz, methanol-d4) δ (ppm): 3.56 (1H, dd, J=13.2 and 7.0 Hz), 3.69 (1H, dd, J=13.2 and 4.6 Hz), 4.96 (1H, m), 6.36 (1H, d, J=7.4 Hz), 7.22-7.79 (11H, m).
Reaction SMILES: C(O[CH:4](OCC)[C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1)C.Cl.[NH2:30][OH:31]>C1COCC1.O.C(Cl)Cl.[Cl-].[Na+].O>[OH:31][N:30]=[CH:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1
Reactant: CCOC(OCC)c1ccc(CN(C(=O)OC(C)(C)C)C2CCOCC2)cc1
Reactant: NO
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccc(C=NO)cc1)C1CCOCC1
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 70.5 %

Procedure:
A solution of tert-butyl 4-(diethoxymethyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-3) (2.80 kg, 7.12 mol) in THF (28.0 L) and water (2.80 L) is stirred at about 20° C. Hydroxylamine hydrochloride (593 g, 8.54 mol) is added while maintaining the reaction temperature between 20-25° C. The reaction mixture is stirred at about 20° C. for 16-20 h then diluted with CH2Cl2 (8.4 L) and 50% brine (11.2 L) and stirred for at least 5 min. The phases are separated then the organic phase is washed with 50% brine (2×2.8 L), dried (Na2SO4) and concentrated. The concentrate is diluted with MeOH (1.4 L) and re-concentrated. The concentrate is diluted with MeOH (14.0 L) and transferred to a reaction vessel. The solution is warmed to about 25° C. then water (14.0 L) is added over about 1-1.5 h; after about 10 L of water is added, the mixture is seeded and a hazy suspension is observed. Additional water (8.4 L) is added over 1.5 h to further precipitate the product. After aging, the solid is collected by filtration. The filter-cake is washed with heptane (5.6 L) and dried to afford tert-butyl 4-((hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (A-4) (1678 g; 71%, 91.5 area % purity by HPLC) as an off-white powder. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.24 (d, J=7.9 Hz, 2H), 4.40 (br s, 3H), 3.96 (dd, J=10.4, 3.6 Hz, 2H), 3.41 (br m, 2H), 1.69-1.61 (m, 4H), 1.39 (br s, 9H).
Reaction SMILES: [I:1][C:2]1[C:3]2[NH:16][CH:15]=[CH:14][C:4]=2[C:5]2[C:10]([CH:11]=1)=[N:9][C:8]([NH2:12])=[N:7][C:6]=2[NH2:13].[OH-].[Na+].[CH3:19]I.[Cl-].[Na+]>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>[I:1][C:2]1[C:3]2[N:16]([CH3:19])[CH:15]=[CH:14][C:4]=2[C:5]2[C:10]([CH:11]=1)=[N:9][C:8]([NH2:12])=[N:7][C:6]=2[NH2:13]
Reactant: Nc1nc(N)c2c(cc(I)c3[nH]ccc32)n1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2c3c(N)nc(N)nc3cc(I)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-iodo-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine VI, 400 mg, 1.23 mmol) in tetrahydrofuran (20 mL) at 25° C. was treated with sodium hydroxide (98 mg, 2.46 mmol), methyl iodide (0.09 mL, 1.48 mmol), and tetrabutylammonium bromide (198 mg, 0.62 mmol), and the resulting mixture stirred at 25° C. for 18 h. The reaction mixture was treated with ethyl acetate, water, and a saturated aqueous sodium chloride solution, shaken and separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 6-iodo-7-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (500 mg) as a yellow solid. The product was taken on into the next reaction without further purification 6-iodo-7-methyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine VIII.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH3:46][C:34]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:27][CH:28]=2)[C:41]2[C:36]([C:35]=1[CH3:45])=[CH:37][C:38]([C:42](=[O:43])[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1)=[CH:39][CH:40]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-trifluoromethylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 557 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:14]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[C:7]2[N:8]([CH3:14])[CH2:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1N=CS2=O
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: Cc1cccc2c1N(C)CS2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
4-Methylbenzothiazolone (4.13 g, 0.025 mole) was dissolved in a solution of sodium hydroxide (1.60 g, 0.0375 mole) in water (100 c.c.), and tetra-n-butylammonium bromide (0.24 g, 7.5×10-4 mole) and toluene (40 c.c.) were added thereto. Dimethyl sulfate (4.70 g, 0.0375 mole) was added dropwise thereto at room temperature, and the mixture was stirred at room temperature for 1 hour, followed by phaseseparation. The toluene layer was washed once with water, and the solvent was removed under reduced pressure to obtain 4.31 g of 4-methyl-N-methylbenzothiazolone as white crystals. Yield 96.2%, purity 98.8%, m.p. 122°-124° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[S:14][C:13]([NH:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[N:12][C:11]=1[C:26]([NH2:28])=[O:27])=[O:8].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CC(N(C)C)=O>[O:32]1[CH2:33][CH2:34][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]2[S:14][C:13]([NH:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)=[N:12][C:11]=2[C:26]([NH2:28])=[O:27])=[O:8])[CH2:30][CH2:31]1
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)CCCCCBr
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)CCCCCN1CCOCC1
Temperature: 120 °C
Yield: 90.2 %

Procedure:
A mixture of 5-(6-bromohexanamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (150 mg, 0.32 mmol) and morpholine (0.06 mL, 0.69 mmol) in DMA (0.5 ml) was heated at 120° C. for 1.5 hrs in a sealed tube. The reaction mixture was then diluted with ice-water. The resulting solids were collected by filtration and washed successively with ether and MeOH to give 135 mg (90% yield) of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH:6][S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([F:10])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1c(F)cc(Br)cc1F
Temperature: 50 °C
Reaction time: 6 h
Yield: 98.3 %

Procedure:
To a solution of 4-bromo-2,6-difluoroaniline (3.0 g, 14.4 mmol) in pyridine (20 ml) was added methanesulfonyl chloride (2.23 ml, 28.8 mmol) at room temperature. Then the mixture was stirred at 50° C. for 6 hours. After cooing to room temperature, the mixture was concentrated in vacuo. The resulting residue was dissolved in THF (40 ml). To this solution was added 2M aqueous sodium hydroxide solution (40 ml) and the reaction was stirred at room temperature for 4 hours. The mixture was acidified with 2M aqueous HCl solution and the whole was extracted with EtOAc. The organic layer was washed with 2M aqueous HCl solution, brine, and dried over sodium sulfate. After concentration in vacuo, the title compound (4.05 g, 98% yield) was obtained as orange solids.