Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:25][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28].[ClH:32]>CN(C=O)C.C(OCC)C>[ClH:25].[ClH:32].[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:18][CH:17]=3)=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)N1CCN(c2cnc(-c3ccc(O)cc3)cn2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)N1CCN(c2cnc(-c3ccc(OCC(=O)N(C)C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
4-(4-Isopropyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl)phenol (0.15 g, 0.404 mmol) was dissolved in DMF (4 mL) in a 5 mL microwave vial. NaH (0.039 g, 1.62 mmol) was added slowly and the mixture was stirred at rt for 30 min. Chloro-N,N-dimethylacetamide (0.147 g, 1.21 mmol) was added and the reaction mixture was heated for 2.5 h at 130° C. in a microwave oven. The reaction mixture was evaporated in vacuo and the residue was redissolved in a mixture of DCM and water. The phases were separated and the aqueous phase was extracted with DCM (2×25 mL). The combined organic extracts were evaporated, redissolved in MeOH and purified by preparative HPLC Method B. This afforded an oil which was treated with HCl in diethyl ether to give a solid material. Recrystallization from acetone and MeOH afforded 75 mg (41%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[O:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[NH2:23].N(CC)(CC)CC.FC(C(O)=O)(F)F>CS(C)=O>[C:14]([C:12]1[O:11][N:10]=[C:9]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:20]([O:19][CH3:18])[CH:21]=3)[N:7]=2)[CH:13]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CC(C)(C)c1cc(Nc2ccnc(Cl)n2)no1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: COc1cc(Nc2nccc(Nc3cc(C(C)(C)C)on3)n2)cc(OC)c1OC
Temperature: 100 °C

Procedure:
A mixture of (2-chloropyrimidin-4-yl)-(5-tert-butyl-isoxazol-3-yl)amine (50 mg 0.198 mmol Step A) and 3,4,5-trimethoxyaniline (36.2 mg 0.198 mmol) was suspended in 0.15 mL of a 2M solution of Et3N-TFA in DMSO (stock solution prepared by combining 1.28 g of Et3N-TFA and 3 mL of DMSO) in a sealed tube. The resulting mixture was heated at 100° C. for 4 h, cooled to RT, diluted with CH2C12 (attempted crystallization), concentrated and purified via preparative HPLC to give N4-(5-tert-butylisoxazol-3-yl)-N2-(3,4,5-trimethoxy-phenyl)-pyrimidine-2,4-diamine as a green-gray amorphous solid. MS m/z=400. Calc'd for C20H25N5O4— 399.19.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:27][CH2:26][C:25](=O)[CH2:24]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[F:1][C:2]1([F:29])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:27][CH2:26][CH:25]([N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:24]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: C1CCNC1
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCC(N4CCCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 133 using 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, pyrrolidine, glacial acetic acid and sodium triacetoxyborohydride. 1H NMR (400 MHz, DMSO-d6): δ 8.80 (t, J=5.82 Hz, 1H), 8.01-7.95 (m, 2H), 7.76-7.74 (m, 1H), 7.61-7.56 (m, 1H), 3.55-3.44 (m, 1H), 3.43-3.41 (m, 1H), 3.27 (t, J=6.2 Hz, 2H), 2.74-2.66 (m, 1H), 2.64-2.50 (m, 1H), 2.27-2.24 (m, 1H), 2.10-1.99 (m, 5H), 1.89-1.76 (m, 6H), 1.75-1.68 (m, 2H), 1.33-1.29 (m, 5H), 1.27-1.24 (m, 2H). m/z: 476.2 [M+H]+
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Br:12][C:13]1[C:22]([O:23][CH3:24])=[C:21]2[C:16]([C:17](=[O:35])[C:18]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:19]([S:28][CH3:29])[N:20]2[CH:25]2[CH2:27][CH2:26]2)=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[C:22]([O:23][CH3:24])=[C:21]2[C:16]([C:17](=[O:35])[C:18]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:19]([S:28]([CH3:29])=[O:6])[N:20]2[CH:25]2[CH2:26][CH2:27]2)=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(SC)n(C2CC2)c2c(OC)c(Br)ccc2c1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(S(C)=O)n(C2CC2)c2c(OC)c(Br)ccc2c1=O
Reaction time: 1 h
Yield: 55.7 %

Procedure:
m-Chloroperoxybenzoic acid (≦77%, 273.5 mg, 1.22 mmol) is added in one portion to a solution of crude ethyl 15 (from above ˜1.22 mmol) in methylene chloride (5.0 mL) at room temperature. The reaction mixture is stirred for 1 h, diluted with methylene chloride (10 mL), and washed with a saturated aqueous solution of sodium bicarbonate (25 mL). The organic layer is dried over magnesium sulfate and evaporated under reduced pressure to give the crude product. This material is purified by flash column chromatography (eluting with ethyl acetate; Rf 0.37) to give 290.9 mg of pure ethyl 16 as a white solid. 1H NMR (CDCl3): δ 0.54 (m, 1H, c-Pr CH2 (A)), 0.93 (m, 1H, c-Pr CH2 (B)), 1.12 (m, 1H, c-Pr CH2 (A)), 1.28 (m, 1H, c-Pr CH2 (B)), 1.38 (t, J=7.0 Hz, 3H, CO2CH2CH3), 3.26 (s, 3H, S(O)CH3), 3.83 (s, 3H, OCH3), 3.92 (m, 1H, c-Pr CH), 4.40 (m, 2H, overlapping CO2CHHCH3), 7.58 (d, J=8.5 Hz, 1H, aromatic H-6), 7.87 (d, J=8.5 Hz, 1H, aromatic H-5). 13C{1H} NMR (CDCl3): δ 10.8 (br, c-Pr CH2 (A)), 13.9 (br, c-Pr CH2 (B)), 14.1 (CO2CH2CH3), 35.1 (c-Pr CH), 41.4 (S(O)—CH3), 61.1 (OCH3), 62.1 (CO2CH2CH3), 118.9 (C-3), 122.8 (CH, C-5), 123.9 (C—Br, C-7), 129.5 (C-4a), 130.0 (CH, C-6), 138.2 (C-8a), 148.3 (C—OCH3, C-8), 164.0 (CO2CH2CH3), 164.1 (br, C—S(O)—CH3, C-2), 174.6 (C═O, C-4). LCMS m/z calcd for C17H1879BrNO5S ([M]+) 427. Found 428 ([M+H]+). HRMS m/z calcd for C17H1879BrNNaO5S 449.9987 ([M+Na]+). Found 449.9977.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C(#N)C>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[S:5])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCN=C=S
Solvent: CC#N
Solvent: O
Product: CCNC(=S)Nc1ccccc1
Temperature: 25 °C

Procedure:
A solution of ethyl isothiocyanate (1-1) (652 mg, 7.5 mmol) and aniline (1-2) (465 mg, 5.0 mmol) in acetonitrile (5 mL) is heated to 80° C. for 14 hours. After cooling to room temperature, the mixture is poured into water (50 mL) and extracted with ethyl acetate (EtOAc) (3×50 mL). The combined organic layers are washed with brine and dried using MgSO4. The drying agents are removed by filtration and the solvent is removed under vacuum. The resulting residue is then purified by flash column chromatography (silica gel, EtOAc/hexane, 0%˜40%) to provide 1-ethyl-3-phenylthiourea (1-3) as a white powder. HPLC-MS calculated for C9H12N2S (M+H+) 181.1. found 181.1.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH:18]=O)[N:13]=2)[N:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[C:1]([NH:6][C:7]1[NH:16][C:15](=[O:17])[C:14]2[C:9](=[N:10][CH:11]=[C:12]([N:13]=2)[CH2:18][NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[N:8]=1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)Nc1nc2ncc(C=O)nc2c(=O)[nH]1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)C(=O)Nc1nc2ncc(CNc3ccc(C(=O)O)cc3)nc2c(=O)[nH]1
Reaction time: 0.17 h

Procedure:
N2-iBu-6-formylpterin (25) 4.0 gm, 15 mmole) was suspended in MeOH. To this suspension was added 4-aminobenzoic acid (2.1 g, 15 mmole) followed by stirring for 10 minutes. The reaction mixture was then cooled in an ice bath with continuous stirring. A solution of pyridinium para-toluene sulfonate (PPTS, 1 M in MeOH, 15 ml, 15 mmol) was added in one portion, followed by the addition of pyridine-borane complex (1.9 ml of 8M solution, 15 mmol) dropwise over a period of 10 minutes. The ice bath was removed, and stirring was continued at room temperature for 3 hours. The fine precipitated product was collected by centrifugation and washed with a 1:1 mixture of hexanes-MeOH several times, and finally with MeOH. The product was dried in vacuum over P205 for 24 sours to give light cream-colored powder, yield=5.3 gm, 91%. 1H NMR (DMSO): δ 8.87 (s, 1H), 4.62 (s, 2H), 2.75-2.82 (m, 1H), 1.13, 1.16 (2s, 6H); MS, m/z , M-H+=383 for C18H18N6O4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH:11]1([N:17]=[C:18]=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1C=CC=CC=1.C(N(CC)CC)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[CH:11]1([NH:17][C:18]([O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C=NC1CCCCC1
Reactant: Oc1ccc(N=C=S)cc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)Oc1ccc(N=C=S)cc1

Procedure:
By a procedure similar to that of Example I, the above compound (3.9 g., m.p. 170°-173° C.) was prepared from 3.8 g. (0.025 m.) of p-hydroxyphenylisothiocyanate and 3.2 g. (0.025 m.) of cyclohexylisocyanate, using 50 mls. of benzene as a solvent and 3 drops each of triethylamine and dibutyltin dilaurate as catalysts.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.[CH:29]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][C:31]([CH2:29][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reaction time: 18 h
Yield: 73.6 %

Procedure:
Following General Procedure B: To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (680 mg, 1.8 mmol) and methyl 4-formylbenzoate (295 mg, 1.8 mmol) in CH2Cl2 (10 mL) was added NaBH(OAc)3 (763 mg, 3.6 mmol) and the mixture stirred for 18 h. The resulting crude material was taken up in neat TFA (2 mL) and stirred 3 h. Saturated aqueous sodium bicarbonate (10 mL) was cautiously added, and the resulting mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic extracts were dried (MgSO4), and concentrated in vacuo. Purification of the crude material by flash chromatography (silica gel, 50:2:1 CH2Cl2/MeOH/NH4OH) afforded the title compound (565 mg, 74%) as a white solid. 1H NMR (CDCl3) δ1.64-1.75 (m, 1H), 2.01-2.08 (m, 2H), 2.26-2.28 (m, 1H), 2.74-2.76 (m, 1H), 2.81-2.86 (m, 1H), 3.81 (s, 2H), 3.86 (s, 3H), 3.94 (d, 1H, J=17 Hz), 4.09 (dd, 11H, J=9, 7 Hz), 4.21 (d, 1H, J=17 Hz), 7.18-7.22 (m, 3H), 7.44 (br d, 1H, J=8 Hz), 7.49 (d, 2H, J=8 Hz), 7.50-7.53 (m, 11H), 7.64-7.66 (m, 1H), 7.91 (d, 2H, J=8 Hz), 8.70 (dd, 1H, J=5, 1 Hz); 13C NMR (CDCl3) δ21.2, 23.6, 29.0, 48.7, 51.9, 53.7, 111.0, 118.6, 121.5, 122.3, 129.3, 128.9, 129.5, 134.7, 137.2, 144.8, 146.8, 155.7, 157.1, 166.8. ES-MS m/z 427 (M+H). Anal. Calcd. for C26H26N4O2.0.6H2O.0.3CH2Cl2: C, 68.26; H, 6.05; N, 12.11. Found: C, 68.57; H, 6.12; N, 11.75.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]([NH:13]C(=O)OC(C)(C)C)[CH:12]=1)=[O:5].FC(F)(F)C(O)=O>ClCCl>[NH2:13][C:11]1[CH:12]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:23])[CH3:1])[CH:8]=[CH:9][C:10]=1[O:21][CH3:22]
Reactant: COc1ccc(NC(=O)CN(C)C)cc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(=O)CN(C)C)cc1N
Yield: 95.5 %

Procedure:
A solution of 1,1-dimethylethyl [5-[(N,N-dimethylglycyl)amino]-2-(methyloxy)phenyl]carbamate (0.44 g, 1.36 mmol) and trifluoroacetic acid (1.55 g, 13.6 mmol, Aldrich) in dichloromethane (50 mL) was stirred overnight at room temperature. The crude reaction was diluted with dichloromethane (100 mL), washed with saturated NaHCO3 (100 mL), evaporated under reduced pressure, and dried under high vacuum to provide N1-[3-amino-4-(methyloxy)phenyl]-N2,N2-dimethylglycinamide (0.29 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.22 (s, 6H) 2.99 (s, 2 H) 3.80 (s, 3 H) 5.29 (s, 2 H) 6.68-6.74 (m, 1 H) 7.03 (d, J=8.61 Hz, 1H) 7.22 (d, J=2.38 Hz, 1 H) 9.49 (s, 1 H). ESIMS (M+H)+=224.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=O)(C)(C)C.[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[C:38]1[N:39]=[N:40][N:41]([C:43]2[CH:50]=[CH:49][C:46](C=O)=[CH:45][CH:44]=2)[CH:42]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CC(N(C)C)=O>[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[C:38]1[N:39]=[N:40][N:41]([C:43]2[CH:44]=[CH:45][C:46]([CH2:20][N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)=[CH:49][CH:50]=2)[CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C=O)cc4)nn3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(CN5CCNCC5)cc4)nn3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (279 mg; 1.32 mmol; 2.0 eq.) was added to a solution of tert-butyl-1-piperazinecarboxylate (1.22 g; 6.59 mmol; 10 eq.) and 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzaldehyde (200 mg; 0.66 mmol; 1.0 eq.) in DMA (4 mL) and the reaction mixture was stirred overnight at RT. Sodium triacetoxyborohydride (279 mg; 1.32 mmol; 2.0 eq.) and glacial acetic acid (75.42 μl; 1.32 mmol; 2.00 eq.) then sodium cyanoborohydride (83 mg; 1.32 mmol; 2. eq.) were added to complete the reaction which was quenched with water and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting gum was stirred at RT in a solution of HCl in dioxane (5 mL, 4N) for 2 hours. The reaction mixture was basified to pH=9-10 and extracted with EtOAc. Organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the title compound as a formic acid salt. It was dissolved in MeOH and passed through a SPE-NH2 cartridge. The fractions containing the desired compound were concentrated to dryness affording a yellow gum, which was twice sonicated in 3 mL of Et2O. The suspension obtained was concentrated then dried overnight under high vacuum to afford the title compound as a beige solid. 1H NMR (300 Mz, DMSO-d6) δ: 13.23 (brs, 1H), 9.25 (s, 1H), 8.14-8.13 (m, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.5 Hz, 1.5 Hz, 1H), 3.52 (s, 2H), 2.72-2.69 (m, 4H), 2.487 (s, 3H), 2.32-2.30 (m, 4H). HPLC (Condition A): Rt 2.22 min (purity 95.4%). MS (ESI+): 374.3, MS (ESI−): 372.3.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15]>C1COCC1>[CH3:1][C:2]1[S:3][C:4]([Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][N:6]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A −78° C. solution of 2-methylthiazole (2 g, 20.17 mmol) in THF (50 mL) was treated drop-wise with n-butyllithium (2.5 M in Hex, 10.49 mL, 26.2 mmol), stirred for 1 h, treated drop-wise with a solution of tributyltin chloride (7.11 mL, 26.2 mmol) in THF (25 mL) and stirred for an additional 1 h at −78° C. The mixture was allowed to warm to RT, stirred for 1 h, treated slowly with ice-cold satd. NaHCO3 (20 mL) and quickly extracted with Et2O (3×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 2-methyl-5-(tributylstannyl)thiazole (6.67 g, 85%). 1H NMR (400 MHz, DMSO-d6): δ 7.55 (s, 1H), 2.67 (s, 3H), 1.54-1.45 (m, 6H), 1.30-1.23 (m, 6H), 1.09-1.04 (m, 6H), 0.83 (t, J=7.3 Hz, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH:11](F)[CH3:12])=[C:9]([NH2:14])[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:6]=1)=[O:4].[OH-:25].[Na+].Cl.[CH3:28]O>>[NH2:14][C:9]1[N:8]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:6]=[C:5]([C:3]([OH:2])=[O:4])[C:10]=1[CH:11]([O:25][CH3:28])[CH3:12]
Reactant: [OH-]
Reactant: CO
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1C(C)F
Agent: Cl
Agent: [Na+]
Product: COc1c(Cl)ccc(-c2nc(N)c(C(C)OC)c(C(=O)O)n2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1-fluoroethyl)pyrimidine-4-carboxylic acid methyl ester (0.100 g, 0.280 mmol) was dissolved/suspended in methanol (10 mL) and 2N sodium hydroxide (0.561 mL, 1.121 mmol) was added. The reaction mixture was stirred overnight at ambient temperature, acidified with 2N HCl, and concentrated. The precipitate that formed was filtered, washed with water, and dried to provide the title compound (0.085 g, 85% yield) as a white solid, mp 165-167° C.: 1H NMR (DMSO-d6 and drop of D2O) δ 7.60 (dd, 1H), 7.39 (dd, 1H), 4.55 (q, 1H), 3.91 (s, 3H), 3.17 (s, 3H), 1.41 (dd, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15](O)[CH3:16])(C)(C)C.O.Cl.[S-:21][C:22]#[N:23].[K+]>C(O)C>[Cl:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][C:22](=[S:21])[NH:23][CH:15]2[CH3:16]
Reactant: N#C[S-]
Reactant: CC(O)c1cc(Cl)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1NC(=S)Nc2ccc(Cl)cc21
Yield: 84.5 %

Procedure:
[4-Chloro-2-(1-hydroxy-ethyl)-phenyl]-carbamic acid tert-butyl ester (525 mg, 1.93 mmol) was suspended in a mixture of ethanol (1.5 ml), water (2.3 ml) and aqueous concentrated hydrogen chloride solution (0.6 ml). Potassium thiocyanate (206 mg, 2.1 mmol) was added and the reaction was heated to reflux for 3 hours. The product precipitated from the reaction and was filtered off after cooling, washed with water and ethanol and dried in vacuo to give the title compound (347 mg, 84%) as a white solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:7]=[CH:6][N:5]=1.[SH:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.[OH-].[Na+]>C(O)C>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:3][S:17][C:18]2[S:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[C:9]=1[CH3:10]
Reactant: Sc1nc2ccccc2s1
Reactant: COCCCOc1ccnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCOc1ccnc(CSc2nc3ccccc3s2)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.9 %

Procedure:
A mixture comprising 0.8 g of 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine hydrochloride, 0.5 g of 2-mercaptobenzothiazole, 0.36 g of sodium hydroxide and 30 ml of ethanol was stirred at a room temperature for 6 hours and distilled under a reduced pressure to remove the ethanol. The residue was purified by silica gel column chromatography to obtain 0.85 g of the title compound as a pale yellow crystal.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH:7]=[CH:8][O:9][C:4]=2[CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O.Cl.CO>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:10])[C:5]3[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][C:4]=3[O:9][CH2:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=c1ccoc2cc(O)ccc12
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1ccc(C=C2COc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3,4-dimethoxybenzaldehyde 1.22 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 40 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, water 100 ml was added and the mixture was allowed to stand for 30 minutes. The precipitated crystals were filtered.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[C:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:31])[CH3:30].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[C:13]([O:12][C:10]([NH:1][C@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7](=[O:9])[CH2:30][C:29]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC[C@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(=O)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of Boc-D-alloIle-OH (15.26 g, 65.9 mmol) in dry THF (200 ml) at 0° C. under argon, was added CDI (16.04 g, 98.96 mmol). After 15 min, the mixture was allowed to warm to room temperature, and stirred over a period of 16 h. The resulting solution was cooled to −78° C., and added via cannula to a well stirred solution of benzyl lithium enolate cooled at −78° C. (625 ml, 0.37 M), [prepared by adding dropwise a solution of benzyl acetate (33.34 ml), in THF (165 ml) to a solution of lithium diisopropylamide (0.36M) in THF/hex 3:1 (642 ml) at −78° C.]. The temperature should be kept <−75° C. The reaction mixture was stirred at −78° C. for 60 min. Then, it was allowed to come to −10° C. (30 min), recooled to −78° C. and quenched with saturated aq. ammonium chloride (200 ml), then extracted with DCM (3×500 ml) at room temperature. The combined extracts were washed successively with aq sat. NaHCO3 (500 ml) and brine (200 ml). Drying (Na2SO4) followed by removal of solvent gave an oil, which was coated on silica C18 and loaded to the top of a LC-RPC18 [Lichroprep RPC-18 (40-60 microns) column. Elution using a gradient ACN-H2O (60 to 100% ACN)] yielded the product C4 as a colourless oil (16.7 g, 70%). [α]20D−20.0 (c 1, CHCl3), TLC: Rf=0.32 (Merck, RP-C18, ACN-H2O7:3).