Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:48])[NH:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:48])[NH:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)[N:27]=2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
To a suspension of 3-t-butyldiphenylsilyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (590 mg, 0.860 mmol) (obtained as described in Reference Example 53(6)) in anhydrous tetrahydrofuran (18 ml) were added successively acetic acid (59 μl, 1.03 mmol) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (1.03 ml, 1.03 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 partitioned between ethyl acetate and water. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (95:5) as the eluant to afford 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (378 mg, yield 98%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:25]>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:24][CH3:25])[CH2:33][CH2:34]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: CCc1ccccc1N1CCNCC1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2CC)CC1
Yield: 77.5 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][N:3]=1.[OH-].[Li+]>CO.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ncc(C(=O)O)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Methyl 2-aminopyrimidine-5-carboxylate (300 mg, 2.0 mmol) was diluted in methanol (5 mL) containing a few drops of water. Lithium hydroxide (122 mg, 5.1 mmol) was added, and the reaction mixture was stirred at 60° C. overnight. The mixture was concentrated under reduced pressure, then diluted in water and adjusted to pH 4 with 1M HCl. 2-Aminopyrimidine-5-carboxylic acid precipitated as a white solid, which was isolated by vacuum filtration (244 mg, 90%): 1H NMR (DMSO-d6) δ: 12.73 (1H, br s), 8.63 (2H, s), 7.44 (2H, br s).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[C:27](OC=C)(=O)[CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH:27]=[CH2:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: C=COC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (329 mg, 0.800 mmol), vinyl acetate (148 μL, 1.60 mmol), di-μ-chlorobis[(η-cycloocta-1,5-diene)iridium (I)] (26.9 mg, 0.0400 mmol) and sodium carbonate (50.9 mg, 0.480 mmol) in o-dichlorobenzene (1.6 mL) was stirred for 3 h at 100° C. After vinyl acetate (148 μL, 1.60 mmol) was added, the reaction mixture was purified by flash column chromatography on silica gel eluting with a 20% ethyl acetate/n-hexane to give the title compound as a pale yellow amorphous (279 mg, 0.638 mmol, 80%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][O:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][OH:31])=[N:28][CH:29]=3)[O:21][N:20]=2)[N:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][O:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][O:31][S:33]([CH3:32])(=[O:35])=[O:34])=[N:28][CH:29]=3)[O:21][N:20]=2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CO)nc3)n2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(COS(C)(=O)=O)nc3)n2)n1
Reaction time: 3 h

Procedure:
To a solution of [5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-yl]-methanol (Intermediate 130, 185 mg, 0.44 mmol) in DCM (40 mL) was added methanesulfonyl chloride (48 μL, 0.61 mmol) drop-wise, followed by triethylamine (92 μL, 0.66 mmol). The resulting solution was stirred for 3 h under an inert atmosphere. Incomplete reaction was observed so additional methanesulfonyl chloride (9 μL, 0.10 mmol) and triethylamine (16 μL, 0.11 mmol) were added and stirring was continued for 1 h. The reaction mixture was washed with water (2×50 mL) and the organic phase dried over magnesium sulfate and evaporated to dryness to afford the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate. In a separate flask 2,2,2-trifluoro-ethanol (190 μL, 2.64 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 97 mg, 2.42 mmol) in anhydrous THF (30 mL) at 0 C under nitrogen. The resulting solution was stirred at 0 C for 30 min and then transferred via cannula to a solution of the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate (220 mg, 0.44 mmol) in anhydrous THF (30 mL) at 0 C drop wise. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with a saturated ammonium chloride aq. solution (5 mL) and extracted with EtOAc (3×50 mL). Combined organics were washed with brine (25 mL), dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica chromatography (2% MeOH in DCM) and then further by preparative HPLC-MS (Method C) to afford the title compound as an off-white solid (21 mg, 10%).
Reaction SMILES: [CH:1]1([CH2:5][C:6]([OH:8])=O)[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1>>[CH:1]1([CH2:5][C:6]([N:29]2[CH2:28][CH2:27][C:26]3[C:31](=[CH:32][C:23]([C:21]4[CH:22]=[C:17]([N:14]5[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]5)[N:18]=[C:19]([NH2:33])[N:20]=4)=[CH:24][CH:25]=3)[CH2:30]2)=[O:8])[CH2:2][CH2:3][CH2:4]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(O)CC1CCC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 41 starting from cyclobutylacetic acid and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=421.1.
Reaction SMILES: [CH3:1][N:2](C)/C=N/[H].[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH3:21])[C:15]([C:18]([OH:20])=O)=[N:16][CH:17]=1.CC([O-])(C)C.[K+].Cl>C1COCC1>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[N:16][C:15]2[C:18](=[O:20])[NH:2][CH:1]=[CH:21][C:14]=2[CH:13]=1
Reactant: [H]/N=C/N(C)C
Reactant: COCCOc1cnc(C(=O)O)c(C)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOc1cnc2c(=O)[nH]ccc2c1
Temperature: 25 °C

Procedure:
5-(2-Methoxy-ethoxy)-3-methyl-pyridine-2-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamine (500 mg, 1.885 mmol) was dissolved in THF (15 ml) and heated to gentle reflux. KOtBu (317 mg, 2.83 mmol) in THF (30 ml) was added dropwise and the reaction mixture was heated to reflux for 2.5 h and then cooled to rt. The pH was adjusted to 7 with concentrated HCl. The reaction mixture was concentrated.
Reaction SMILES: [C:1]1([C:7]2([OH:21])[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:23][C:24](=[O:46])[C@@H:25]([CH2:44]O)[NH:26]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[C:1]1([C:7]2([O:21][CH2:44][C@H:25]([C:24]([OH:46])=[O:23])[NH2:26])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2)c2ccccc2Oc2ccccc21
Reactant: COC(=O)[C@@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Product: N[C@H](COC1(c2ccccc2)c2ccccc2Oc2ccccc21)C(=O)O

Procedure:
from 9-phenyl-9H-xanthen-9-ol (Example 1f) and Nα -(9-fluorenylmethoxycarbonyl)-D-serine methyl ester;
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=1>>[CH2:16]([O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[NH:24][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)[CH3:15]
Reactant: CCOc1cccc(N)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: CCOc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and m-phenetidine (65 μl, 0.486 mmol) similar to Example 11 and isolated as a light tan solid (116 mg, 78%). 1H NMR (CDCl3): 8.86-8.83 (m, 1H), 8.50 (d, J=8.1 Hz, 1H), 7.89-7.83 (m, 1H), 7.42-7.38 (m, 1H), 7.35-7.30 (m, 1H), 7.09 (s, 1H), 6.96-6.84 (m, 2H), 6.76 (d, J=3.3 Hz, 1H), 6.71 (s, 1H), 4.09 (q, J=7.2 Hz, 2H), 2.53 (s, 3H), 1.47 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>CN(C=O)C>[CH3:11][C@H:10]([NH:12][C:13](=[O:15])[CH3:14])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)N[C@@H](C)CCc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)CCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
N—[(S)-3-(4-Hydroxyphenyl)-1-methylpropyl]acetamide (770 mg, 3.72 mmol) and sodium hydride (55% in oil, 243 mg, 5.57 mmol) were stirred in 30 ml of DMF under argon at room temperature for 30 min. Following addition of 2-chloro-5-nitropyridine (648 mg, 4.09 mmol) the mixture was stirred at 80° C. for 1.5 h, concentrated, and mixed with ethyl acetate and water, and the organic phase was separated off and concentrated. The crude product was further reacted without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=O)=[N:27]1.N1CCCCC1>CO>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](/[CH:35]=[C:8]2\[O:9][C:5]3[C:4]([CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:27]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1C1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1C1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A solution of tert-butyl 4-(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)piperidine-1-carboxylate (0.0341 g, 0.0981 mmol) in methanol (3 mL) was added with 1H-indazole-3-carboxaldehyde (0.0151 g, 0.103 mmol) and piperidine (0.0800 mL, 0.810 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain tert-butyl (Z)-4-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}piperidine-1-carboxylate (0.0446 g, 96%).
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.[NH2:53][C@H:54]([C:67]([N:69]1[CH2:80][CH2:79][CH2:78][C@H:70]1[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])=[O:68])[CH2:55][CH2:56][CH2:57][CH2:58][NH:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>CN(C=O)C.C(Cl)Cl>[NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([NH:53][C@H:54]([C:67]([N:69]1[CH2:80][CH2:79][CH2:78][C@H:70]1[C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])=[O:68])[CH2:55][CH2:56][CH2:57][CH2:58][NH:59][C:60]([O:62][C:63]([CH3:65])([CH3:66])[CH3:64])=[O:61])=[O:5]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Yield: 70.1 %

Procedure:
C] Z-Gly-OH (0.762 g, 3.64 mmoles) was dissolved in 15 ml of DMF/methylene chloride (1:1 v/v) and sequentially added with BOP (1.61 go 3.64 mmoles), HOBT (0.491 g, 3.64 mmoles), TEA (1.01 ml, 7.28 mmoles) and H-Lys(Boc)-Pro-OtBu (1.119 g, 2.8 mmoles) dissolved in 15 ml of the same mixture. The reaction mixture was treated as described under A]. There were obtained 1.16 g of Z-Gly-Lys(Boc)-Pro-OtBu.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][CH2:17][CH2:18][OH:19]>C(OCC)(=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:16][CH2:17][CH2:18][OH:19])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:7]=1
Reactant: NCCO
Reactant: Fc1ccc(OCCBr)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: OCCNCCOc1ccc(F)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
A mixture of 1-(2-bromoethoxy)-4-fluoro-2-(trifluoromethyl)benzene (C35) (600 mg, 2.09 mmol) and 2-aminoethanol (2.20 mL, 52.4 mmol) was heated to 80° C. for 1.5 hours. The reaction was allowed to cool to room temperature, diluted with ethyl acetate (75 mL) and washed with aqueous sodium hydroxide solution (1 N, 4×50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to provide the title compound as a white solid. Yield: 550 mg, 2.06 mmol, 99%. LCMS m/z 268.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 2.80 (br dd, J=5.5, 5.4 Hz, 2H), 3.04 (dd, J=5.4, 5.2 Hz, 2H), 3.68 (br dd, J=5.6, 5.4 Hz, 2H), 4.20 (dd, J=5.3, 5.3 Hz, 2H), 7.22 (br dd, J=8.8, 4.2 Hz, 1H), 7.30-7.37 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[C:9]1([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>O1CCCC1>[C:3]([CH:22]([C:19]1[CH:20]=[CH:21][C:16]([S:15][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][CH:18]=1)[C:23]#[N:24])(=[O:5])[CH3:4]
Reactant: N#CCc1ccc(Sc2ccccc2)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)C(C#N)c1ccc(Sc2ccccc2)cc1
Yield: 73.3 %

Procedure:
To a stirred suspension of 144 mg of 60% sodium hydride, in 10 ml of tetrahydrofuran at 0° C. under nitrogen atmosphere was added a mixture of 396 mg of ethyl acetate, 675 mg of 4-phenylthiophenylacetonitrile and 5 ml of tetrahydrofuran. Thirty minutes later, the ice bath was removed. Seventeen hours later, the tetrahydrofuran was distilled off in vacuo, and 10 ml of 2N hydrochloric acid and 20 ml of dichloromethane were added and separated, and the water layer was further extracted twice in 20 ml of dichloromethane. The organic layer and extract were combined, and dried by anhydrous magnesium sulfate, and concentrated in vacuo, and the residue was isolated and refined by silica gel chromatography (the eluent was a mixed solvent of hexane:ethyl acetate at a (v/v) rate of 4:1), and 587 mg of the title compound was obtained.
Reaction SMILES: C(O[C:9](=N)[C:10]([Cl:13])([Cl:12])[Cl:11])C1C=CC=CC=1.[C:15]1([NH2:22])[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.O>C(O)(=O)C>[Cl:11][C:10]([Cl:13])([Cl:12])[C:9]1[NH:22][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:21]=1
Reactant: Nc1ccccc1N
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: ClC(Cl)(Cl)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
2,2,2-trichloro-acetimidic acid benzyl ester (16) (2.3 g, 9.22 mmol, Alfa Aesar) was added to a solution of Benzene-1,2-diamine (15) (1.0 g, 9.2 mmol) in acetic acid (30 mL), the solution was stirred at RT for 1 h. H2O (20 mL) was added to the mixture and the suspension was filtered. The filter cake was washed with water and dried under vacuum to afford compound (17) (1.90 g yield 88%) which was used directly for the next step without further purification. ESI-MS (M+1): 235 calc. for C8H5Cl3N2 234.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1[CH:12]=O.[C:14]([CH2:16]C(O)=O)#[N:15]>N1C=CC=CC=1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH:4]=[C:3]1/[CH:12]=[CH:16]/[C:14]#[N:15]
Reactant: O=Cc1coc2ccccc2c1=O
Reactant: N#CCC(=O)O
Solvent: c1ccncc1
Product: N#C/C=C/c1coc2ccccc2c1=O
Temperature: 110 °C

Procedure:
A mixture of 10.44 parts of 4-oxo-4H-1-benzopyran-3- carboxaldehyde and 5.4 parts of cyanoacetic acid are heated in an oil bath at 110° C., and to the mixture 25 volume parts of pyridine are added dropwise over about 30 seconds, after which time the whole mixture is further heated for 8 minutes. After cooling, the separated crystals are recovered by filtration, treated with activated carbon and recrystallized three times from ethanol. This procedure yields trans-3-(4-oxo-4H-1-benzopyran-3-yl)-acrylonitrile as pale-yellowish prisms. Melting point: 192°-194° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[CH3:13][N:14](/[CH:16]=[C:3]1\[C:2](=[O:10])[NH:1][C:9]2[C:4]\1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:15]
Reactant: O=C1Cc2ccccc2N1
Reactant: COC(OC)N(C)C
Solvent: ClC(Cl)Cl
Product: CN(C)/C=C1\C(=O)Nc2ccccc21
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
To a solution of 1,3-dihydro-2H-indol-2-one 25.0 g, 189 mmol) in CHCl3 (150 mL) was added N,N-dimethylformamide dimethyl acetal (29.2 mL, 209 mmol) and the reaction was heated at 70° C. under an atmosphere of argon. After 4.5 h, the reaction was cooled to RT and was concentrated. The resulting solid was triturated with ether and filtered to give (3Z)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-indol-2-one as a yellow solid (iii-a, 33.0 g, 93%). NH4OAc QC conditions. DAD Retention Time=1.19 min. M+H=189.
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>CO>[OH:1][CH:2]([CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NOCC1CO1
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)NOCC(O)CN1CCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
A 150 mg (0.79 mmol) portion of tert-butyl N-(2,3-epoxypropoxy)carbamate was dissolved in 1 ml of methanol, and the solution was mixed with 0.08 ml (0.95 mmol) of pyrrolidine and stirred at room temperature for 14 hours. The reaction solution was mixed with a saturated ammonium chloride aqueous solution and extracted with chloroform. The chloroform layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain 181 mg (yield, 88%) of tert-butyl N-(2-hydroxy-3-pyrrolidinylpropoxy)-carbamate.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:31])[NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=3)[N:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd].C>[CH3:30][O:29][C:26]1[N:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[NH:18][C:17]([CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)=[O:31]
Reactant: COc1ccc2nccc(NC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2nccc(NC(=O)C3CCNCC3)c2n1
Yield: 58.6 %

Procedure:
A solution of (e) (6.0 g, 14.3 mmol) in ethanol/ethyl acetate (150 ml/150 ml) was hydrogenated over 10% Pd/charcoal (5 g) for 1.5 hours. Filtration, washing with ethanol (400 ml) and evaporation of the filtrate gave a white solid (2.4 g, 59%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[NH2:32][C:33]([NH2:35])=[S:34]>CC(C)=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][N:20]2[C:24](=[O:25])[C:23]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]3[C:21]2=[O:30])[O:7][C@H:6]1[S:34][C:33](=[NH:32])[NH2:35])(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)O[C@H](CN2C(=O)c3ccccc3C2=O)[C@@H]1OC(C)=O
Solvent: CC(C)=O
Product: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@@H](SC(=N)N)[C@@H]1OC(C)=O
Yield: 85.8 %

Procedure:
A solution of 2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-α-D-galactopyranosyl bromide (4.0 g.) and thiourea (0.67 g.) in dry acetone (20 ml.) is heated under reflux for 4 hours. The solution is evaporated in vacuo to a syrup which is partitioned between water and dichloromethane. The organic layer is reextracted with water three times. The combined aqueous extracts are evaporated to give 2-S-(2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-β-D-galactopyranosyl)-2-thiopseudourea (3.40 g.).