Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8](=[O:32])[CH:9]([C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]([C:8](=[O:32])[CH:9]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:30][CH:31]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of tert-butyl 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoate, prepared in the previous step, in CH2Cl2 (200 mL) at room temperature was added trifluoroacetic acid (50 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated. The crude acid was dissolved in CH2Cl2, filtered, and precipitated with hexanes. The solid was collected by filtration, washed with hexanes, and dried under high vacuum to yield 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoic acid (7.58 g, 71% from dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate) as an off white solid: 1H NMR (600 MHz, DMSO-d6) δ 12.94 (s br, 1H), 10.26 (s br, 2H), 7.94 (d, J=8.2 Hz, 2H), 7.58 (d, J=7.6 Hz, 4H), 7.54 (d, J=8.2 Hz, 2H), 7.30 (t, J=7.6 Hz, 41-1), 7.05 (t, J=7.3 Hz, 2H), 4.97 (s, 1H); ESIMS calcd 375.1 (M++H), found 375.1 (M++H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:10]1[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14])[CH2:23]2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: Nc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccc(N)cc4C3)cc21
Yield: 24.5 %

Procedure:
177 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 113 mg of 5-aminoisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 63 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[C:8]([N:18]1C(C2C=CC=CC=2)O1)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>C(Cl)Cl>[C:8]([NH:18][NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: O=C(OCc1ccccc1)N1OC1c1ccccc1
Reactant: COC(CN)OC
Solvent: ClCCl
Product: COC(CNNC(=O)OCc1ccccc1)OC
Temperature: 23 °C
Reaction time: 18 h
Yield: 43.2 %

Procedure:
Aminoacetaldehyde dimethyl acetal (0.430 g, 3.95 mmol) was added to a solution of N-CBZ-3-phenyl-oxaziridine (1.11 g, 4.35 mmol) (prepared as described in Tetrahedron Let. 1993, 6859, the disclosure of which is entirely incorporated herein by reference) in CH2Cl2 (20 mL) at 23° C. The resulting yellow solution was stirred at 23° C. for 18 h, and it then was concentrated under reduced pressure. Purification of the residue by flash column chromatography (3% CH3OH/CH2Cl2) provided 1-CBZ-2-(2,2-dimethoxyethyl)-hydrazine (0.434 g, 43%) as a pale yellow oil: Rf =0.40 (5% CH3OH/CH2Cl2); IR (thin film) 3317, 1721, 1456 cm-1 ; 1H NMR (C6D6) δ 2.96 (bs, 2H), 3.06 (bs, 6H), 3.97 (bs, 1H), 4.37 (bs, 1H), 4.97 (bs, 2H), 5.87 (bs, 1H), 6.98-7.18 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]1=[O:23].[CH3:24][C:25]1[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:27][C:28]([CH3:31])=[CH:29][N:30]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]([N:35]2[CH2:36][CH2:37][N:32]([C:26]3[C:25]([CH3:24])=[N:30][CH:29]=[C:28]([CH3:31])[N:27]=3)[CH2:33][CH2:34]2)=[O:16])[CH2:12][N:11]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:10]1=[O:23]
Reactant: Cc1cnc(C)c(N2CCNCC2)n1
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccc(F)cc2F)C1=O
Product: Cc1cnc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)C(C)C)C(=O)N3c3ccc(F)cc3F)CC2)n1

Procedure:
In analogy to example 1, (RS)-3-(2,4-difluoro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid (example 82, step 3) was coupled with 3′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (CAS [59215-42-8]) to give the title compound as a colorless solid. MS: 523.2 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]([CH:10]([CH3:12])[CH3:11])=[C:3]([Cl:9])[C:4](OCC)=[O:5].[CH:13]([NH2:15])=O.C[O-].[Na+]>CO>[Cl:9][C:3]1[C:4]([OH:5])=[N:15][CH:13]=[N:1][C:2]=1[CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(Cl)=C(N)C(C)C
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)c1ncnc(O)c1Cl

Procedure:
45.1 g (0.24 mol) of ethyl 3-amino-2-chloro-4-methyl-2-pentenoate are reacted with 36.8 g (0.59 mol) of formamide and 109 ml of sodium methylate solution in 130 ml of methanol and worked up in analogy to Example 9. Yield: 34.5 g (83.3%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=O)=[CH:7]2)([O-:3])=[O:2].[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([C:13]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)=[O:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: O=C(c1cc2cc([N+](=O)[O-])ccc2[nH]1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 5-nitroindole-2-carboxylic acid (J. Am. Chem. Soc., 4621 (1958)] and 4-benzylpiperidine according to the method described in Example 1/c. Mp.: 220-224° C. (diethylether).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](O)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.CO>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][OH:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Solvent: CO
Solvent: C1CCOC1
Product: OCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
A solution of benzo[1,3]dioxol-5-yl-acetic acid (2.5 g, 13.9 mmol) in tetrahydrofuran (15 ml) under argon at −10° C. was treated dropwise with borane-dimethylsulfide complex (1.45 ml, 15.3 mmol). The mixture was stirred at ambient temperature for 1.5 hours (CAUTION—exothermic reaction). The orange solution was cooled to ˜5° C. (ice bath) and methanol (1.4 ml) was added. After 0.5 hour at room temperature, the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried and evaporated to give a yellow oil (1.95 g, 84%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.[CH:13](O)=O>CO.[Fe]>[CH3:1][N:2]1[C:3]2[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=2[N:9]=[CH:13]1
Reactant: CNc1cc(O)ccc1[N+](=O)[O-]
Reactant: O=CO
Agent: [Fe]
Solvent: CO
Product: Cn1cnc2ccc(O)cc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a suspension of 3-methylamino-4-nitro-phenol (300 mg, 1.786 mmol) in formic acid (4 mL) was added iron powder (1.0 g, 17.86 mmol). The reaction mixture was stirred at 100° C. overnight, then it was cooled to room temperature and diluted with methanol. The insolubles were filtered and washed with methanol. The filtrate was concentrated in vacuo and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-15% methanol/dichloromethane afforded 249 mg of 3-methyl-3H-benzoimidazol-5-ol as a light brown solid (94% yield): 1H NMR (DMSO-d6) δ 3.71 (s, 3H), 6.69 (dd, 1H), 6.81 (d, 1H), 7.40 (d, 1H), 7.94 (s, 1H), 9.3 (broad s, 1H); MS (m/z) 149 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:25]2[C@:20]([CH3:27])([CH2:21][CH2:22][C:23](=[O:26])[CH:24]=2)[C@@H:19]2[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]2)([CH3:16])[CH2:14][C:13](=[O:28])[CH2:12]3)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:16][C@:15]12[CH2:17][CH2:18][C@H:19]3[C@@H:10]([CH2:9][NH:8][C:25]4[C@:20]3([CH3:27])[CH2:21][CH2:22][C:23](=[O:26])[CH:24]=4)[C@@H:11]1[CH2:12][C:13](=[O:28])[CH2:14]2
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H]3CC(=O)C[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CNC4=CC(=O)CC[C@@]43C)[C@@H]1CC(=O)C2
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a solution of 6-t-butyloxycarbonyl-6-azaandrost-4-ene-3,16-dione (11, R2 =H) (693 mg, 1.79 mmoles) in methylene chloride (12 mL) was added trifluoroacetic acid (3mL) and the mixture stirred at room temperature for 1.75 hours. The mixture was evaporated in vacuo and the residue dissolved in methylene chloride and shaken with 10% NaHCO3. The resulting solid was filtered and dried in a vacuum oven at 60° C. to give (12, R2 =H) as a white solid. NMR (CDCl3): δ 0.98 (s, 3H, 18-Me); 1.36 (s, 3H, 18-Me); 4.88 (s,1H; NH); 5.09 (s, 1H, 4-H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1([CH2:18][OH:19])[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.CN([CH:23]=[O:24])C>CCCCCC>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1([C:18]([O:24][CH3:23])=[O:19])[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1
Reactant: CN1CCC(CO)(c2cc(F)ccc2F)CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: COC(=O)C1(c2cc(F)ccc2F)CCN(C)CC1
Temperature: 90 °C
Yield: 92 %

Procedure:
NaH (158 mg, 6.56 mmol) was added to 4-(2,5-difluorophenyl)-4-hydroxymethyl-1-methylpiperidine (1.45 g, 6.56 mmol) in DMF (20 mL). The slurry was heated to 90° C. for 6 h. The reaction was diluted with hexane (200 mL), washed with water (200 mL), brine (50 mL), dried (MgSO4), and concentrated to yield 1.21 g (92%) of the title compound as a white crystalline solid; 1H NMR (400 MHz, CDCl3) δ 6.98 (dd, 1H), 6.54 (dt, 1H), 6.48 (dd, 1H), 4.37 (s, 2H), 2.84 (m, 2H), 2.31 (s, 3H), 1.97 (4H, pentuplet), 1.71 (m, 2H) ppm.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:27].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][N:16]3[C:21]4[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=4[O:19][CH2:18][C:17]3=[O:27])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: C1CC(OCC2CC2)CCN1
Reactant: O=C1COc2cc(F)ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2cc(F)ccc2N1CCCN1CCC(OCC2CC2)CC1
Yield: 50.1 %

Procedure:
4-Cyclopropylmethoxypiperidine (0.042 g, 0.27 mmol), 4-(3-chloropropyl)-7-fluoro-4H-benzo[1,4]oxazin-3-one (0.08 g, 0.32 mmol), K2CO3 (0.075 g, 0.54 mmol) and KI (0.081 g, 0.54 mmol) were mixed according to GP3. Purified by prep TLC (SiO2; heptanes/EtOAc 1:1) to give the title compound (0.049 g, 42%). Rf=0.47 (CH2Cl2/MeOH 10:1); 1H NMR (CDCl3) d 7.09-7.04 (m, 1H), 6.75-6.69 (m, 2H), 4.57 (s, 2H), 3.95 (t, J=7.2 Hz), 3.34-3.25 (m, 3H), 2.77-2.70 (m, 2H), 2.36 (t, J=6.8 Hz, 2H), 2.11-2.02 (m, 2H), 1.93-1.76 (m, 4H), 1.64-1.54 (m, 2H), 1.09-0.98 (m, 1H), 0.55-0.49 (m, 2H), 0.21-0.16 (m, 2H); 13C NMR (CDCl3) d 163.6, 158.9 (d, J=243.7 Hz), 146.3 (d, J=11.6 Hz), 125.2 (d, J=3.1 Hz), 115.8 (t, J=11.2 Hz), 109.2 (d, J=22.3 Hz), 105.2 (dd, J=25.7 Hz, J=3.8 Hz), 75.0, 72.8, 67.8 (t, J=8.1 Hz), 55.4, 51.6 (J=9.2 Hz), 39.9 (t, J=12.3 Hz), 31.7, 24.9, 11.1, 3.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[N:16]([CH3:24])[C:17]([C:21](O)=[O:22])=[C:18]([CH3:20])[N:19]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:21]([C:17]1[N:16]([CH3:24])[C:15]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]2=[O:25])=[N:19][C:18]=1[CH3:20])=[O:22])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)n(C)c1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)n(C)c1C(=O)NCc1ccccc1
Yield: 62 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-1,4-dimethyl-1H-imidazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a colorless solid in 62% yield: mp 232-233° C.; 1H NMR (300 MHz, CDCl3) δ 7.43-7.29 (m, 10H), 7.19 (d, J=7.7 Hz, 1H), 6.17 (t, J=5.6 Hz, 1H), 6.09 (dd, J=7.7, 2.5 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.02 (s, 2H), 4.62 (d, J=5.6 Hz, 2H), 3.67 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 168.3, 163.3, 160.9, 141.5, 138.0, 137.8, 136.8, 134.7, 128.84, 128.8, 128.6, 127.7, 127.7, 127.6, 123.5, 102.8, 97.8, 70.6, 43.6, 32.7, 15.2; MS (ES+) m/z 429.3 (M+1).
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)=[N:5][CH:4]=1)=O.Cl.[CH:24]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][CH2:31][NH:32][CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=3)=[N:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC(=O)c1ccc(Oc2ncc(C=O)c3ccccc23)cc1
Reactant: NCCC1CCCCC1
Agent: Cl
Product: NC(=O)c1ccc(Oc2ncc(CNCCC3CCCCC3)c3ccccc23)cc1

Procedure:
Using the procedure outlined in Example 96, 4-(4-formylisoquinolin-1-yloxy)-benzamide (Preparation 16) and 2-cyclohexylethylamine hydrochloride were converted to the title compound: RT=2.70 min; m/z (ES+)=404.0 [M+H]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]([S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:36]=[CH:35][C:18]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[N:30]([CH:31]([CH3:33])[CH3:32])[C:29]([CH3:34])=[N:28][CH:27]=4)[CH:23]=[CH:22][N:21]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])=[O:7])=[CH2:5]>CO>[CH3:1][O:2][CH2:5][CH2:4][S:6]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:36]=[CH:35][C:18]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[N:30]([CH:31]([CH3:32])[CH3:33])[C:29]([CH3:34])=[N:28][CH:27]=4)[CH:23]=[CH:22][N:21]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:7])=[O:8]
Reactant: C[O-]
Reactant: C=CS(=O)(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Agent: [Na+]
Solvent: CO
Product: COCCS(=O)(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium methoxide (40 mg 0.74 mmol) was added to 2-{4-[4-(vinylsulphonyl)piperazin-1-yl]anilino}-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 29; 300 mg 0.64 mmol) in MeOH (4 ml). After stirring at room temperature for 5 hours, the reaction was evaporated. After chromatography on silica gel using MeOH:DCM:EtOAc (5:47.5:47.5) and trituration with ether, the title compound was obtained as a yellow solid. NMR: 1.41 (d, 6H), 2.47 (s, 3H), 3.13 (m, 4H), 3.26 (4H alongside exchangeables), 3.37 (t, 2H), 3.67 (t, 2H), 5.69 (septuplet, 1H), 6.93 (d, 2H), 6.96 (d, 1H), 7.39 (s, 1H), 7.49 (d, 2H), 8.32 (d, 1H), 9.18 (s, 1H); m/z 500.
Reaction SMILES: O[CH2:2][C:3]1[C:4]2[N:5]([C:9]([C:12]3[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.COCCN(S(F)(F)[F:32])CCOC.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:32][CH2:2][C:3]1[C:4]2[N:5]([C:9]([C:12]3[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1ncc(C#N)c(-c2cnc3c(CO)cccn23)n1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CSc1ncc(C#N)c(-c2cnc3c(CF)cccn23)n1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
4.23 g of the 4-[8-(hydroxymethyl)imidazo[1,2-a]pyridin-3-yl]-2-(methylthio)pyrimidine-5-carbonitrile [147-2] was dissolved in 500 mL of chloroform, then 5.2 mL of bis-(2-methoxyethyl)aminosulfur trifluoride was added thereto at −40° C., and stirred at the same temperature for 1 hour. 2.6 mL of bis-(2-methoxyethyl)aminosulfur trifluoride was further added, and stirred at the same temperature for 1 hour. Thereto, a saturated aqueous solution of sodium hydrogen carbonate was slowly added, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine in the subsequent order, and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the thus obtained residue was dissolved in a small amount of chloroform and solidified by adding diethyl ether, to obtain 3.43 g of 4-[8-(fluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-(methylthio)pyrimidine-5-carbonitrile [147-3] as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][C:25]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)[CH2:22][NH:21][C:20]1=[O:36]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][C:25]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:27]=3)[CH2:22][NH:21][C:20]2=[O:36])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NCc2cc(Cc3ccccc3)ccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2cc(Cc3ccccc3)ccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 159-166° C. C27H25N3O3F2 (MW=477); mass spectroscopy: 477.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[S:14][C:13]=2[C:12]([C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1Br
Reactant: OB(O)c1cccc2c1sc1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Nc1ccccc1-c1cccc2c1sc1ccccc12
Yield: 78.9 %

Procedure:
The 300 ml round-bottom flask equipped with reflux condenser and magnetic stirrer was charged with 2-bromoaniline (8.00 g, 46.5 mmol), 4-dibenzothiopheneboronic acid (10.5 g, 46.5 mmol), potassium carbonate (20 g, saturated solution in water), tetrakis(triphe-nylphoshine)palladium (0) (500 mg) and 100 ml of toluene. The reaction mixture was refluxed overnight under nitrogen atmosphere, filtered through silica plug and evaporated. Product was purified by column chromatography on silica gel, eluent hexane/ethyl acetate 4/1 mixture, providing 2-(dibenzo[b,d]thiophen-4-yl)aniline (10.1 g) as yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C1(C)C=CC=CC=1.Cl>[CH3:23][S:24]([O:15][C:6]1[CH:7]=[CH:8][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
21.00 g (0.102 mol) of 2,4-di-tert-butylphenol and 11.84 g (0.117 mol) of triethylamine were dissolved in 200 mL of toluene followed by dropping in 12.24 g (0.107 mol) of methanesulfonyl chloride over the course of 30 minutes at 10° C. Following completion of dropping, the mixture was stirred for 2 hours at 25° C. and the 2,4-di-tert-butylphenol was confirmed to no longer be present. The reaction liquid was placed in 3% aqueous hydrochloric acid solution and following separation of the organic layer, was washed once with saturated aqueous NaHCO3 solution and twice with saturated brine followed by drying with MgSO4 and concentrating. The resulting crude crystals were purified by crystallization with n-heptane to obtain 25.8 g (yield: 90%) of 2,4-di-tert-butylphenyl methanesulfonate (white crystals, melting point: 63° C.).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14](=[O:16])[CH3:15]>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:1]([O-:4])=[O:2])=[CH:8][C:7]=1[NH:13][C:14](=[O:16])[CH3:15]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C)cc1C
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(C)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of concentrated nitric acid (20 mL) and concentrated sulfuric acid (20 mL) was cooled in an ice-salt bath to 0° C. N-(2,4-dimethylphenyl)acetamide (9.5 g) was added portionwise at such a rate to maintain the temperature below 5° C. The mixture was then allowed to stir in the cold for an additional one hour.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:26])[C:13]([N:23]([CH3:25])[CH3:24])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH3:15])=[CH:8][CH:7]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:51]I>C(Cl)Cl>[I:51][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:26])[C:13]([N:23]([CH3:25])[CH3:24])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH3:15])=[CH:8][CH:7]=1
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCCO)cc1)N(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCCI)cc1)N(C)C
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
14.5 g (0.041 mol) of 1-[4-(3-Hydroxypropylamino)phenyl]-2-dimethylamino-2-benzyl-butan-1-one, 6.96 g (0.1 mol) of imidazole and 26.8 g (0.1 mol) of triphenyl phosphine are dissolved in 100 ml of methylene chloride. To the solution are added 20.8 g (0.082 mol) of iodine and stirred at room temperature (about 20° C.) for 20 min. 200 ml of methylene chloride are added to the reaction mixture and washed with aqueous solution of sodium sulfite and water, and dried over MgSO4. After distilling off the methylene chloride, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:4) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 0.68 (t, 3H), 1.82-1.88 (m, 1H), 2.02-2.35 (m, 3H), 2.35 (s, 6H), 3.17 (d, 1H), 3.20 (d, 1H), 3.27 (t, 2H), 3.34-3.37 (m, 2H), 4.17 (br, 1H), 6.53 (d, 2H), 7.15-7.28 (m, 5H), 8.32 (d, 2H).