Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[C:2]([O-:7])(=[O:6])[CH:3]([CH3:5])[OH:4].[NH4+]>O>[C:2]([OH:7])(=[O:6])[CH:3]([CH3:5])[OH:4].[C:2]([O-:7])(=[O:6])[CH:3]([CH3:5])[OH:4].[NH4+:1]
Reactant: N
Agent: CC(O)C(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(O)C(=O)O

Procedure:
The process resulted in the mixture containing a viscous phase that adhered to the bottom of the stainless steel beaker that it had been heated and mixed in. Based on an ammonia analysis of the residue, and the overall mass balance, it appeared that there was about 80 wt % removal of ammonia. About 27 wt % of the ammonia was removed in overhead vapors, while about 53 wt % of the ammonia was converted to new lactamide that was not present at the start of the run. About 20 wt % of the ammonia was not removed from the system. The final water content was about 0.4 wt %. Salt solutions provide significant boiling point elevation, and water is strongly attracted to ammonium lactate, and thus it would be unlikely to obtain a concentrated lactic acid/ammonium lactate solution with less than 0.4 wt % water at an exit temperature of 160° C. Lactic dimer and trimer levels increased 2-fold and 3-fold, respectively in the bottoms product relative to their amounts in the feed stream.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[CH3:15][S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:15][S:16]([CH2:19][CH2:20][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)(=[O:18])=[O:17]
Reactant: C=CS(C)(=O)=O
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(CCS(C)(=O)=O)c2)OC1(C)C
Temperature: 90 °C
Yield: 63.4 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.3 g, 27.31 mmol), methylvinyl sulfone (4.349 g, 40.97 mmol) and DBU (2.042 mL, 13.66 mmol) were suspended in dry acetonitrile (54.63 mL) in a sealed glass bomb and heated in a sand bath at 90° C. overnight. The resulting reaction mixture was concentrated to a solid and the solids were washed with hexanes to yield 5.2 g (63.4%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[N-:21]=[N+:22]=[N-:23].[Na+].O.C([O-])(O)=O.[Na+]>CS(C)=O>[N:21]([CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CBr)c2F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN=[N+]=[N-])c2F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
2-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (2.00 g, 5.32 mmol) and sodium azide (0.346 g, 5.32 mmol) were combined in DMSO (10 mL) and stirred 16 h at 25° C. at which time TLC indicated complete conversion (10% Et2O/hexanes). Water (150 mL) and saturated aqueous NaHCO3 (30 mL) were added and the mixture stirred vigorously for 30 min. The resultant precipitate was filtered off, washed with water, and air dried to give 2-{[3-(azidomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (1.76 g, 5.21 mmol, 98% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, J=0.73 Hz, 1H), 7.96 (d, J=0.73 Hz, 1H), 7.48-7.60 (m, 2H), 4.60 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:12]CCNC)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:37]1[CH:41]=[CH:40][N:39]=[C:38]1[NH:42][C:43]([N:45]1[CH:49]=[CH:48]N=[CH:46]1)=[O:44]>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:12][CH2:48][CH2:49][N:45]([CH3:46])[C:43]([NH:42][C:38]2[NH:37][CH:41]=[CH:40][N:39]=2)=[O:44])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CNCCCCN(Cc1ncc(C)cc1C)Cc1nccc2ccccc12
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(CCCCN(C)C(=O)Nc2ncc[nH]2)Cc2nccc3ccccc23)c(C)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a warm (70° C.), stirred, solution of N-(3,5-Dimethyl-pyridin-2-ylmethyl)-N-isoquinolin-1-ylmethyl-N′-methyl-butane-1,4-diamine (0.204 g, 0.56 mmol) and DIPEA (0.59 mL, 3.39 mmol) in DMF (5 mL) was added freshly prepared imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equivs). After 1.5 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (50 mL) and washed with water (5×10 mL). The organic phase was dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 234 mg (86%) of COMPOUND 156 as a white solid. 1H NMR (CDCl3) δ 1.26-1.34 (m, 2H), 1.42-1.48 (m, 2H), 2.09 (s, 3H), 2.28 (s, 3H), 2.58 (t, 2H, J=7.5 Hz), 2.74 (s, 3H), 3.10 (t, 2H, J=7.5 Hz), 3.80 (s, 2H), 4.17 (s, 2H), 6.68 (s, 2H), 7.24-7.26 (m, 1H), 7.35-7.40 (m, 1H), 7.52-7.60 (m, 2H), 7.73 (d, 1H, J=8.1 Hz), 7.97 (d, 1H, J=8.7 Hz), 8.22 (s, 1H), 8.41 (d, 1H, J=5.7 Hz); 13C NMR (CDCl3) δ 18.33, 18.40, 23.93, 25.82, 34.90, 48.89, 54.57, 59.86, 59.96, 120.82, 126.71, 126.92, 127.20, 128.12, 130.13, 132.27, 133.15, 136.62, 139.08, 141.76, 145.16, 146.87, 154.33, 156.14, 159.39; ES-MS m/z 472 (M+1). Anal. Calcd. For C27H33N7O.0.5H2O: C, 67.48; H, 7.13; N, 20.40. Found: C, 67.57; H, 7.08; N, 20.52.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]3)=[C:18]([F:30])[CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6]C=CC=1.CN(C)[C@@H]1CCN(C2C=CC(NC(=O)C3C=CC(O)=CC=3)=CC=2F)C1.C1(CBr)CC1>>[CH:2]1([CH2:1][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:26][CH2:25][C@@H:24]([N:27]([CH3:29])[CH3:28])[CH2:23]4)=[C:18]([F:30])[CH:17]=3)=[O:14])=[CH:31][CH:32]=2)[CH2:7][CH2:6]1
Reactant: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3ccc(OCc4ccccc4)cc3)cc2F)C1
Agent: BrCC1CC1
Agent: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2F)C1
Product: CN(C)[C@@H]1CCN(c2ccc(NC(=O)c3ccc(OCC4CC4)cc3)cc2F)C1

Procedure:
(R)-4-Benzyloxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]benzamide underwent debenzylating hydrogenation by method B. The resulting (R)-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-hydroxybenzamide was alkylated with cyclopropylmethyl bromide by method H. This resulted in the product with the molecular weight of 397.50 (C23H28N3O2); MS (ESI): 398 (M+H+).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[CH2:3][CH2:2]1.O.[CH3:14][N:15]=[C:16]=[O:17]>C1C=CC=CC=1>[CH3:14][NH:15][C:16]([O:12][N:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH2:2][CH2:3]1)=[O:17]
Reactant: ON=C1CCOc2ccccc21
Reactant: CN=C=O
Solvent: c1ccccc1
Solvent: O
Product: CNC(=O)ON=C1CCOc2ccccc21
Reaction time: 8 h

Procedure:
A 60 g (0.37 mole) portion of 4-chromanone oxime in 770 ml of benzene was refluxed until all water was removed via a Dean-Stark trap, 0.5 hrs. The solution was cooled to 25-30°, treated with 0.5 ml of triethylamine followed by the dropwise addition of 20 ml (0.33 mole) of methyl isocyanate at less than 70°. The reaction mixture was refluxed for 3 hrs., stored at room temperature overnight, filtered, and stripped of benzene under reduced pressure. The residue was treated with 200 ml of ether, cooled 20 min. and filtered. The white crystalline product was washed with 100 ml of ether and dried, m.p. 123°-126°. Yield: 64 g (88%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9](Cl)[CH:8]=[C:7]2[C:3]=1[C:4]([C:12]([OH:14])=[O:13])=[CH:5][NH:6]2.N1[C:23]2[C:18](=CC=CC=2)[CH:17]=C1>>[CH:23]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]([C:12]([OH:14])=[O:13])=[CH:5][NH:6]3)[CH2:18][CH2:17]1
Reactant: O=C(O)c1c[nH]c2cc(Cl)cc(Cl)c12
Reactant: c1ccc2[nH]ccc2c1
Product: O=C(O)c1c[nH]c2cccc(C3CC3)c12

Procedure:
Compound 4 was converted into the target indole acid using a similar procedure to Example 42.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[N:6]=2)[CH2:3][CH2:2]1.[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:24]4/[C:22](=[O:23])[NH:21][C:19](=[O:20])[NH:18]/4)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CSc1nc(NC2CC2)n2ncc(C=O)c2n1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CSc1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reaction time: 3 h

Procedure:
4-(Cyclopropylamino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine-8-carbaldehyde (1.0 eq, 3.00 g, 12.03 mmol) was suspended in ethanol (40 ml). Hydantoin (1.5 eq, 1.81 g, 18.08 mmol) and piperidine (1.5 eq, 1.78 ml, 18.01 mmol) were added. The mixture was heated at reflux under vigorous magnetic stirring for 3 hours. After cooling of the reaction mixture, the precipitate was filtered, washed with ethanol, then with a mixture of ethanol and water (1:1). After drying in vacuo, (Z)-5-((4-(cyclopropylamino)-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione was isolated as a yellow solid (3.80 g, 95%). LCMS (ES): >85% pure, m/z 332 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=O)=[CH:11][CH:10]=1)#[N:2].P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][CH:11]=2)[C:20]2[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Product: COC(=O)c1cccc2nc(Cl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 28 %

Procedure:
A mixture of methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-oxo-2,3-dihydrobenzimidazole-7-carboxylate (8.02 g) in phosphorus oxychloride (30 ml) was heated under reflux for 8 hours. The reaction mixture was concentrated and the resulting residue was poured into ice-water. The mixture was extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was purified by column chromatography on silica gel to give crystals, which were recrystallized from chloroform-methanol to afford colorless needles (2.2 g, 28%), m.p. 154°-157° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13])#[N:2].[Cl-].[NH4+].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH:16]1[C:1]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][NH:7][C:6]3=[O:13])=[N:2][N:18]=[N:17]1
Reactant: N#Cc1ccc2nc[nH]c(=O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2ccc(-c3nnn[nH]3)cc12
Temperature: 100 °C
Yield: 89.5 %

Procedure:
6-Cyanoquinazolin-4-one (0.5 g) in dimethylformamide (5 ml) was treated with ammonium chloride (0.33 g) and sodium azide (0.38 g) and heated at 100° C. under nitrogen for 45 minutes. The resulting mixture was cooled, diluted with ethyl acetate and filtered. The filter cake was washed with dimethylformamide and ethyl acetate to give the title compound (0.56 g) as a cream solid; δH [2H6]DMSO 13.00(1H, bs), 8.70(1H, d), 8.40(1H, dd), 8.38(1H, bs), 8.05(1H, s), 7.68(1H, d); m/z (M−1+) 213.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1cccc(I)c1C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(C)cccc1I
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
A solution of 2-iodo-6-methylbenzoic acid (I57) (2.50 g, 9.54 mmol) in DCM (30 mL) and methanol (8 mL) under an atmosphere of nitrogen was cooled to 0° C. and trimethylsilyldiazomethane (2.0 M in diethyl ether, 9.54 mL, 19.1 mmol) was added dropwise. The reaction was stirred at 0° C. for 45 minutes and then quenched with 2 M aq. HCl (50 mL). DCM (150 mL) was added to the quenched reaction and the layers were separated. The aqueous layer was extracted with DCM (100 mL), the organics were combined and washed with sat. aq. NaHCO3 (100 mL), water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I58) (2.00 g, 76% yield) as a colourless oil; 1H NMR (400 MHz, CDCl3) δ 7.65 (ddd, J=7.9, 1.0, 0.5 Hz, 1H), 7.19-7.15 (m, 1H), 6.99 (t, J=7.8 Hz, 1H), 3.95 (s, 3H), 2.33 (s, 3H). LCMS Method C: rt 6.08 min; m/z 277.0 [M+H]+.
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1>>[CH2:4]([O:3][CH2:2][N:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[N:14][C:15]1=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ClCOCc1ccccc1
Reactant: O=c1ncc(Br)c[nH]1
Product: O=c1ncc(Br)cn1COCc1ccccc1
Reaction time: 20 h
Yield: 29 %

Procedure:
was prepared as described in Example 3 from benzyl chloromethyl ether (see Preparation 1a and 1b) (4 mmol) and 5-bromopyrimidin-2-one by allowing the reaction to proceed for 20 hours at room temperature; yield 29% (0.34 g), m.p. 169° C. 1H NMR (CDCl3): δ4.65 (CH2Ph), 5.30 (CH2O), 7.18 (Ph), 7.78 and 8.40 (H-4, H-6, J 4 Hz). IR(KBr): 1670 cm-1 (CO).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])[CH2:2][CH2:3][CH3:4].[C:16](OC(=O)C)(=[O:18])[CH3:17].[CH3:23][CH2:24][O:25][C:26](OCC)(OCC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C.C1CCCCC1.CO>[C:16]([N:11]1[C:12]2[C:8](=[CH:7][C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=2)[C:9](=[C:26]([O:25][CH2:24][CH3:23])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:10]1=[O:15])(=[O:18])[CH3:17]
Reactant: CCCC(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CO
Product: CCCC(=O)c1ccc2c(c1)C(=C(OCC)c1ccccc1)C(=O)N2C(C)=O

Procedure:
Prepared from 5-butyryl-2-indolinone, acetic anhydride and triethyl orthobenzoate Rf=0.79 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27](O)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1.[NH2:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:35]3[CH2:36][CH2:37][C@H:33]([NH2:32])[CH2:34]3)=[O:28])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: N[C@H]1CCNC1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](N)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
2.92 g of N,N'-carbonyldiimidazole were added to a solution of 6.70 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid in 50 ml of dry acetonitrile, and the resulting mixture was stirred at room temperature for 1 hour. A solution of 1.55 g of (3S)-3-aminopyrrolidine in 10 ml of dry acetonitrile was then added to the mixture, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with water and with an aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 4.10 g of the title compound, as a powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19]C)=[O:18])[CH:15]=2)[NH:10][N:9]=1.Cl>CO.O1CCCC1.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=2)[NH:10][N:9]=1
Reactant: COC(=O)c1ccc2[nH]nc(-c3ccccc3F)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2[nH]nc(-c3ccccc3F)c2c1
Temperature: 70 °C
Yield: 98.9 %

Procedure:
A total of 1.6 g of methyl 3-(2-fluorophenyl)-1H-5-indazolecarboxylate was dissolved in 15 ml of a 1:1 solvent mixture of methanol and tetrahydrofuran, 2 ml of 5 N aqueous sodium hydroxide solution was added, followed by heating at 70° C. for 6 hours. After cooling to room temperature, the reaction mixture was added with diluted hydrochloric acid and was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 1.5 g of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.Cl.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>>[ClH:1].[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:2][CH:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:17]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1ccc(CC=CCCl)cc1
Agent: Cl
Product: CCN(CC)CC=CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 250 ml of diethylamine at 0° C. add 30 g (0.14 mole) of 1chloro-4-(4-nitrophenyl)-2-butene over a 30 minute period. Stir for 16 hr at room temperature. Remove the solvent in vacuo. Extract the residue with 200 ml of 10% hydrochloric acid. Extract the resulting solution 2×100 ml ethyl acetate and discard. Adjust the pH of the water layer to about 12 with 10% sodium hydroxide. Extract 3×100 ml methylene chloride. Take the combined organic extracts and dry over Na2SO4. Remove the solvent in vacuo. Dissolve the residue in 100 ml ethanol, and add 1.5 equivalents of concentrated hydrochloric acid. Evaporate off the solvent, and crystallize the residue with acetone to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:12](=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=[N:14]4)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:28](Br)[CH:29]=[CH2:30]>COCCOC.C1(C)C=CC=CC=1>[CH2:30]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:21]3[C:12](=[C:13]4[C:18](=[CH:19][CH:20]=3)[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=[N:14]4)[N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: C=CCOc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Temperature: 35 °C
Reaction time: 24 h

Procedure:
4-p-hydroxyphenyl-7-phenyl-1,10-phenanthroline (0. 348 g) is reacted with Na metal (0.023 g) in ethylene glycol dimethyl ether (100 mL). To this mixture is added a solution of allylbromide (0.125 g) in ethylene glycol dimethyl ether (10 mL). The resulting mixture is stirred at 35° C. for 24 hours, or until the reaction is judged complete by TLC. The reaction mixture is diluted with toluene, washed with 10% NaOH, washed with water and dried over MgSO4. Roto-evaporation of the solvent gives a residue that is purified by column chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([C:20](O)=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:24].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[OH:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([C:20]([N:53]2[CH2:54][CH2:55][N:50]([CH2:49][CH2:48][OH:47])[CH2:51][CH2:52]2)=[O:21])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:24]
Reactant: Cn1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C(=O)O)ccc21
Reactant: OCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C(=O)N3CCN(CCO)CC3)ccc21
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
In a similar manner to Step 1 of Example 20, Compound 157 (20.0 mg, 0.0587 mmol) was dissolved in DMF (1 mL), and the solution was treated with EDCI (23 mg, 0.12 mmol), HOBT monohydrate (7.9 mg, 0.059 mmol) and 1-(2-hydroxyethyl)piperazine (31 mg, 0.24 mmol). The mixture was added with water and ethyl acetate and extracted with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9 and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, and the solution was added with hexane and stirred for 30 minutes. The solid was collected by filtration and washed with hexane, followed by drying under reduced pressure to obtain Compound 159 (18.5 mg, yield 70%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].Cl[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([NH2:30])[N:21]=1.[OH-].[Na+].CO>O.Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:23]=[C:22]([NH2:30])[N:21]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Reactant: Nc1ccc(Cc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1nc(Nc2ccc(Cc3ccnc4[nH]ccc34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
32 mg (0.11 mmol) of 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)aniline and 26 mg (0.12 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 5 ml of water and 0.07 ml of 2N hydrochloric acid. The reaction mixture is heated at reflux for 20 hours. After cooling, the mixture is made alkaline using dilute aqueous sodium hydroxide solution, a little methanol is added and the mixture is extracted with ethyl acetate. The extract is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[OH:22][CH:23]1[CH2:26][N:25]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=2)[CH2:24]1>>[OH:22][CH:23]1[CH2:26][N:25]([C:27]2[N:28]=[CH:29][C:30]([NH:33][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:21])=[CH:31][CH:32]=2)[CH2:24]1
Reactant: Nc1ccc(N2CC(O)C2)nc1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: O=C(Nc1ccc(N2CC(O)C2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1

Procedure:
The process is carried out according to the method described in example 2, using 0.5 g (1.74 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 0.35 g (2.09 mmol) of 2-(3-hydroxyazetidin-1-yl)-5-aminopyridine, obtained in step 10.2 (Compound Ve).