Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([F:24])[CH2:23][NH:22][CH2:21]4)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1.O>C(Cl)Cl>[CH:36]1([C:39]([N:22]2[CH2:23][C:20]([C:17]3[CH:18]=[CH:19][C:14]([C:11]4[CH2:10][C:9]([C:4]5[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=5)([C:25]([F:27])([F:26])[F:28])[O:13][N:12]=4)=[CH:15][CH:16]=3)([F:24])[CH2:21]2)=[O:40])[CH2:38][CH2:37]1
Reactant: O=C(Cl)C1CC1
Reactant: FC1(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(C1CC1)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of the 5-(3,5-dichlorophenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 15, 65 mg) in 2 mL CH2Cl2 was added triethyl amine (50 μL) followed by cyclopropane carbonyl chloride (19 mg). The reaction was allowed to stir at room temperature for 30 minutes. Water (5 mL) was added. The reaction was diluted with an additional 5 mL of CH2Cl2, stirred for 5 minutes at room temp then passed through a phase separation tube. The CH2Cl2 layer was collected and condensed. The crude material was adsorbed on silica and chromatographed on a 12 g silica column, eluting with a gradient of 0% to 100% ethyl acetate in heptane. Fractions containing the desired material were combined and concentrated. Et2O (˜½ mL) was added to the resulting film. Placing the flask on high vacuum overnight resulted in formation of a white foam. Yield 67 mg (98%) of the desired product. 1H NMR (CDCl3) δ ppm 7.76 (d, 2H), 7.63-7.51 (s, 4H), 7.45 (s, 1H), 4.8-4.7 (m, 1H), 4.6-4.3 (m, 3H), 4.12 (d, 1H), 3.74 (d, 1H), 1.6-1.4 (m, 1H), 1.07 (m, 2H), 0.86 (m, 2H). LC/MS retention time=3.654 minutes, MS calculated for (C23H18Cl2F4N2O2), 500.07; found 501.0 M+H.
Reaction SMILES: [N:1]1([CH2:7][CH:8]([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[CH:24]=[CH:23][N:22](COCC[Si](C)(C)C)[C:18]=4[N:19]=[CH:20][N:21]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.ClCCl.C(O)(C(F)(F)[F:48])=O>CO>[N:19]1[C:18]2[NH:22][CH:23]=[CH:24][C:17]=2[C:16]([C:14]2[CH:13]=[N:12][N:11]([CH:8]([CH2:9][CH3:10])[CH2:7][N:1]3[CH2:6][CH2:5][N:4]([C:33]([C:34]4[CH:39]=[CH:38][C:37]([F:48])=[CH:36][CH:35]=4)=[O:40])[CH2:3][CH2:2]3)[CH:15]=2)=[N:21][CH:20]=1
Reactant: CCC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CCC(CN1CCN(C(=O)c2ccc(F)cc2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of 4-{1-[1-(piperazin-1-ylmethyl)propyl]-1H-pyrazol-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.010 g, 0.022 mmol, from step 4 in example 1) and benzoyl chloride, 4-fluoro-(3.4 uL, 0.028 mmol) in dichloromethane (1 mL, 20 mmol) was stirred for 2 hour. 1 mL TFA was added. After 1 hour, the solvent was evaporated by rotary evaporation to give a glass which was stirred in 1 mL MeOH and 50 microL EDA for 2 hours. The reaction was purified by LCMS (pH 10) to give 3.1 mg white solid (52% yield). 1H NMR (400 MHz, DMSO): δ 12.0 (1H, br); 8.62 (1H, s); 8.599 (1H, s); 8.22 (1H, s); 7.55 (1H, m); 7.18 (1H, m); 6.95 (1H, d); 6.91 (1H, d); 4.4 (1H, m); 3.43 (2H, br); 3.18 (2H, br); 2.82 (1H, m); 2.61 (1H, m); 2.47 (2H, br); 2.24 (2H, br); 1.78 (2H, m); 0.65 (3H, t). LCMS (M+1); 448.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][CH2:17][CH2:18][C:19](=O)[CH2:20][CH2:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:18]([C:19]1([CH2:20][CH2:21][CH3:22])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH2:17][CH3:16]
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CCCC(=O)CCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCC1(CCC)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 100 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.120 g, 0.550 mmol), 4-heptanone (1.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (1.5 mL) was stirred for 1 h at 100° C. in a sealed tube. Then, this mixture was stirred for 2 h at 120° C. and stirring was continued for 2 h at 110° C. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate, drying over magnesium sulfate, filtration and concentration at reduced pressure gave a solid. This solid was triturated with dichloromethane (10 mL), and the precipitate was collected by filtration. Then, the obtained solid was stirred at 60° C. in ethyl acetate (5 mL). After 10 min, the mixture was cooled, and the precipitate was collected by filtration to afford the title compound (0.0406 g, 23%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([NH:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][N:23]([C:25]([O:27]C(C)(C)C)=O)[CH2:22]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([O:32][CH3:33])[CH:3]=1.[C:34](O)(=O)[CH:35]=C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>Cl.CO.CN(C=O)C>[Cl:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[CH:6][C:5]([NH:11][CH2:12][C:13]([N:15]2[CH2:16][CH2:17][N:18]([CH:21]3[CH2:24][N:23]([C:25](=[O:27])[CH:34]=[CH2:35])[CH2:22]3)[CH2:19][CH2:20]2)=[O:14])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(Cl)c(C(C)C)cc1NCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Reactant: C=CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: C=CC(=O)N1CC(N2CCN(C(=O)CNc3cc(C(C)C)c(Cl)cc3OC)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A mixture of tert-butyl 3-(4-(2-(4-chloro-5-isopropyl-2-methoxyphenylamino)acetyl)piperazin-1-yl)azetidine-1-carboxylate (102 mg, 0.212 mmol) in HCl/MeOH (2.86 M, 5 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuo to afford the crude product, the crude was dissolved in DMF (5 mL) at RT, acrylic acid (17 mg, 0.233 mmol), BOP (113 mg, 0.254 mmol) and DIEA (82 mg, 0.636 mmol) were added and the resulting mixture was stirred at RT for 1 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (77 mg, 85% yield, 2 steps). ESI-MS m/z: 435.4[M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H]1O[C@H](CO)[C@@H](O)C1)#[C:2][CH3:3]>P([O-])([O-])([O-])=O>[C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[NH:8][CH:17]=1)#[C:2][CH3:3]
Reactant: CC#Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Product: CC#Cc1c[nH]c(=O)[nH]c1=O
Reaction time: 24 h

Procedure:
To a stirred solution of 2′-deoxy-5-propynyluridine (European Patent Specification No. 272065) (20 g, 75 mmol) in aqueous phosphate buffer at pH 6.84 (1250 mL) was added purified E.coli thymidine phosphorylase (10,000 units) (T.A. Krenitsky et al, Biochemistry, 20, 3615, 1981; U.S. Patent Specification No. 4,381,344) and alkaline phosphatase (10,000 units) [Sigma type VII-S from bovine intestinal mucosa] and the whole mixture was incubated at 37° C. for 24 hours. The resulting white precipitate was filtered, washed with water (3×100 mL), ethanol (2×100 mL), ether (2×100 mL) and dried in vacuo over phosphorus pentoxide to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25]>C(Cl)Cl>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:24](=[O:25])[O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Reactant: COCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)NC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a solution of (S)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (500 mg, 2.33 mmol) in CH2Cl2 at −10° C. was added triethylamine (650 μL, 4.66 mmol) followed by the dropwise addition of 2-methoxyethyl chloroformate (325 μL, 2.79 mmol). The reaction was warmed to room temperature and quenched with water. The aqueous layer was extracted with CH2Cl2, and the combined extracts were dried over MgSO4, filtered, and evaporated. Purification via silica gel chromatography using 0 to 10% EtOAc in CH2Cl2 afforded 2-methoxyethyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate (496 mg, 67%). LC/MS: m/z 317.3 (M+H)+ at 2.56 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[CH2:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([NH:29][NH:30][C:31]([NH2:33])=[S:32])C.[CH2:34](O)[CH3:35]>C(O)(=O)C>[CH2:34]([N:30]([C:31]([NH2:33])=[S:32])[N:29]=[CH:18][C:17]1[CH:20]=[CH:21][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:23]([F:26])([F:25])[F:24])[CH2:13][N:12]=2)=[CH:15][C:16]=1[CH3:22])[CH3:35]
Reactant: CCO
Reactant: CCNNC(N)=S
Reactant: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Solvent: CC(=O)O
Product: CCN(N=Cc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)C(N)=S
Temperature: 70 °C
Yield: 76 %

Procedure:
A mixture of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-benzaldehyde (208 mg, 0.520 mmol) and ethyl thiosemicarbazide (93 mg 0.12 mmol) in ethanol (5 mL) and glacial acetic acid (0.1 mL) was heated at 70° C. for 4 h. After cooling, the resulting precipitate was filtered and dried to give the title compound (198 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH:24]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=1)=[O:10].[OH-].[Na+].Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH:24]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=1)=[O:10]
Reactant: COC(=O)c1cccc(NC(=O)c2cc(OCc3ccccc3Cl)cc(OCc3ccccc3Cl)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(NC(=O)c2cc(OCc3ccccc3Cl)cc(OCc3ccccc3Cl)c2)c1
Temperature: 25 °C

Procedure:
A suspension of methyl [3,5-di-(2-chlorobenzyloxy)benzoyl]aminobenzene-3-carboxylate (455 mg, 1.04 mmol) in THF was treated with sodium hydroxide solution (0.85 ml of 2M, 1.7 mmol), and the reaction stirred at ambient temperature, with tlc monitoring. Methanol (3 drops) and further additions of sodium hydroxide solution (2×0.85 ml of 2M, 3.4 mmol) were made, until complete hydrolysis was achieved. The resulting solution was diluted with water (30 ml) and acidified to pH1 (2M HCl); the precipitate thus formed was filtered off, washed (water) and dried to give the title compound as a colourless solid, 328 mg, 1H NMR δ (d6-DMSO): 5.25 (4H, s); 7.0 (1H, s); 7.4 (6H, m); 7.5 (2H, m); 7.6 (2H, m); 8.2 (1H, d).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][C:19](=O)[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.C[NH+](C)C>CO.C(O)(=O)C>[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][CH:19]([N:1]3[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]3)[CH2:18]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(O)C1CCNCC1
Agent: C[NH+](C)C
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 120 °C
Yield: 99.9 %

Procedure:
To a mixture of piperidine-4-carboxylic acid (0.13 g, 1.0 mmol) and 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, 0.24 g, 1.0 mmol), methanol (3 mL) and acetic acid (0.3 mL) was added (polystyrylmethyl) trimethylammonium cyanoborohydride (4.1 mmol/g, 0.25 g). The reaction mixture was heated for 5 min at 120° C. using microwave single node heating. Methanol was added and then the resin was filtered off. The solvent was removed by evaporation. There was obtained 0.35 g (100%) of 1-[1-(diphenylmethyl)azetidin-3-yl]piperidine-4-carboxylic acid. 1H NMR (500 MHz, CDCl3): 1.6-1.8 (m, 2H), 1.9-2.0 (m, 4H), 2.3-2.4 (m, 1H), 2.7-2.8 (m, 2H), 2.9-3.0 (m, 3H), 3.4 (t, 2H), 4.4 (s, 1H), 7.2 (t, 2H), 7.2-7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 351 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Fc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5cc(F)ccc5n4)cc3CC[C@@H]12
Yield: 62.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-6-fluoro-quinoline (84 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 96 mg (62%) of the title compound as a solid. mp 152°-155°. FDMS: m/e=406. α[D]589 =+63.16 (c=0.61, chloroform).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])(C)(C)C.[O:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[CH3:20].[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34](C(O)=O)=[C:33]([O:41][CH3:42])[CH:32]=1>>[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([O:19][CH3:20])=[CH:22][CH:23]=3)[CH2:11]2)=[O:7])=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Product: COc1ccc(C(=O)NCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)C2)cc1

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (1.03 g) as starting compound was reacted and treated in the same manner as in Example 1 using 4-methoxylbenzoyl chloride (0.68 g) and 4-amino-5-chloro-2-methoxybenzoic acid (0.41 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(3-(4-methoxybenzoylamino)propyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:16]#[N:17])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=1)=O)[CH3:2].[BrH:19]>CCOCC.C(Cl)Cl.CC(O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=2)[NH:17][C:16]=1[Br:19])=[O:18])[CH3:2]
Reactant: Br
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccnc(N)n1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1Br
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of 4-(2-amino-pyrimidin-4-yl)-2-cyano-4-oxo-butyric acid ethyl ester (364 mg, 1.47 mmol) in anhydrous Et2O and DCM (1:1 10 mL) was added dropwise to 4.5 mL of 33% HBr in AcOH at 0° C. The mixture was left at 0° C. for 30 min and then at rt until disappearance of the starting material. The solid was filtered, washed with acetone and MeOH, neutralized with 7N NH3 in MeOH to afford 400 mg (88%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][OH:27]>C(C(C)=O)C(C)C>[OH:27][CH2:26][CH2:25][CH2:24][N:14]1[CH2:15][CH2:16][CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][N:7]=2)[CH2:12][CH2:13]1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 54.1 %

Procedure:
To a mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (438 mg, 2 mmol) and dry potassium carbonate (1.1 g, 6 mmol) in 30 ml methyl isobutyl ketone was added 3-bromo-1-propanol (276 mg, 2 mmol). The mixture was refluxed for 48 h, cooled, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel 60 eluting with ethyl acetate:methanol (9:1, v/v). Concentration of the appropriate fractions afforded 300 mg (53%) of 3-[1-(1-hydroxyprop-3-yl)-4-piperidinyl]-6-fluoro-1 H-indazole as an oil.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][C:22]1[C:27]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:12][C@@H:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@@H:14]5[CH3:18])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)=[CH:26][CH:25]=[C:24]([CH3:37])[N:23]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@@H](N5CCC[C@@H]5C)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 19A for the product of Example 1E and substituting the product of Example 2A for pyrimidine-5-boronic acid. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (d, J=8.29 Hz, 1H) 7.76 (d, J=1.53 Hz, 1H) 7.45 (d, J=7.67 Hz, 1H) 7.38 (dd, J=8.44, 1.69 Hz, 1H) 7.06 (d, J=7.67 Hz, 1H) 3.58-3.70 (m, 1H) 3.16-3.30 (m, 1H) 3.00-3.13 (m, 1H) 2.69-2.86 (m, 1H) 2.59-2.68 (m, 1H) 2.59 (s, 3H) 2.49 (s, 3H) 2.42-2.52 (m, 3H) 1.91-2.03 (m, 1H) 1.78-1.87 (m, 1H) 1.67-1.77 (m, 1H) 1.42-1.57 (m, 1H) 1.16 (s, 3H). MS: (M+H)+=378.
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[NH2:14][CH2:15]COS(O)(=O)=O.[OH-].[K+].[CH:24](O)(C)C>O>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH:2]1[O:1][CH2:13][CH2:15][NH:14][CH2:24]1
Reactant: NCCOS(=O)(=O)O
Reactant: COc1ccccc1OCC1CO1
Reactant: CC(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1OCC1CNCCO1

Procedure:
A mixture of 2-epoxy-1-(2-methoxyphenoxy)-propane (13.0 g, 72 mmol), 2-aminoethylhydrogensulfate (51 g, 361 mmol), potassium hydroxide (41 g, 722 mmol) in isopropanol (300 ml) and water 100 ml was refluxed for 8 h. Water was added and the product was extracted with two portions of ethylacetate. Drying and evaporation gave a crude product that was used without further purification. Yield 9.2 g.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])=[N:9][C:8]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[N:7][C:6]=2[C@@H:5]1[CH3:33])(=[O:3])[CH3:2].C(NC(NC1C=CC(C2N=C(N3CCOC[C@@H]3C)C3CCNC(C)C=3N=2)=CC=1)=O)C.CN(C)C=O.C(N(CC)C(C)C)(C)C.C(Cl)(=O)C>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])=[N:9][C:8]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[N:7][C:6]=2[C@H:5]1[CH3:33])(=[O:3])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)=O)[C@H]3C)cc1
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(C)=O)[C@@H]3C)cc1
Reaction time: 2 h

Procedure:
and 1-(4-((S)-7-acetyl-8-methyl-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (wr2): 1-Ethyl-3-(4-(8-methyl-4-((S)-3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.172 g, 0.419 mmol) in dry N,N-Dimethylformamide (2.00 mL, 25.8 mmol) was added N,N-Diisopropylethylamine (0.219 mL, 1.26 mmol) followed by Acetyl chloride (0.0448 mL, 0.630 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was purified by HPLC and the diastereomers were separated by SFC. R-Diastereomer (wr1): 1H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 8.18 (d, J=8.6, 2H), 7.48 (d, J=8.6, 2H), 6.21 (s, 1H), 3.99 (s, 1H), 3.88 (d, J=12.3, 2H), 3.71 (d, J=10.8, 1H), 3.58 (dd, J=23.8, 11.1, 2H), 3.13 (dd, J=13.5, 6.4, 2H), 3.06-2.91 (m, 3H), 2.71 (t, J=14.7, 1H), 2.38 (d, J=39.3, 1H), 2.12 (d, J=6.4, 3H), 1.58 (d, J=6.8, 1H), 1.47-1.42 (m, 3H), 1.13 (t, J=7.2, 3H), 1.06 (t, J=7.1, 3H). LC/MS-m/z+453.2 (M+H)+; and
Reaction SMILES: Cl.[N:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][CH:35]1[CH2:37][CH2:36]1.O>CN(C)C=O>[CH:35]1([CH2:34][N:5]2[CH2:6][CH2:7][N:2]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[N:9]=3)[CH2:3][CH2:4]2)[CH2:37][CH2:36]1
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Reactant: ClCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-n2nc(N3CCN(CC4CC4)CC3)c3ccccc32)cc1
Yield: 51.6 %

Procedure:
A stirred mixture of 5.0 g of 3-(1-piperazinyl)-1-[4(trifluoromethyl)phenyl]-1H-indazole hydrochloride, 2.2 g of potassium carbonate, and 1.4 g of chloromethylcyclopropane in 50 ml of dimethylformamide was heated at 85°-90° for 20 hours. The reaction mixture was poured into water and the aqueous suspension extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was flash chromatographed on silica gel utilizing ethyl acetate as the eluent. Concentration of the appropriate fractions gave 2.7 g (48%) of 3-[4-(cyclopropyl)methyl-1piperazinyl]-1-[4-(trifluoromethyl)phenyl]-1H-indazole, mp 98°-100°.
Reaction SMILES: Cl[C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:4](=[O:14])[C:5]2[C:6]([N:13]=1)=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O.O.[Cl-].[Na+].O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:3]1[C:4](=[O:14])[C:5]2[C:6](=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[N:13]2[N:22]=[N:23][N:24]=[C:2]12
Reactant: [N-]=[N+]=[N-]
Reactant: CSc1ncc2c(=O)n(-c3ccccc3Cl)c(Cl)nc2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc2c(=O)n(-c3ccccc3Cl)c3nnnn3c2n1

Procedure:
A mixture of Example 1B (0.175 g, 0.516 mmol) and sodium azide (0.037 g, 0.568 mmol) in N,N-dimethylformamide (5 mL) was heated at 70° C. for 1 hour. The reaction mixture was diluted with water and brine and extracted with ethyl acetate (2×). The combined organic layers were washed with brine (2×), dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (95:5 to 90:10) to provide the title compound.