Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[O:13])=[C:7]([C:29]1[C:34]([F:35])=[CH:33][C:32]([F:36])=[CH:31][C:30]=1[F:37])[CH:6]=[CH:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:44]>C1COCC1>[ClH:44].[OH:13][CH:12]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1)[C:8]1[C:7]([C:29]2[C:30]([F:37])=[CH:31][C:32]([F:36])=[CH:33][C:34]=2[F:35])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([OH:1])=[CH:3]2
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2c(F)cc(F)cc2F)ccc2cc(O)ccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Temperature: 0 °C
Yield: 100 %

Procedure:
Dissolve [6-hydroxy-2-(2,4,6-trifluoro-phenyl)-naphthalen 1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (728 mg, 1.4 mmol) in THF (85 mL) and cool to 0° C. Add 1M lithium aluminum hydride in THF (5.8 mL, 5.8 mmol) and bring to room temperature. Heat the reaction to reflux for 30 minutes. Cool reaction and pour onto ice/chloroform to form a suspension. Add 6N HCl dropwise to obtain a pH of 1. Extract with 20% isopropyl alcohol in chloroform. Wash organic layer with brine, dry, filter, and concentrate in vacuo to yield 730 mg (100%) of the title compound. HPLC Rt (0.01% heptafluorobutyric acid:1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric acid:1.0% isopropylalcohol:acetonitrile is mobile phase B; gradient: 5 to 95% B, Purity@254 nm)=2.41 (100%); mass spectrum (ion spray): m/z=508.3 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[NH:6])[NH2:5].[C:7](OC)(=[O:13])[CH2:8][C:9](OC)=[O:10].C[O-].[Na+]>CO>[CH3:2][O:3][C:4]1[N:5]=[C:9]([OH:10])[CH:8]=[C:7]([OH:13])[N:6]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(O)cc(O)n1
Temperature: 25 °C
Yield: 109.5 %

Procedure:
In a sealed tube O-methylisourea hydrochloride (3.0 g, 27 mmol) and dimethyl malonate (3.1 mL, 27 mmol) were dissolved in 30% w/v solution of sodium methoxide in methanol. The reaction mixture was refluxed for four hours before being allowed to cool to ambient temperature overnight. The resultant white precipitate was filtered and dried in vacuo yielding 4.2 g (quantitative yield) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH3:21][C:22]1([CH3:38])[O:27][CH:26]([C:28]([NH:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:29])[C:25]([CH3:37])([CH3:36])[CH2:24][O:23]1>>[CH3:21][C:22]1([CH3:38])[O:27][CH:26]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:34])=[O:29])[C:25]([CH3:37])([CH3:36])[CH2:24][O:23]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCCCCCCCCCCC(=O)NCCCO
Product: CCCCCCCCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 88 %

Procedure:
N-(3-Hydroxypropyl)tetradecanamide (2.87 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 4.63 g of the title compound (yield: 88%)
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[C:13]3[CH2:16][CH2:17][NH:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][Cl:23])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.I([O-])(=O)(=O)=[O:26].[Na+]>>[CH:1]1([CH2:4][S:5]([C:6]2[CH:15]=[C:14]3[C:9]([CH:10]=[CH:11][CH:12]=[C:13]3[CH2:16][CH2:17][NH:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][Cl:23])=[CH:8][CH:7]=2)=[O:26])[CH2:3][CH2:2]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(CCCCl)NCCc1cccc2ccc(SCC3CC3)cc12
Agent: [Na+]
Product: O=C(CCCCl)NCCc1cccc2ccc(S(=O)CC3CC3)cc12
Reaction time: 8 h

Procedure:
The product obtained in Example 43 (10 mmol) is added to an aqueous 0.5M sodium periodate solution (21 ml, 10.5 mmol) at 0° C. Stirring at 0–5° C. is carried out overnight. The solution is filtered and the filtrate is extracted with chloroform.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([O:18][C:19]2[C:20]([CH3:28])=[N:21][C:22]([O:25][CH2:26][CH3:27])=[CH:23][CH:24]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)=O)(C)(C)C.Cl>>[CH2:26]([O:25][C:22]1[N:21]=[C:20]([CH3:28])[C:19]([O:18][CH:13]([C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:24][CH:23]=1)[CH3:27]
Reactant: CCOc1ccc(OC(CC(C)C)[C@H]2CCN(C(=O)OC(C)(C)C)C2)c(C)n1
Agent: Cl
Product: CCOc1ccc(OC(CC(C)C)[C@H]2CCNC2)c(C)n1
Yield: 21 %

Procedure:
Stir a mixture of (3S)-3-[1-(6-ethoxy-2-methyl-3-pyridyloxy)-3-methyl-butyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (S-2) and aqueous HCl (4N in dioxane, 0.261 mL, 1.04 mmol) at room temperature for 1 hour. After full conversion, concentrate the mixture, dissolve the residue in chloromethane and load onto a pre-packed SCX column. Wash the column with dichloromethane followed by methanol. Release the product with 2M NH3 in methanol and concentrate under reduced pressure. Purify the crude residue by reverse phase chromatography (34-60% gradient actonitrile in 0.01 M ammoniumformate in water, 85 mL/min, for 8 min., C18 ODB XBridge column, 30×75 mm, 5 μm) to give 13.4 mg (21%) of (3S)-3-[1-(6-ethoxy-2-methyl-3-pyridyloxy)-3-methyl-butyl]-pyrrolidine (S-2). MS (m/z)=293 [M+1].
Reaction SMILES: [C:1](Br)#[N:2].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].CCN(C(C)C)C(C)C.O>ClCCl>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:1]#[N:2])[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C#N)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
3.76 g bromcyane was added to 6 g piperazine-1-carboxylic acid tert-butyl ester and 6.3 mL DIPEA in 30 mL dichlormethane at 0° C. The reaction was stirred 1.5 h at 0° C. Water and dichlormethane was added and the layers were separated. The organic layer was washed with brine and water and evaporated to give 6.8 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:10](=[O:11])[NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:18][CH:19]2[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:20]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1nccs1)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Yield: 49.8 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-N-thiazol-2-yl-propionamide (prepared as in Example 36, 147.8 mg, 0.38 mmol) and acetic anhydride (72 μL, 0.77 mmol) in pyridine (2 mL) and methylene chloride (1 mL) was stirred at 25° C. for 20 h. The resulting reaction mixture was concentrated in vacuo. Since the reaction did not go to completion, the residue was re-dissolved in pyridine (1.8 mL) and acetic anhydride (1.4 mL, 14.84 mmol) and then stirred at 25° C. for an additional 7 h. The reaction mixture was concentrated in vacuo and then diluted with ethyl acetate (50 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (3×50 mL), water (50 mL), and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 35% ethyl acetate/hexanes) afforded acetic acid 3-[2-(3,4-dichloro-phenyl)-2-(thiazol-2-ylcarbamoyl)-ethyl]-cyclopentyl ester (80.8 mg, 49%) as a white solid: mp 49–52° C.; (ES)+-HRMS m/e calcd for C19H20Cl2N2O3S (M+H)+ 427.0645 found 427.0648.
Reaction SMILES: [CH2:1](O)[CH3:2].S(Cl)(Cl)=O.[Cl:8][CH2:9][CH:10]=[N:11][O:12][CH2:13][C:14]([OH:16])=[O:15]>>[Cl:8][CH2:9][CH:10]=[N:11][O:12][CH2:13][C:14]([O:16][CH2:1][CH3:2])=[O:15]
Reactant: O=C(O)CON=CCCl
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CON=CCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A dry 25 ml two-necked round bottom flask was equipped with a stirring bar, addition funnel, reflux condenser and nitrogen bubbler. The flask was charged with absolute ethanol (9.2 gm, 200 mmoles) and the addition funnel charged with thionyl chloride (4.3 gm, 36 mmoles). The flask and its contents were cooled to about 0° C. The thionyl chloride was added dropwise while maintaining the flask temperature at 5° C. or below. After the addition was completed, the resulting mixture was stirred for 1 hour at 0° C. Beta-chloroethylideneaminooxyacetic acid (2.7 gm, 18 mmoles) was added in one portion. The resulting mixture was allowed to warm to room temperature during 1 hour. The flask was warmed to 40°-45° C. and maintained for 4 hours. The resulting mixture was cooled, then solvents were removed in vacuo. The residue was taken up in ethyl acetate which was extracted with an aqueous solution of sodium bicarbonate. The ethyl acetate layer was dried over magnesium sulfate, filtered, then taken to "dryness" in vacuo. A brown oil (2.1 gm) was obtained. Distillation at 0.5 mm Hg gave the desired product as a clear oil (2.0 gm), b.p. 60°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]2)[CH:6]=[CH:5][C:4]=1[C:15]([N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][N:20]2[CH:28]=[CH:29][CH:30]=[C:19]2[CH2:18]1)=[O:16].C(O)(=O)C.C=O>CO>[CH3:15][N:17]([CH2:23][C:28]1[N:20]2[C:19]([CH2:18][N:17]([C:15]([C:4]3[CH:5]=[CH:6][C:7]([N:9]4[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]4)=[CH:8][C:3]=3[O:2][CH3:1])=[O:16])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21]2)=[CH:30][CH:29]=1)[CH3:18]
Reactant: COc1cc(-n2ccc(C)n2)ccc1C(=O)N1Cc2cccn2Cc2ccccc21
Agent: C=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(-n2ccc(C)n2)ccc1C(=O)N1Cc2ccc(CN(C)C)n2Cc2ccccc21

Procedure:
To a stirred solution of [2-methoxy-4-(3-methyl-pyrazol-1-yl)-phenyl](5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl) methanone from Example 107 (0.57 g) in warm methanol (10 ml) was added N,N,N,N′-tetramethyldiaminomethane (0.392 ml) and acetic acid (0.164 ml). Following the addition of aqueous 37% formalin solution (2.9 ml) the reaction was stirred for fifteen minutes. The mixture was concentrated in vacuo and partitioned between dichloromethane and sodium hydrogen carbonate. The organic phase was removed, washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica eluting with chloroform/methanol (50/1) to afford a solid. Recrystallisation of the solid from acetone gave the title compound as a colorless solid, m.p. 196-198° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[C:15]([Br:17])[N:14]=[C:13]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[C:15]([Br:17])[N:14]=[C:13]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Agent: Cl
Solvent: C1COCCO1
Product: NCCCCNc1cc(S(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.4 %

Procedure:
0.36 g (0.00072 mol) of tert-butyl [4-[4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-ylamino]-butyl]-carbamate was dissolved in 15 ml of dioxane and treated with 5 ml of 3N aqueous HCl. After stirring at room temperature for 18 hrs. the pH was adjusted to 9, the reaction mixture was extracted with ethyl acetate and the organic phase was washed with water and sat. sodium chloride solution, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel with 10% methanol in dichloromethane and then with 20% methanol in dichloromethane. After removal of the solvent from the product-containing fractions the residue was dissolved in diethyl ether and the product was precipitated by the addition of hexane. There was obtained 0.03 g (10%) of N1-[4-(4-aminobenzenesulphonyl)-6-bromopyridin-2-yl]-butane-1,4-diamine as orange-red crystals. MS (ISP): me/e=401, 399 (C15H20BrN4O2S+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@:20]2([CH3:36])[C:32](OC)=[O:33])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[C:67]([O:71][NH2:72])([CH3:70])([CH3:69])[CH3:68]>[Cl-].[Na+].O.CN(C=O)C.C(N(CC)CC)C.CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:21][C@@:20]2([C:32](=[O:33])[NH:72][O:71][C:67]([CH3:70])([CH3:69])[CH3:68])[CH3:36])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@]1(C)CN(C(=O)OC(C)(C)C)CC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)ON
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)ONC(=O)[C@@]1(C)CN(C(=O)OC(C)(C)C)CC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a mixture of (3S,4R)-1-tert-butyl 3-methyl 4-(4-(benzyloxy)phenylsulfonamido)-3-methylpiperidine-1,3-dicarboxylate (4.494 g, 8.67 mmol), 5 M NaOH (10 mL), and THF (20 mL) was added methanol until the reaction became homogeneous. The solution was stirred at 45° C. overnight, then diluted with pH 4 NaH2PO4 (aq) and extracted with ethyl acetate (3×). Combined organic extracts were dried over Na2SO4 and concentrated to give an orange solid. The solid was then combined with benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (4.766 g, 10.78 mmol), O-tert-butylhydroxylamine hydrochloride (2.442 g, 19.28 mmol), triethylamine (5.4 mL), and DMF (10 mL) and the reaction mixture was stirred overnight at room temperature. The mixture was then diluted with brine and extracted with ethyl acetate (3×). The combined organic extracts were dried over Na2SO4 and purified via column chromatography on silica gel eluting with 30% ethyl acetate/hexanes to give (3S,4R)-tert-butyl 4-(4-(benzyloxy)phenylsulfonamido)-3-(tert-butoxycarbamoyl)-3-methylpiperidine-1-carboxylate (4.659 g, 8.09 mmol, 93%) as a colorless solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.09 (s, 3H) 1.23-1.25 (m, 9H) 1.40-1.51 (m, 10H) 1.57-1.60 (m, 3H) 1.65-1.72 (m, 1H) 2.49 (d, J=15.16 Hz, 1H) 2.72-2.83 (m, 1H) 3.16 (ddd, J=12.38, 8.72, 3.92 Hz, 1H) 3.98 (dt, J=13.58, 2.31 Hz, 1H) 4.31 (d, J=14.65 Hz, 1H) 5.11 (s, 2H) 7.01 (ddd, J=9.41, 2.78, 2.46 Hz, 2H) 7.33-7.44 (m, 5H) 7.78-7.82 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:43]#[N:44])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:38][CH2:39][O:40][CH3:41])[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([C:24](=[O:37])[N:25]([CH3:36])[N:26]4C(OC(C)(C)C)=O)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:42])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:43]#[N:44])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:38][CH2:39][O:40][CH3:41])[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([C:24](=[O:37])[N:25]([CH3:36])[NH:26]4)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:42])[CH:9]=2)[CH:7]=1
Reactant: COCCC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: COCCC(C(=O)Nc1ccc2c(=O)n(C)[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
225 mg (362 μmol) of tert-butyl 6-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 205 mg (purity 92%, 100% of theory)
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.ClCl.[Cl:15][CH2:16][C:17]1[C:18]([CH2:23]Cl)=[CH:19][CH:20]=[CH:21][CH:22]=1>CC1C=CC=CC=1C>[Cl:15][CH2:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClCc1ccccc1CCl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: ClCl
Solvent: Cc1ccccc1C
Product: Cc1ccccc1CCl
Temperature: 90 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A condenser tube, a stirring blade and a thermometer were set to a 500-mL-volume four-necked flask and in this reaction device, 86.9 g (0.82 mol) of o-xylene and 2.17 g (0.013 mol) of AIBN were placed to prepare a mixed solution. After the reaction device was heated to 90° C., chlorine gas was blown therein at a flow rate of 0.378 mol/hr, and the reaction was carried out for 4 hour with stirring. After completion of the reaction, a part of the reaction mixture was sampled. Then, the components of reaction mixture were analyzed by GC. As a result, the conversion of raw material o-xylene was 99.7%, the yield of α,α′-dichloro-o-xylene was 50.5% (based on o-xylene), and the selectivity of α,α′-dichloro-o-xylene was 50.7%. At this time, α-chloro-o-xylene was obtained in a yield of 30% (based on o-xylene), α,α-dichloro-o-xylene was obtained in a yield of 7%, and α,α,α′-trichloro-o-xylene was obtained in a yield of 9%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[O:4][N:3]=1.[CH2:16]([C:23]1([OH:29])[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.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][N:26]([C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[O:9])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: Cc1noc(-c2ccncc2)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccncc2)c1C(=O)N1CCC(O)(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
A suspension of 3-methyl-5-(pyridin-4-yl)-1,2-oxazole-4-carboxylic acid (0.25 g), 4-benzyl-4-hydroxypiperidine (0.35 g), HATU (0.70 g) and triethylamine (0.85 mL) in DMF (5.0 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then purified by preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), and the obtained fraction was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.29 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:36][CH2:37][N:38]([CH2:41][C:42]2[CH:48]=[CH:47][C:45]([NH:46]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:44][CH:43]=2)[CH2:39][CH2:40]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(4-tert.butoxycarbonyl-piperazin-1-yl-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C33H36N4O5
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[C:41]([O:14][C:13]1[CH:12]=[C:11]2[C:6]([C:7]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=5)[N:29]([CH3:39])[C:28]4=[O:40])[CH2:23][CH2:22]3)=[N:8][C:9]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:10]2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])(=[O:43])[CH3:42]
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
In 3 ml of pyridine was dissolved 360 mg (0.66 mmol) of Compound 47 obtained in Example 47, 0.12 ml (1.32 mmol) of acetic anhydride was added, and the mixture was stirred at room temperature for 4 hours. The solvent was removed at reduced pressure and water was added to the residue, the resulting precipitate was collected by filtration, washed with water, dried at heating and recrystallized from ethanol to give 205 mg (yield: 53%) of Compound 52 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:5]2[N:11]=[CH:10][C:9]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH:30][CH:27]4[CH2:29][CH2:28]4)=[O:17])=[CH:14][CH:13]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)cc1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.8 %

Procedure:
To a 50 mL round bottom flask, 4-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)benzoic acid (0.2 g, 0.00054 mol), cyclopropyl amine (0.046 g, 0.00081 mol) and DMF (10 mL) were added. To the same flask, HATU (0.3 g, 0.00081 mol) and TEA (0.23 mL, 0.0018 mol) were added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with 10% methanol in chloroform and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by flash column chromatography (0-1% methanol in chloroform) to provide the title compound (0.15 g, 68%). 1H NMR (300 MHz, DMSO-d6): δ 9.21 (d, J=2.4 Hz, 1H), 8.59 (d, J=4.2 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.94-8.06 (m, 4H), 4.52 (br s, 4H), 3.80 (t, J=4.8 Hz, 4H), 2.88-2.90 (m, 1H), 0.60-0.62 (m, 2H), 0.70-0.73 (m, 2H): LC-MS (ESI): Calculated mass: 409.1; Observed mass [M+H]+: 410.1. (RT=1.34 min).