Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([O:8][CH:9]2[C:14]3[C:15]([OH:42])=[C:16]4[C:27](=[O:28])[C:26]5[C:21](=[C:22]6[O:35][CH:34]7[O:36][C:30]([CH3:41])([CH:31]([OH:40])[CH:32]([NH:38][CH3:39])[CH:33]7[OH:37])[C:23]6=[CH:24][C:25]=5[OH:29])[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[CH:12]([C:43]([O:45][CH3:46])=[O:44])[C:11]([OH:48])([CH3:47])[CH2:10]2)[CH:5]([O:49][CH3:50])[C:4]([O:52][CH3:53])([CH3:51])[CH:3]1[O:54][CH3:55].[C:56](OC(=O)C)(=[O:58])[CH3:57]>CO>[CH3:1][CH:2]1[O:7][CH:6]([O:8][CH:9]2[C:14]3[C:15]([OH:42])=[C:16]4[C:27](=[O:28])[C:26]5[C:21](=[C:22]6[O:35][CH:34]7[O:36][C:30]([CH3:41])([CH:31]([OH:40])[CH:32]([N:38]([C:56]([CH3:57])=[O:58])[CH3:39])[CH:33]7[OH:37])[C:23]6=[CH:24][C:25]=5[OH:29])[C:19](=[O:20])[C:17]4=[CH:18][C:13]=3[CH:12]([C:43]([O:45][CH3:46])=[O:44])[C:11]([OH:48])([CH3:47])[CH2:10]2)[CH:5]([O:49][CH3:50])[C:4]([O:52][CH3:53])([CH3:51])[CH:3]1[O:54][CH3:55]
Reactant: CNC1C(O)C2Oc3c(cc(O)c4c3C(=O)c3cc5c(c(O)c3C4=O)C(OC3OC(C)C(OC)C(C)(OC)C3OC)CC(C)(O)C5C(=O)OC)C(C)(O2)C1O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: COC(=O)C1c2cc3c(c(O)c2C(OC2OC(C)C(OC)C(C)(OC)C2OC)CC1(C)O)C(=O)c1c(O)cc2c(c1C3=O)OC1OC2(C)C(O)C(N(C)C(C)=O)C1O
Reaction time: 4 h

Procedure:
Eight hundred mg of N-demethylnogalamycin is dissolved in a mixture of 10 ml of methanol and 2 ml of acetic anhydride. After the solution has stood at room temperature for 4 hours, it is evaporated to dryness under reduced pressure. The residue is chromatographed on 90 g of silica gel using chloroform-methanol (19:1) and collecting 201 five-ml fractions. Fractions 100-201 are combined and evaporated to dryness in vacuo to give 470 mg of N-acetyl-N-demethylnogalamycin; homogenous by TLC, Rf 0.38 in CHCl3 --CH3OH (9:1); [α]D +485°; (c 0.286, CHCl3); UV (EtOH) 236 nm (ε38,400), 258 nm (ε19,200), 290sh nm (ε12,800); IR (Nujol) 3380, 1715, 1705, 1650, 1615, 1585, 1285, 1215, 1135, 1100, 1045, 1025, 1000, 915, 875, 820, 750 cm-1 ; 1H NMR (CDCl3) δ1.1-1.7 (m, 12H), 2.10 (s, 3H), 3.20 (s, 3H), 3.25, 3.53, 3.62, 3.68 (4s, 12H), 2.8-4.62 (m), 5.22, 5.55, 5.88 (3 broad s, 3H), 7.26 (s, 1H), 7.52 (s, 1H), 13C NMR (CDCl3) δ191.1, 179.8, 174.7, 171.6, 161.6, 155.8, 146.9, 143.8, 136.5, 133.5, 130.4, 125.2, 116.1, 114.2, 113.9, 100.7, 95.62, 84.3, 81.0, 77.8, 75.7, 74.0, 71.5, 69.4, 67.3, 61.1, 59.2, 58.7, 56.8, 52.2, 48.5, 40.0, 32.2, 29.4, 23.6, 22.4, 18.0, 14.6; mass spectrum m/e 815.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH:44]([N:47]([CH:51]([CH3:53])[CH3:52])[CH2:48][CH2:49][NH2:50])([CH3:46])[CH3:45]>C(Cl)(Cl)Cl.O>[CH:44]([N:47]([CH:51]([CH3:53])[CH3:52])[CH2:48][CH2:49][NH:50][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([CH3:24])[C:18]=1[CH3:23])=[O:42])([CH3:46])[CH3:45]
Reactant: CC(C)N(CCN)C(C)C
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCCN(C(C)C)C(C)C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diisopropyl-1,2-ethanediamine (68 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (46 mg, yield 30%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH2:11][S:10][C:9]2=[NH:13])=[CH:5][N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH2:11][S:10][C:9]2=[N:13][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:5][N:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C1SCCN1Cc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(N=C1SCCN1Cc1cnc(Cl)s1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(2-Chloro-5-thiazolylmethyl)-2-iminothiazolidine (233 mg, 1.0 mmol) and sodium carbonate (120 mg, 1.1 mmol) were dissolved in 10 ml of water, into which, benzoyl chloride (141 mg, 1.0 mmol) dissolved in 5 ml of chloroform was added under cooling with ice, and thereafter stirred at room temperature for 2 hours. The chloroform layer was washed successively with 1% hydrochloric acid and water, dehydrated and dried, chloroform was distilled off, and remaining oil was purified by a silica gel column chromatography to obtain the intended substance. The crude crystal of the intended substance was recrystallized from ethyl acetate. Yield: 101 mg (30%). Melting point: 120° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3([C:30]#[N:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.Cl>O1CCOCC1>[N:11]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3([C:30]#[N:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3(C#N)CCOCC3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N#CC1(c2ccc(OCCCN3CCNCC3)cc2)CCOCC1
Yield: 72 %

Procedure:
4-{3-[4-(4-Cyano-tetrahydro-pyran-4-yl)-phenoxy]-propyl}-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.16 mmol), MeOH (5 ml), 1,4-dioxane (1 ml) and HCl in dioxane (4M, 1.8 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo at 40° C., and diluted with TBME (5 ml). Aqueous NaOH (2M solution) was added to attain a pH of 14 and the mixture separated and extracted with TBME (2×5 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to provide title compound as a yellow oil (275 mg, 72%). 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.11-4.05 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 2.90 (t, 4H), 2.51 (t, 2H), 2.44 (br s, 4H), 2.15-2.00 (m, 4H), 1.97 (m, 2H), 1.74 (br s, 1H).
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:39]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CC(OC)(C)C>[CH2:35]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:11]([CH3:39])[CH:12]=1)=[O:7])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
To a stirred solution of methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (80 mg, 0.15 mmol) in dry DMF (3 mL) was added K2CO3 (42 mg, 0.30 mmol) and methyl iodide (22 mg, 0.15 mmol, a solution in 100 μL of DMF) at 0° C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 4 h. The reaction mixture was diluted with MTBE and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo to give crude product. The crude material was purified by flash chromatography (gradient from 0% to 2% MeOH/CHCl3) to provide the title compound (65 mg, 79%). 1H NMR (CD3OD) δ 8.25-8.00 (m, 2H), 7.92-7.00 (m, 6H), 4.80-4.60 (m, 2H), 4.02 (s, 3H), 3.70-3.40 (m, 6H), 3.01 (s, 3H), 2.90-2.80 (m, 2H), 1.60-1.50 (m, 4H), 1.50-1.30 (m, 4H), 1.05-0.90 (m, 6H); MS(ESI+) m/z 531.4 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O-:5])=[O:4].[CH2:6]([O:13][CH:14]([O-])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH:17]S([O-])(=O)=O.[K+]>C(OCC)(=O)C>[C:7]1([CH2:6][O:13][CH2:14][CH2:15][O:17][CH2:2][C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC([O-])OCc1ccccc1
Reactant: O=C([O-])CBr
Reactant: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(O)COCCOCc1ccccc1
Yield: 93 %

Procedure:
This solution of bromoacetate is added dropwise to the prepared solution of benzyloxyethanolate anion, and the mixture is heated at reflux for 19 h. The reaction is stopped with 5% KHSO4. 250 ml ethyl acetate is added and the organic phase is extracted three times with the aid of 5% NaOH. The pH of the alkaline phase is reduced to 1 with 10% HCl and extraction is performed twice with EtOAc. The organic phase is washed three times with sodium chloride solution, dried on Na2SO4, and evaporated to obtain 6.4 g (93%) 7-phenyl-3,6-dioxaheptanoic acid in the form of a colourless liquid.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.[OH-].[K+].O>C(O)(C)C>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1CCN(Cc2ccc(Oc3nc4ncccc4s3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)C1CCN(Cc2ccc(Oc3nc4ncccc4s3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a solution of ethyl 1-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)benzyl]piperidine-4-carboxylate (97 mg, 0.24 mmol) in isopropyl alcohol (750 μL) was added 1 N KOH (240 μL). The mixture was allowed to stir at rt for 2 h. The reaction mixture was then poured into water (20 mL) and basified to pH 9. The resultant solution was extracted with a 1:1 solution of CHCl3/isopropyl alcohol (2×30 mL). The combined organic extracts were dried, filtered, and concentrated to afford the title compound (38 mg, 43%). 1H NMR (400 MHz, CD3OD): 8.49 (d, J=4.8, 1H), 8.32 (dd, J=8.0, 1.6, 1H), 7.61-7.54 (m, 2H), 7.52-7.45 (m, 2H), 7.35 (dd, J=8.0, 4.9, 1H), 3.95 (s, 2H), 3.22-3.09 (m, 2H), 2.65-2.46 (m, 1H), 2.38-2.22 (m, 1H), 2.05-1.92 (m, 2H), 1.91-1.75 (m, 2H), 0.98-0.79 (m, 1H). MS (ESI): mass calcd for C19H19N3O3S, 369.12; m/z found, 370.2 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]1C(=O)[C:11](=[O:14])[C:10]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:9]=1.[NH2:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][CH2:23][S:24][CH3:25].C(OCC)(=[O:31])C.Cl>CN1CCOCC1.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([NH:9][C:10]1([C:11]([NH:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:14])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:31]
Reactant: CCOC(C)=O
Reactant: O=C1C(=O)C2(CCCCC2)N=C1/C=C/c1ccco1
Reactant: CSCC[C@H](N)C(=O)O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Product: CSCC[C@H](NC(=O)C1(NC(=O)/C=C/c2ccco2)CCCCC1)C(=O)O
Yield: 9 %

Procedure:
A solution of 491 mg (2 mmol) of 2-[(E)-2-(2-furanyl)ethenyl]-3-oxo-1-azaspiro[4.5]dec-1-en-4-one and 597 mg (4 mmol) of L-methionine in 20 ml of N-methylmorpholine was heated under reflux for 15 hours. After ethyl acetate and water were added to the reaction solution, the mixture was acidified using concentrated hydrochloric acid. The organic layer was separated and successively washed with water and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography to obtain 74 mg (9%) of the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.S(Cl)([Cl:33])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:33][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[CH:19][CH:20]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)c1
Yield: 93.4 %

Procedure:
To a mixture of ethyl (3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (7.50 g) and toluene (300 mL) was added thionyl chloride (2.38 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl (3-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate as colorless crystals (7.32 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CN(c1ccc(C(=O)O)c(Cl)c1)S(C)(=O)=O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CN(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1)S(C)(=O)=O

Procedure:
100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-methylmethylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methylmethylsulfonamido)benzamide. MS (Q1) 450 (M)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:10])[CH:8]=[CH2:9])[CH:2]=1.Br[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:10]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:8][CH2:9][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: C=CC(O)c1cccnc1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(=O)c2cccnc2)cc1
Temperature: 120 °C
Yield: 69.3 %

Procedure:
1-(3-Pyridyl)-2-propen-1-ol (1.36 g), methyl p-bromobenzoate (1.44 g) and palladium acetate II (0.02 g) were dissolved in 30 ml of N,N-dimethylformamide, and stirred under heating at 120° C. overnight. The obtained reaction mixture was concentrated, to which was poured water and extracted with ethyl acetate. The extract with ethyl acetate was washed in saturated aqueous sodium chloride solution and dried over magnesium sulfate. The residue was subjected to chromatography on a silica gel column, which was eluted with chloroform-methanol (20:1 v/v), to obtain 1.25 g of methyl 4-[3-oxo-3-(3-pyridyl)propyl]benzoate.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@H:19]([CH3:22])[CH2:20][OH:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1.F[B-](F)(F)F.[H+].O>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C@H:19]([CH3:22])[CH2:20][O:21][CH3:1])(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[C@H](CO)NS(=O)(=O)c1ccc(Br)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Solvent: O
Product: COC[C@@H](C)NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
(Trimethylsilyl)diazomethane (10 mL, 10 mmol) was added to a vigorously stirred mixture of 4-bromo-N-[(1R)-2-hydroxy-1-methylethyl]benzenesulfonamide (1.0 g, 3.4 mmol) and aqueous fluoroboric acid (conc. 42%, 6.8 mmol) in methylene chloride (25 mL), in 5 portions over 1 h at 0° C. The stirring was continued at 0° C. and another portion of trimethylsilyldiazomethane (5 mL, 5 mmol) was added over 30 min. The stirring was continued for 30 min, poured into water and extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and concentrated. Purification by column chromatography using gradient heptane to heptane/ethylacetate, (2:1), as the eluent gave 0.155 g (15% yield) of the title compound: MS (ESI) 309 m/z (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[N:3]=1.[CH2:20]([O:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34](OCC)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1)[CH3:21]>O1CCCCC1.O1CCCC1>[CH2:20]([O:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][N:28]2[C:31]([C:34]([NH:11][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[C:2]([CH3:1])=[N:3][N:4]4[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=3)=[O:35])=[CH:32][N:33]=[C:27]2[CH:26]=1)[CH3:21]
Reactant: CCOCOc1ccn2c(C(=O)OCC)cnc2c1
Reactant: Cc1cccc(Cn2nc(C)c3c(N)cccc32)n1
Solvent: C1CCOCC1
Solvent: C1CCOC1
Product: CCOCOc1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 0 °C
Yield: 59.5 %

Procedure:
3-Methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (22 mg, 0.09 mmol) was dissolved in tetrahydropyran (DriSolve; 0.5 mL) and degassed before back-filling with nitrogen gas. The solution was then cooled in an ice water bath for 15 minutes before drop-wise addition of lithium bis(trimethylsilyl)amide (0.09 mL, 1 M in tetrahydrofuran). The reaction stirred for 10 minutes before drop-wise addition into a solution of ethyl 7-(ethoxymethoxy)imidazo[1,2-a]pyridine-3-carboxylate (11 mg, 0.04 mmol) in tetrahydrofuran (DriSolve; 0.2 mL) cooled in an ice-water bath. The reaction was then stirred while being cooled in the ice-water bath for 1.5 hours. The reaction was quenched with water and concentrated. The resulting crude material was purified by reverse phase chromatography, eluting with a gradient from 10% to 70% ACN/water over 25 column volumes, to give 7-(ethoxymethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24]([CH:29]=O)=[CH:25][CH:26]=[CH:27][CH:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ccccc1-c1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccccc1-c1ccccc1CN1CCN(c2ccccc2OC)CC1

Procedure:
382 mg of the target compound (0.98 mmol, 59.6%) was obtained using 1-(2-methoxyphenyl)piperazine (634 mg, 3.30 mmol), 2′-methoxybiphenyl-2-carbaldehyde (350 mg, 1.65 mmol) and NaBH(OAc)3 (1.1 g, 4.95 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[CH3:18])=[N:4][N:3]=1.C(N(CC)C(C)C)(C)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:14][C@H:13]2[CH3:18])=[N:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CNCCN1c1nnc(Cl)c2ccccc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-chloro-4-(2-methylpiperazin-1-yl)phthalazine (2.94 g, 11.94 mmol) was dissolved in dry DMF (24 mL) and N,N-diisopropylethylamine (3.12 mL, 17.9 mmol). Benzoyl chloride (1.43 mL, 12.3 mmol) was added dropwise and the reaction stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (200 mL), and washed with aqueous K2CO3 (10%), water, and then saturated sodium chloride. The organic phase was dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-70% ethyl acetate gave an off-white solid. MS (M+H)+=367.
Reaction SMILES: [OH:1][C@@:2]([CH3:53])([C:5](=[O:52])[C@@H:6]([NH:11][C:12]([C@@H:14]([NH:22][C:23](=[O:51])[C@@H:24]([NH:29][C:30](=[O:50])[C@@H:31]([NH:40][C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1)[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:3][I:4].[C:54](O)(=[O:59])[CH2:55][CH2:56][C:57]#[CH:58].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:54]([O:1][C@:2]([CH3:53])([CH2:3][I:4])[C:5](=[O:52])[C@H:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[NH:11][C:12](=[O:13])[C@H:14]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH:22][C:23](=[O:51])[C@H:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[NH:29][C:30](=[O:50])[C@H:31]([CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:40][C:41](=[O:49])[CH2:42][N:43]1[CH2:44][CH2:45][O:46][CH2:47][CH2:48]1)(=[O:59])[CH2:55][CH2:56][C:57]#[CH:58]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)[C@](C)(O)CI
Reactant: C#CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#CCCC(=O)O[C@](C)(CI)C(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
(2S)—N—((S)-1-((2S,4S)-2-hydroxy-1-iodo-2,6-dimethyl-3-oxoheptan-4-yl carbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide (1.18 g, 1.39 mmol) was dissolved in DMF. DMAP (19.2 mg, 0.139 mmol), 4-pentynoic acid (205 mg, 2.09 mmol) and DCC (430 mg, 2.09 mmol) were added. The mixture was stirred at room temperature for 16 hours and then diluted with 200 mL EtOAc. The organic phase was washed with 1N HCl (50 ml), brine (50 mL), and saturated NaHCO3 solution. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude product was purified by prep HPLC to afford 539 mg of product as a white solid.