Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=[O:3])C.[CH:5]1[C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.OO>O>[CH:5]1[C:18]2[S:17](=[O:3])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: c1ccc2c(c1)Oc1ccccc1S2
Agent: OO
Solvent: O
Product: O=S1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 168 h
Yield: 83 %

Procedure:
Into 1600 g of acetic acid was dissolved 100 g (0.5 mole) of phenoxathiin, and 48.5 g (0.5 mole) of an aqueous hydrogen peroxide (35%) was added into it dropwise at room temperature. The mixture was agitated at room temperature for 7 days, and then added by 3,000 g of water to precipitate white crystals. They were collected by filtration and dried under reduced pressure to obtain the intended compound. The amount of the white crystals was 90 g and the yield was 83%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:49]1[CH2:53][CH2:52][CH:51]([C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)[CH2:50]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:49]3[CH2:53][CH2:52][CH:51]([C:54]4[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=4)[CH2:50]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: c1cncc(C2CCNC2)c1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CCC(c3cccnc3)C2)cc1Cl
Yield: 65.1 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-pyrrolidin-3-ylpyridine (6 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (10 mg). MS (ESI, pos. ion) m/z 384 (M+1); HRMS, calcd for C20H18ClN3O3: 383.1037, found 383.1033.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:15]([C:17]1[CH:22]=[C:21]([CH2:23]Br)[CH:20]=[CH:19][N:18]=1)#[N:16]>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([C:15]#[N:16])[CH:22]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1cc(CBr)ccn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccnc(C#N)c2)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 122, Part F using 2-cyano-4-(bromomethyl)pyridine in place of 4-bromomethylthiophene-2-carbonitrile. The crude product is purified by column chromatography eluting with gradient of 25% EtOAc/CH2Cl2 to 50% EtOAc/CH2Cl2 to afford the title compound as a solid.
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[CH2:22]([O:24][C:25](=[O:28])[CH2:26][NH2:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][NH:27][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][O:14][C:10]1[CH:9]=[CH:8][C:7]2[N:6]=[C:5]3[NH:21][C:2](=[O:1])[NH:3][C:4]3=[CH:13][C:12]=2[CH:11]=1)[CH3:23]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Product: CCOC(=O)CNC(=O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1

Procedure:
This compound, m.p. 274°-276° C., was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and glycine ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH3:14])[C:10](OC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]([CH3:14])[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](C)OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: C[C@@H](C=O)OCc1ccccc1
Temperature: -2.5 °C
Reaction time: 3 h

Procedure:
A mixture of (S)-methyl 2-(benzyloxy)propanoate compound of formula-14 obtained in example-11 (100 g) and toluene (200 ml) was cooled to −75 to 70° C. under nitrogen atmosphere. DIBAL (500 ml) was added to the reaction mixture and stirred for 3 hours at the same temperature. After completion of the reaction, the reaction mixture was quenched with methanol and 30% hydrochloric acid was added to it at −75 to −70° C. Temperature of reaction mixture was raised to 25-30° C. Both organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Both organic layers were combined, washed with 5% sodium bicarbonate and 10% sodium chloride solution. The organic layer containing title compound is carried for the next step without distillation.
Reaction SMILES: [CH3:1][O:2][C:3]([C:17]1[N:18]=[CH:19][N:20](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:21]=1)([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)[CH3:4].Cl.N1C=CC=CC=1.Cl>CO>[CH3:1][O:2][C:3]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1)[CH3:4]
Reactant: COc1ccc2cc(C(C)(OC)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc2cc(C(C)(OC)c3c[nH]cn3)ccc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
4-[1-Methoxy-1-(6-methoxynaphthalen-2-yl)ethyl]-1-trityl-1H-imidazole (1.5 g) and pyridine hydrochloride (500 mg) were dissolved in methanol (8 ml). The solution was stirred at 60° C. for 2 h. After cooling, 1 N-hydrochloric acid was added to the solution, and precipitate was filtered off. The filtrate was washed with ether and neutralized with potassium carbonate. The filtrate was extracted with ethyl acetate, washed with saturated aqueous solution of sodium chloride, dried and concentrated. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:methanol=30:1) to give the titled compound (0.33 g) as a colorless powder.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][Cl:13].[N:15]([O-])=O.[Na+]>Cl.O>[Cl:13][CH2:12][CH2:11][C:10]1[C:9](=[O:14])[C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:2][N:15]=1
Reactant: O=N[O-]
Reactant: Nc1ccccc1C(=O)CCCCl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1c(CCCl)n[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A solution of 1-(2-aminophenyl)-4-chlorobutan-1-one hydrochloride (b 11.3 g, 0.0427 mol) in concentrated hydrochloric acid (1200 ml) was cooled down to 0° with stirring. Then sodium nitrite (3.54 g, 0.051mol) in water (25 ml) was added dropwise. On completion of the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The solution was evaporated under reduced pressure to dryness. The solid obtained was washed with a solution of sodium acetate and collected by filtration to give the title compound, 5.32 g. Recrystallization from methanol gave the product, m.p. 201-203°.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C@H:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:23](=O)[C:24](=[O:29])[C:25]=2[O:26]CC)=[C:17]([OH:31])[C:16]=1[S:32]([N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>CO>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:25](=[O:26])[C:24](=[O:29])[C:23]=2[NH:13][C@@H:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[C:17]([OH:31])[C:16]=1[S:32]([N:35]1[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]1)(=[O:33])=[O:34]
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N3CCN(C)CC3)c2O)c(=O)c1=O
Reactant: Cc1ccc([C@H](N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc([C@H](Nc2c(Nc3ccc(Cl)c(S(=O)(=O)N4CCN(C)CC4)c3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 68.7 %

Procedure:
A mixture of 250 mg (1.4 mmol, 1.2 eq) of C—(R)-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine (prepared in EXAMPLE 50, steps 1 to 4) and 500 mg (1.16 mmol, 1 eq) of 3-[4-chloro-2-hydroxy-3-(4-methylpiperazine-1-sulfonyl)phenylamino]-4-ethoxycyclobut-3-ene-1,2-dione in 20 ml of methanol was heated at 50° C. for 16 hours. The methanol was evaporated off and the residue was chromatographed on silica gel eluted with dichloromethane/methanol (98/2). The residue was washed with a 1 M aqueous sodium dihydrogen phosphate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. 450 mg of 3-[4-chloro-2-hydroxy-3-(4-methylpiperazine-1-sulfonyl)phenylamino]-4-{[(R)-(5-methylfuran-2-yl)-(3-methyloxetan-3-yl)methyl]amino}cyclobut-3-ene-1,2-dione were obtained in the form of a dark yellow solid. Yield=68%.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:8]1[C:9]([Cl:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cccc(-c2csc(Br)n2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(Cl)c3Cl)cs2)CC1
Yield: 7.4 %

Procedure:
A solution of 2-bromo-4-(2,3-dichlorophenyl)-1,3-thiazole (3.68 mg, 12.3 mmol), tert-butyl piperazine-1-carboxylate (4.44 g, 24.6 mmol) and potassium carbonate (1.65 g, 12.3 mmol) in dimethylformamide (40 ml) was stirred at 120° C. for 13 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 376 mg (7.6%) of the desired product as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:6]2=[C:7]([CH:25]=1)[C:8](=[O:24])[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:10]3=[O:15].O=P(Cl)(Cl)[Cl:29]>CN(C=O)C>[Cl-:29].[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:9]1[C:8](=[O:24])[C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[C:4]3[CH2:1][N+:2]([CH3:26])([CH3:3])[CH2:26][N:2]([CH3:1])[C:3]=3[CH:25]=2)[C:10]1=[O:15])([OH:23])=[O:22]
Reactant: CN(C)c1cc2c3c(cccc3c1)C(=O)N(CCCCCC(=O)O)C2=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN1C[N+](C)(C)Cc2c1cc1c3c(cccc23)C(=O)N(CCCCCC(=O)O)C1=O
Product: [Cl-]
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 90 mg (0.25 mmol) of 6-(5-dimethylamino-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-2-yl)hexanoic acid in 0.4 mL of DMF 0.09 ml of POCl3 were added dropwise at 40° C. The mixture was heated under stirring at 80° C. for 1.5 h, cooled to RT and poured into ice water. The product was precipitated with isopropyl alcohol and purified by column chromatography on reverse phase (PR-18, H2O-acetonitrile 5:1, v/v). Yield: 45 mg (40%) 4a. M.p. 186-188° C. 1H-NMR (200 MHz, DMSO-d6, δ, ppm): 8.39-7.82 (5H, arom), 5.17 s (2H, CH2), 4.85 s (2H, CH2), 4.04 t (2H, α-CH2, J 7.3 Hz), 3.65 s (3H, NCH3), 3.19 s (6H, +N(CH3)2), 1.94 t (2H, ε-CH2, J 7.3 Hz), 1.54 m (4H, β,γ-CH2 J 7.3 Hz), 1.26 m (2H, δ-CH2, J 7.3 Hz).
Reaction SMILES: [N:1]1([C:6]2[CH:37]=[CH:36][C:9]([O:10][CH2:11][CH2:12][N:13](CC3C=CC=CC=3)[CH2:14][CH:15]([OH:28])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][O:26][CH3:27])=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>Cl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:28])[CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][O:26][CH3:27])=[CH:20][CH:19]=3)=[CH:36][CH:37]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COCCc1ccc(OCC(O)CN(CCOc2ccc(-n3ccnc3)cc2)Cc2ccccc2)cc1
Agent: Cl
Product: COCCc1ccc(OCC(O)CNCCOc2ccc(-n3ccnc3)cc2)cc1

Procedure:
Dissolve 6.36 g (.013 mol) 1-[[2-[4-(1H-imidazol-1-yl)phenoxy]ethyl](phenylmethyl)amino]-3-[4-(2-methoxyethyl)phenoxy]-2-propanol in 50 mL 5 M methanolic HCl and remove the solvents in vacuo. Dissolve the residue in glacial acetic acid with 0.86 g10% palladium hydroxide on carbon. The reaction mixture is hydrogenated under 52 psi H2 on a Parr Hydrogenator. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile:ammonia,9:1). At the completion of the reaction, the catalyst is filtered and the solvents are removed in vacuo. The resulting oil is chromatographed on alumina (activity III) using 2% methanol in methylene chloride to provide the title compound.
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)[C:3]1[C:12]([C:13]2[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=2F)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([OH:22])=[CH:8]2.CC(C)([O-])C.[K+]>CN(C=O)C>[F:20][C:16]1[CH:15]=[C:14]2[C:13](=[C:18]([F:19])[CH:17]=1)[C:12]1[C:3](=[C:4]3[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:22])[CH:6]=[CH:5]3)[CH:2]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)=[CH:27][CH:28]=1)[O:1]2
Reactant: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc2c3c(ccc2c1)-c1c(F)cc(F)cc1OC3c1ccc(OCCN2CCCCC2)cc1
Temperature: 50 °C

Procedure:
Alternatively, dissolve enantiomerically enriched 5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-6-(2,4,6-trifluoro-phenyl)-naphthalen-2-ol (804 mg, 1.59 mmol) in DMF (10 mL). Add potassium tert-butoxide (532 mg, 4.75 mmol). Heat at 50° C. for 2 minutes. Pour the reaction mixture into ice (5 g). Extract with ethyl acetate (100 mL). Separate the layers and wash the organic layer with 10% aqueous lithium chloride solution (20 mL×2). Dry with magnesium sulfate and concentrate in vacuo. Purify the residue over silica gel, eluting the material with a step gradient of methanol/dichloromethane (0 to 10%), to give the enantiomerically enriched title compound.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH:37]=[C:36]([CH3:38])[O:35][N:34]=1)[NH2:32]>>[CH3:38][C:36]1[O:35][N:34]=[C:33]([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH:37]=1
Reactant: Cc1cc(C(N)=NO)no1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: Cc1cc(-c2noc(C3CC(c4ccc(OC(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)no1

Procedure:
150 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 80 mg (0.56 mmol) of N′-hydroxy-5-methylisoxazole-3-carboximidamide were reacted according to the General Method 2. Yield: 101 mg (54% of theory).
Reaction SMILES: Cl.O1CCOCC1.[O:8]=[C:9]([N:29]1[CH2:34][CH2:33][C:32]2([CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=3)[CH2:36][CH2:35]2)[CH2:31][CH2:30]1)[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[CH2:20][NH:21]C(=O)OC(C)(C)C)[CH:13]=[CH:12]1>O1CCOCC1>[NH2:21][CH2:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[N:11]([CH2:10][C:9]([N:29]1[CH2:34][CH2:33][C:32]3([CH2:35][CH2:36][N:37]([C:40]4[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=4)[CH2:38][CH2:39]3)[CH2:31][CH2:30]1)=[O:8])[CH:12]=[CH:13]2
Reactant: CC(C)(C)OC(=O)NCc1cccc2ccn(CC(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)c12
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cccc2ccn(CC(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
Dioxane-HCl (6 ml) was added to a solution of tert-butyl (1-(2-oxo-2-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)-1H-indol-7-yl)methylcarbamate (600 mg, 1.16 mmol, 1.0 equiv.) in dioxane (6 ml), and the mixture was stirred for 1 h at RT. When the reaction was complete (TLC monitoring), the solvent was removed under vacuum and the residue was adjusted to a basic pH value with TEA and was concentrated again. The crude product was purified by column chromatography (Alox neutral; 5-10% MeOH/DCM), and the desired product was thus obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:24]=[CH:23][C:11]([C:12]([N:14]2[CH2:19][CH2:18][C:17]3[CH:20]=[CH:21][O:22][C:16]=3[CH2:15]2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:25][NH:26][CH3:27].[CH2:28]=O>C(O)(=O)C>[CH3:25][N:26]([CH2:28][C:21]1[O:22][C:16]2[CH2:15][N:14]([C:12](=[O:13])[C:11]3[CH:23]=[CH:24][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:9][CH:10]=3)[CH2:19][CH2:18][C:17]=2[CH:20]=1)[CH3:27]
Reactant: C=O
Reactant: CNC
Reactant: CCCCCCCc1ccc(C(=O)N2CCc3ccoc3C2)cc1
Solvent: CC(=O)O
Product: CCCCCCCc1ccc(C(=O)N2CCc3cc(CN(C)C)oc3C2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.260 g (0.799 mmol) of 6-(4-heptylbenzoyl)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 20 ml of acetic acid, 0.108 ml (1.20 mmol) of 50% aqueous dimethylamine and 0.097 ml (1.20 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. Additionally, 0.072 ml (0.799 mmol) of 50% aqueous dimethylamine and 0.064 ml (0.799 mmol) of 37% aqueous formaldehyde were added, followed by stirring for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous solution of sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1 to 25/1) to yield the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:19]1[C:27]2[O:26][CH:25]=[CH:24][C:23]=2[CH:22]=[C:21]([CH3:28])[CH:20]=1.COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[C:27]3[O:26][CH:25]=[CH:24][C:23]=3[CH:22]=[C:21]([CH3:28])[CH:20]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)c2occc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: COc1ccc(-c2cc(C)cc3ccoc23)cc1
Yield: 90.4 %

Procedure:
A mixture of 4-methoxyphenylboronic acid (4.76 g, 31.3 mmol), Na2CO3 (32.6 2 N aqueous, 65.2 mmol), Pd(PPh3)4 (1.5 g, 1.3 mmol), 7-bromo-5-methylbenzofuran (5.5 g, 26.1 mmol), and ethylene glycol dimethyl ether (275 ml) was heated to reflux for 12 h. The reaction was cooled, ether (500 ml) was added and the layers separated. The aqueous was further extracted with ether and the organic layers were dried over anhydrous Na2SO4, passed through a silica plug and concentrated to 7.16 g brown oil. Further purification by column chromatography (10% EtOAc/hexanes) afforded 5.62 g (91%) product as a clear oil: 1H NMR (300 MHz, DMSO-d6): δ 3.44 (3H, s), 3.82 (3H, s), 6.94 (1H, d, J=2.2 Hz), 7.108 (2H, d, J=8.8 Hz), 7.30 (1H, s), 7.38 (1H, s), 7.81 (2H, d, J=8.8 Hz), 8.00 (1H, d, J=2.2 Hz).
Reaction SMILES: [CH3:1][N:2](C=O)C.[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[C:8]=1[CH2:18][C:19]([O:21]C)=[O:20]>O>[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:1]#[N:2])[CH:13]=2)[C:8]=1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1c(O)ccc2cc(Br)ccc12
Solvent: O
Product: N#Cc1ccc2c(CC(=O)O)c(O)ccc2c1

Procedure:
100 Milliliters of DMF was added to 177 g of methyl 2-hydroxy-6-bromo-1-naphthylacetate and 70.9 g of cuprous cyanide, and refluxed under heating for 3.5 hours in a nitrogen stream. With stirring under heating, 300 ml of water was added and supernatant liquid was decanted, and then this procedure was repeated. To the resulting residue was added 2.3 liters of a 4% aqueous sodium hydroxide solution, followed by stirring at 25° C. for 1 hour. The insoluble matter was filtered, and concentrated hydrochloric acid was added to the filtrate and the precipitate was collected by filtration. To this collected precipitate was added 200 ml of water, and thereto were added 501 g of ferrous sulfate.heptahydrate and 60 ml of concentrated hydrochloric acid, followed by stirring at 70° C. for 1 hour. After leaving for cooling, the resulting precipitate was collected by filtration and sufficiently washed with water. Thereafter, 3 liters of methanol was added thereto to dissolve the precipitate at 40° C. The insoluble matter was filtered off, and 3 liters of water was added to the filtrate to obtain a crude product. The product was repeatedly subjected to recrystallization with 10% hydrous methanol to obtain 42 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[N:25]1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C=O)C>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29]([C:27]2[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=2)=[O:30])=[CH:3][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cn1cc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc([C@@H]3C[C@H]3N(CC3CC3)C(=O)OC(C)(C)C)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (85.8 mg) and 1-methyl-1H-pyrazole-4-carboxylic acid (42.9 mg) in DMF (1.42 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (82 mg). The mixture was stirred at room temperature overnight, and poured into water. The mixture was extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (114.8 mg).