Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[OH:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1.C(#N)C.CCCCCCC=CCCC>ClCCl>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:36]3[CH:35]=[CH:34][C:33]([OH:32])=[CH:38][CH:37]=3)(=[O:40])=[O:41])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: CCCC=CCCCCCC
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(O)cc3)cc2)c(C)c1-c1ccccc1
Yield: 75.6 %

Procedure:
A mixture of phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22, 100 mg, 0.24 mmol), 4-hydroxybenzenesulfonamide (42 mg, 0.24 mmol), acetonitrile (3 mL) and 1,8-[5.4.0]-7-undecene (36 μL, 0.24 mmol) was stirred at room temperature for 16 h. The mixture was diluted with dichloromethane, and washed with 1 M hydrochloric acid and sat. NaHCO3 aq. The organic fraction was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by TLC with dichloromethane/methanol (10:1) to afford 89 mg (74%) of the title compound as white solids: 1H-NMR [CDCl3/CD3OD(4:1)] δ 7.73-7.68 (2H, m), 7.48-7.23 (9H, m), 6.88-6.83 (2H, m), 3.47 (2H, t, J=6.7 Hz), 2.84 (2H, t, J=6.7 Hz), 2.33 (3H, s), 2.26 (3H, s).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:19][CH:18]4[O:20][CH:15]([CH2:16][CH2:17]4)[CH2:14]3)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>CN(C1C=CN=CC=1)C>[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH2:14][CH:15]5[O:20][CH:18]([CH2:17][CH2:16]5)[CH2:19]4)[N:10]=3)=[CH:22][CH:23]=2)=[O:37])=[CH:31][CH:30]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Agent: CN(C)c1ccncc1
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (100 mg, 0.27 mmol)-4-fluoro phenylisocyanate (50 mg, 0.36 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; mp: 248; Yield 86 mg (86%); (M+H) 506.4
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C.O.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([B:20]([OH:23])[OH:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: -80 °C
Yield: 41 %

Procedure:
10.0 g (0.032 mol) of 4,4′-dibromobiphenyl was put in a 500 mL three neck flask, and nitrogen was substituted for air in the flask, and then 200 mL of tetrahydrofuran was added and stirred at −80° C. 20 mL (0.032 mol) of n-butyllithium (1.60 M hexane solution) was dropped into a reaction solution, and stirred for 1 hour at −80° C., and 40 mL (0.060 mol) of trimethyl borate was added and stirred for 1 hour while returning to room temperature. After 200 mL (1.0 mol/L) of hydrochloric acid water was added to the reaction solution, and stirred for about 12 hours, an organic layer was washed with a saturated sodium hydrogen carbonate solution and saturated saline, and then dried with magnesium sulfate. After the reaction solution was naturally filtered, a solid which was obtained by concentrating a filtrate, was recrystallized with a mixture of ethyl acetate and hexane. 3.7 g of 4-(4-bromophenyl)phenylboronic acid that was a target substance and was a white solid was obtained in a yield of 41% (Synthesis Scheme (e-1)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:36](Cl)(=[O:38])=[O:37])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)(=[O:37])=[O:38])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(OC)c(OC)c4)cc3)cc2C1=O

Procedure:
The compound of example 85 was prepared analogous to compound of example 77 by reaction of compound of example 6 with 3,4-dimethoxybenzene sulfonyl chloride. The compound of example 85 was used directly without isolation for the preparation of compound of example 86.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].C(N(CC)CC)C.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35]>O1CCCC1>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:2][C:3]2[S:4][CH:5]=[CH:6][C:7]=2[S:8]([N:11]([CH3:26])[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][C:18]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[CH:17]3)(=[O:10])=[O:9])[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CCl
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2sccc2S(=O)(=O)N(C)c2cccc3cc(-c4nccs4)[nH]c23)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 81.3 %

Procedure:
To a solution of 2-(chloromethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (110 mg) and triethylamine (150 μL) in tetrahydrofuran (5 mL) was added N-acetylpiperazine (33 mg). The reaction mixture was stirred at room temperature for 10 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (108 mg, yield 81%) as pale-yellow crystals. melting point 242° C.
Reaction SMILES: [CH3:1][CH:2]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:8](Br)[CH2:7][C:6]=2[CH2:5][C:4](=[O:17])[NH:3]1.[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(O)C>[CH3:1][CH:2]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:8]([NH:21][CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]=2[CH2:5][C:4](=[O:17])[NH:3]1
Reactant: CC(C)N
Reactant: CC1NC(=O)CC2=C1c1cccnc1N(Br)C2
Solvent: CCO
Product: CC(C)NN1CC2=C(c3cccnc31)C(C)NC(=O)C2
Yield: 87 %

Procedure:
3.6 g (0.012 mol) of 1-methyl-6-bromo-1,2-dihydropyrido[4,3-c][1,8]naphthyridin-3(4H)-one, 30 ml of absolute ethanol and 10 ml of isopropylamine are stirred for 6 hours at 160° C. in an autoclave. After cooling, the crystalline precipitate is filtered off under suction and recrystallized from methanol. 2.82 g (87% of theory) of 1-methyl-6-isopropylamino-1,2-dihydropyrido-[4,3-c][1,8]naphthyridin-3(4H)-one are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:22](=[O:32])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.B.[Na]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:22](=[O:32])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][CH:17]([OH:21])[CH2:18][CH2:19][CH3:20])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCCC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Agent: B
Agent: [Na]
Solvent: CO
Product: CCCC(O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.9 %

Procedure:
10-bromo-2-(2-oxopentyloxy)-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (400 mg) obtained in Example 40 was suspended in anhydrous methanol (20 ml), and to the suspension was added in small portions sodium boron hydride (92 mg) in an ice bath, and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure and the residue was extracted by adding water and methylene chloride. The methylene chloride layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 4% methanol) to obtain the title compound (140 mg; 28%).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56]([C:58]4[O:59][C:60]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)=[CH:61][N:62]=4)=[O:57])=[CH:51][N:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56]([C:58]4[O:59][C:60]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)=[CH:61][N:62]=4)=[O:57])=[CH:51][N:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)o4)cn3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)o4)cn3)cc2C1=O
Yield: 77 %

Procedure:
The compound of example 635 was prepared analogous to the compound of example 98 by hydrolysis of compound of example 634.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[CH:23]=[C:22]([C:24]2([OH:28])[CH2:27][O:26][CH2:25]2)[CH:21]=[C:20]([C:29]([F:32])([F:31])[F:30])[N:19]=1.[Cl-].[NH4+]>O1CCCC1.O>[OH:28][C:24]1([C:22]2[CH:21]=[C:20]([C:29]([F:32])([F:31])[F:30])[N:19]=[C:18]([O:3][CH:4]3[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]3)[CH:23]=2)[CH2:25][O:26][CH2:27]1
Reactant: OC1(c2cc(Cl)nc(C(F)(F)F)c2)COC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C3(O)COC3)cc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To sodium hydride (60% in mineral oil, 0.20 g, 4.9 mmol) in a dry flask was added tetrahydrofuran (20 mL), followed by tert-butyl 4-hydroxypiperidine-1-carboxylate (0.98 g, 4.9 mmol, Aldrich). After stirring for 1 hour at room temperature, a solution of 3-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]oxetan-3-ol (0.31 g, 1.2 mmol, from Step 1) in tetrahydrofuran (11 mL) was introduced. The reaction was stirred at ambient temperature for 2 hours, followed by heating to 65° C. overnight. The reaction was cooled to room temperature and water was added, followed by saturated ammonium chloride to adjust the pH to between 7 and 8. The product was extracted with two portions of DCM. The combined organic extracts were dried over sodium sulfate, decanted and concentrated. The product was purified by flash chromatography, eluting with a gradient from 0-20% EtOAc in hexanes, on a 40 g silica gel column to afford 0.17 g of desired product (yield 30%). 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=1.3 Hz, 1H), 7.22-7.15 (m, 1H), 5.28 (tt, J=7.6, 3.7 Hz, 1H), 4.91 (d, J=7.6 Hz, 2H), 4.77 (d, J=6.9 Hz, 2H), 3.72 (ddd, J=12.5, 6.6, 3.9 Hz, 2H), 3.32 (ddd, J=13.8, 8.0, 3.7 Hz, 2H), 1.98 (ddt, J=13.6, 7.1, 3.6 Hz, 2H), 1.73 (ddt, J=16.5, 8.1, 3.9 Hz, 2H), 1.46 (s, 9H). 19F NMR (376 MHz, CDCl3) δ −68.78 (s). LCMS (M+Na)+: 441.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].I[C:16]1[NH:17][CH:18]=[CH:19][N:20]=1>>[NH:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:2]#[C:1][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8]
Reactant: Ic1ncc[nH]1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncc[nH]1
Yield: 77 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (79 mg, 0.43 mmol) was converted (using 2-iodo-1H-imidazole instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 83 mg, 77%) which was obtained as an off-white solid. MS: m/e=250.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[C:22]#[N:23])[CH:18]([NH:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1)[CH2:17][CH2:16]2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[OH:40].OO.[OH-].[Na+]>O>[CH2:1]([O:8][CH2:9][C:10]1[NH:23][C:22](=[O:40])[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][CH2:17][CH:18]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=4)[C:19]=3[CH:20]=2)[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc(NC(=O)COCc4ccccc4)c(C#N)cc32)cc1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(NC2CCc3cc4nc(COCc5ccccc5)[nH]c(=O)c4cc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred, ice-bath cooled mixture of tert-butyl 4-[N-(5-(2-benzyloxy-ethanoylamino)-6-cyanoindan-1-yl)amino]benzoate (3.77 g, 7.59 mmol), EtOH (70 ml), and H2O (11 ml) was added 30% H2O2 (8.05 ml) followed by granulated NaOH pellets (0.640 g, 16.0 mmol). The reaction mixture was stirred at 0° C. for 10 min, then placed in an oil-bath preheated to 55° C. and stirred at this temperature for 1 hour. The solvents were then removed in vacuo; the residue was treated with H2O (80 ml) and the pH was adjusted to ˜5 with 1N HCl. The pale yellow solid was collected by filtration, washed with H2O and dried in vacuo over P2O5 (3.56 g, 95%); mp 194-195° C.; 1H-NMR (250 MHz, DMSO-d6, TMS) 1.52 (s, 9H, C(CH3)3), 1.90 (m), 2.62 (m) (1H each, 7-CH), 2.90-3.17 (m, 2H, 8-CH2), 4.43, 4.60 (2×s, 2H each, PhCH2 and OCH2CO), 5.18 (q, J=7.43 Hz, 1H, 6-CH), 6.79 (d, J=8.8 Hz, 2H, 3′,5′-ArH), 6.87 (d, J=8.0 Hz, 1H, N10—H), 7.34 (m, 5H, PhCH2), 7.54, 7.92 (2×s, 1H each, 5-H and 9-H), 7.68 (d, J=8.9 Hz, 2H, 2′,6′-ArH), 12.20 (s, 1H, CONH); MS (ESI, m/z) 520 {(M+Na)+, 90%,}, 498 {(M+H)+, 100%}; Found: C, 72.13; H, 6.25; N, 8.38; C30H31N3O4 requires C, 72.41; H, 6.28; N, 8.44%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].C([Li])CCC.[C:16](=[O:18])=[O:17]>C1COCC1>[C:5]([C:4]1[CH:3]=[C:2]([F:1])[C:9]([C:16]([OH:18])=[O:17])=[C:8]([F:10])[CH:7]=1)#[N:6]
Reactant: O=C=O
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(C(=O)O)c(F)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of 3,5-difluorobenzonitrile (3.48 g, 25 mmol, Fluorochem) in THF (35 ml) was added slowly butyl lithium (1.6M in hexanes) (15.63 ml, 25.00 mmol) at −75° C. The resulting solution was stirred for 1 hr at −70-75° C. Then this solution was poured on freshly crushed dry ice CO2 (44.0 g, 1000 mmol). The contents were stirred at room temperature until dry ice disappearance. The solvent was evaporated off under HV. Then residual organic layer was suspended in water and extracted with ethyl acetate (3×50 ml). The product containing aqueous layer was acidified with aqueous HCl solution and the product was re-extracted in the organic layer with Ethylacetate (4×50 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give a white crystalline solid (2.5731 g, 13.91 mmol, 55.6% yield)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[N:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H][H]>CCO.C(OCC)(=O)C.[Pd]>[NH2:7][C:5]1[N:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:2]([CH3:1])[CH:6]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc(N)cn1C

Procedure:
Im-2 (0.4 g) in EtOH/ethyl acetate (1:1, 14 mL) and Pd/C (10%, 0.3 g) were stirred under a slight positive pressure of hydrogen (ca 1.1 atm) for 3-4 hr. The reaction mixture was filtered using celite and solvent evaporated on the rotary. The remaining solid was freeze dried to yield a slightly yellow product. Yield (0.38 g, 95%). 1H NMR (DMSO): δ 6.45 (s, 1H), 4.5 (bs, 2H, NH2), 4.2 (q, 2H, J=7 Hz), 3.76 (s, 3H), 1.24 (t, 3H, J=7.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.C1(CN)CCCCC1.[O:19]=[C:20]1[C:28]2([CH2:32][O:31][C:30]3[CH:33]=[C:34]4[C:38](=[CH:39][C:29]2=3)[CH2:37][CH2:36][O:35]4)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[CH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:45](=[O:46])[C:44]3[CH:48]=[CH:49][C:41]([CH2:40][N:21]4[C:22]5[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:28]5([CH2:32][O:31][C:30]6[CH:33]=[C:34]7[C:38](=[CH:39][C:29]5=6)[CH2:37][CH2:36][O:35]7)[C:20]4=[O:19])=[CH:42][CH:43]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: Nc1ccc2c(c1)CCC2
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1ccc2c(c1)CCC2)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 5-aminoindan to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2,3-dihydro-1H-inden-5-yl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (65%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.83 (d, J=8.1 Hz, 2H), 7.79 (s, 1H), 7.56 (s, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.28-7.21 (m, 2H), 7.21-7.14 (m, 2H), 7.08-6.97 (m, 1H), 6.74 (d, J=7.7 Hz, 1H), 6.46 (s, 1H), 6.42 (s, 1H), 4.99 (ABq, 2H), 4.83 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 3.03-2.80 (m, 6H), 2.15-1.97 (m, 2H); MS (ES+) m/z 529.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.N1C=CC=CC=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O>O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1ccc(F)c(F)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc(F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a mixture of 2-chloro-3,4-difluorobenzamide (1.20 g), pyridine (1.01 mL) and N,N-dimethylformamide (18 mL) was added oxalyl chloride (0.82 mL) at 0° C. over 10 min. The mixture was stirred for 1 hr while raising the temperature to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane) to give the title compound as a solid (yield: 983 mg).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-:18].[C:19]([O:23][C:24]([N:26]([CH3:52])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]2[CH:51]=[CH:50][C:38]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44]OS(C)(=O)=O)=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].ClCCl>C1COCC1>[C:19]([O:23][C:24](=[O:25])[N:26]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]2[CH:51]=[CH:50][C:38]([O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][F:18])=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)[CH3:52])([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCOS(C)(=O)=O)cc2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCF)cc2)cc1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
Anhydrous TBAF (Cox D P, et al., J Org Chem. 1984; 49:3216-19) (38.5 mg 0.15 mmol) was added to a solution of compound 10a (14.5 mg, 0.03 mmol) in anhydrous THF (3 ml). The mixture was refluxed for 4 hours. After cooled to room temperature, standard workup with dichloromethane was applied and the residue was purified by silica gel preparative TLC (2% methanol in dichloromethane) to afford compound 11a (7 mg, 57%): 1H NMR δ 7.43 (d, 4H, J=8.6 Hz), 7.20 (d, 2H, J=8.4 Hz), 6.97 (q, 2H), 6.91 (d, 2H, J=8.6 Hz), 4.60 (d, t, 2H, J1=47 Hz, J2=4.0 Hz), 4.17 (t, 2H), 3.90 (t, 3H), 3.75 (t, 1H), 3.27 (s, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([OH:77])[C@H:2]1[O:7][C@@H:6]2[O:8][C@H:9]3[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]4[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]5[C@H:32]([OH:33])[C@@H:31]([OH:34])[C@@H:30]([O:35][C@H:36]6[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]7[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]8[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]1[C@H:4]([OH:76])[C@H:5]2[OH:75])[O:56][C@@H:55]8[CH2:63][OH:64])[O:47][C@@H:46]7[CH2:65][OH:66])[O:38][C@@H:37]6[CH2:67][OH:68])[O:29][C@@H:28]5[CH2:69][OH:70])[O:20][C@@H:19]4[CH2:71][OH:72])[O:11][C@@H:10]3[CH2:73][OH:74].[Na+].[Cl-]>>[CH3:3][CH:2]([OH:7])[CH2:1][O:70][CH2:69][C@H:28]1[O:29][C@@H:30]2[O:35][C@H:36]3[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]4[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]5[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]6[C@H:4]([OH:76])[C@@H:5]([OH:75])[C@@H:6]([O:8][C@H:9]7[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]8[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]1[C@H:32]([OH:33])[C@H:31]2[OH:34])[O:20][C@@H:19]8[CH2:71][O:72][CH2:60][CH:54]([OH:53])[CH3:55])[O:11][C@@H:10]7[CH2:73][O:74][CH2:32][CH:27]([OH:26])[CH3:28])[O:7][C@@H:2]6[CH2:1][O:77][CH2:14][CH:9]([OH:8])[CH3:10])[O:56][C@@H:55]5[CH2:63][O:64][CH2:37][CH:36]([OH:35])[CH3:41])[O:47][C@@H:46]4[CH2:65][O:66][CH2:46][CH:45]([OH:44])[CH3:50])[O:38][C@@H:37]3[CH2:67][O:68][CH2:19][CH:18]([OH:17])[CH3:23]
Reactant: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Agent: [Cl-]
Agent: [Na+]
Product: CC(O)COC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8COCC(C)O)O[C@@H]7COCC(C)O)O[C@@H]6COCC(C)O)O[C@@H]5COCC(C)O)O[C@@H]4COCC(C)O)O[C@@H]3COCC(C)O

Procedure:
61 mg (0.21 mmol) of compound described in example 67 and 1.47 g of hydroxypropyl-beta-cyclodextrin (DS 0.58-Mw 1386 g·L−1) were dissolved in 15 mL of dichloromethane and 10 mL of methanol. The limpid mixture was evaporated under reduced pressure at room temperature. The solid obtained was then dissolved in 3 mL of MilliQ water and filtered through filter with 45 micron pore size. The filter was rinsed with 9 mL of MilliQ water. The aqueous solution was then freeze dried giving 2 g of a pale yellow powder containing 4 wt % of product described in example 67 (mol/mol ratio for the complex “dihydro-compound/beta-cyclodextrine”: ⅕). The included molecule is now soluble (20 g·L−1) in a 9 wt % NaCl aqueous solution.