Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2ccccc2)C1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)c2ccco2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
To a stirred suspension of N-(1-Boc-piperidin-3-ylmethyl)-aniline 4 (61.0 mg, 0.21 mmol) and piperidinomethyl polystyrene resin (60 mg) in 0.6 mL of dry CH2Cl2 was added 2-furoyl chloride (95%, 35.1 mg, 1.2 eq.) at room temperature. After being shaken at room temperature for 4 hours, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded furan-2-carboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl amide 13 (75 mg, 93%). LRMS 285 (M−100)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.[C:44](=[O:47])([O-:46])[O-].[Cs+].[Cs+].[CH2:50]([OH:54])[CH2:51][CH2:52][OH:53]>[Cu]I.C1(C)C=CC=CC=1>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[CH:8]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:53][CH2:52][CH2:51][CH2:50][OH:54].[C:19]([O-:18])(=[O:53])[C:44]([O-:46])=[O:47]
Reactant: CN1CCC(OC(c2cccc(I)c2)c2nc3ccccc3s2)CC1
Reactant: OCCCO
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CN1CCC(OC(c2cccc(OCCCO)c2)c2nc3ccccc3s2)CC1
Product: O=C([O-])C(=O)[O-]
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A screw-capped tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (example 41, 150 mg), copper(I) iodide (6.5 mg), 3,4,7,8-tetramethyl-1,10-phenanthroline (16.3 mg), cesium carbonate (223 mg), propan-1,3-diol (74 mg), ground 4 Å molecular sieves (80 mg) and toluene (4 mL). The tube is evacuated, filled with argon and sealed. After stirring at 90° C. for 24 h, the mixture is diluted with dichloromethane, water and ammonia. After filtration and decantation, the aqueous phase is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5). The base is converted into its oxalate salt in acetone to give 3-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenoxy}propan-1-ol, oxalate melting at 79° C.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@:19]2([CH3:52])[C:23](=[O:24])[N:22]([CH2:25][C:26]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[O:27])[C:21](=[O:40])[N:20]2[CH2:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)=[CH:15][CH:14]=1)#[N:12]>C(O)C>[NH2:12][C:11](=[N:3][OH:2])[C:13]1[CH:18]=[CH:17][C:16]([C@@:19]2([CH3:52])[C:23](=[O:24])[N:22]([CH2:25][C:26]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[O:27])[C:21](=[O:40])[N:20]2[CH2:41][C:42]2[CH:51]=[CH:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH:43]=2)=[CH:15][CH:14]=1
Reactant: [NH3+]O
Reactant: C[C@]1(c2ccc(C#N)cc2)C(=O)N(CC(=O)OCc2ccc3ccccc3c2)C(=O)N1Cc1ccc2ccccc2c1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@]1(c2ccc(C(N)=NO)cc2)C(=O)N(CC(=O)OCc2ccc3ccccc3c2)C(=O)N1Cc1ccc2ccccc2c1
Yield: 86.4 %

Procedure:
1.67 g (24 mmol) of hydroxylammonium chloride and 5.04 ml (36 mmol) of triethylamine were added to a solution of 6.64 g (12 mmol) of 2-naphthylmethyl ((S)-4-(4-cyanophenyl)-3-(2-naphthylmethyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetate in 120 ml of absolute ethanol and the mixture was heated under reflux for 2.5 h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The phases were separated and the water phase was extracted with ethyl acetate. The combined organic phases were washed with water and dried over magnesium sulfate. After filtration, the solvent was removed in vacuo and 6.08 g (86%) of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 16 h
Yield: 89.6 %

Procedure:
1st stage: A solution of 21 g of indole-4-carboxylic-acid-methylester in 100 ml of methylene-chloride, 24.9 ml of triethylamine and 7.34 g of 4-dimethyl-aminopyridine is proportionately mixed at 0° C. with 34.2 g of p-toluene-sulfonic-acid-chloride. After 16 h at 0° C., the mixture is diluted with methylene chloride, washed neutral with saturated sodium bicarbonate solution and NaCl solution, and the solvent is distilled off in vacuum. 35.37 g of 1-tosylindole-4-carboxylic-acid-methylester with a m.p. of 145°-147° C. (diisopropylether) is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1cccs1
Reactant: N#Cc1c(N2CCNCC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)ccc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 48 (362 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 359 mg (76%) of white solids. M.P. 246° C. 1H NMR (DMSO-d6): δ 3.67 (m, 4H), 3.94 (m, 4H), 5.49 (s, 2H), 7.16 (m, 1H), 7.20-7.26 (m, 3H), 7.45 (dd, J=4.6, 9.4 Hz, 1H), 7.50 (d, J=3.9 Hz, 1H), 7.55 (td, J=2.7, 9.2 Hz, 1H), 7.66 (dd, J=2.8, 9.7 Hz, 1H), 7.80 (d, J=5.1 Hz, 1H). EIMS m/z 473 (M+1). Anal. (C26H21FN4O2S) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=1>C(#N)C>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9]2[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:4]=1
Reactant: OCc1cccc(Br)n1
Reactant: Nc1ccncc1
Solvent: CC#N
Product: OCc1cccc(Nc2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.35 g (14.3 mmol) of 4-aminopyridine and 1.34 g (7.1 mmol) of (6-bromopyridin-2-yl)methanol are stirred at 150° C. for 4 h. After cooling to RT, 50 ml of acetonitrile are added and the reaction mixture is stirred for 20 min. The precipitate formed is filtered off with suction at 0° C. and washed with 10 ml of acetonitrile.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:24])[C@H:9]([CH:21]([CH3:23])[CH3:22])[NH:10][C:11](OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]1([C:31]2[CH:38]=[CH:37][CH:36]=[C:33](C=O)[C:32]=2[OH:39])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCCCCC.C(OCC)(=O)C>CO.[C].[Pd]>[CH:1]1([NH:7][C:8](=[O:24])[C@H:9]([CH:21]([CH3:22])[CH3:23])[N:10]=[CH:11][C:33]2[C:32](=[C:31]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:38]=[CH:37][CH:36]=2)[OH:39])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cccc(-c2ccccc2)c1O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC1CCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CC(C)[C@H](N=Cc1cccc(-c2ccccc2)c1O)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.6 %

Procedure:
The carbobenzoxy-(S)-valine cyclohexylamide (0.33 g, 1 mmol) was dissolved in methanol (30 ml) and the solution was stirred at room temperature for 3 hours in the presence of 5% palladium-carbon (30 mg) under a hydrogen gas atmosphere. After the reaction was over, the palladium-carbon catalyst was filtered off to obtain a colorless solution. To this solution was added 3-phenylsalicylaldehyde (0.22 g, 1.1 mmol). This solution was stirred at room temperature for 24 hours and concentrated under reduced pressure to obtain yellow solids. These solids were subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 0.29 g (76%) of the desired N-(3-phenylsalicylidene)-(S)-valine cyclohexylamide which was further recrystallized from ether. m.p. 87.0°-89.5° C. [α]26D +158.3° (c 1.02, CHCl3)
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([CH:22]4C[CH2:23]4)=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:25])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(COC3C(CC)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.CS(N)(=O)=O.[N:55]1([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:58][CH2:57][CH2:56]1>>[C:1]12([CH2:11][O:12][C:13]3[C:21]([CH2:22][CH3:23])=[CH:20][C:16]([C:17]([NH:62][S:59]([N:55]4[CH2:58][CH2:57][CH2:56]4)(=[O:61])=[O:60])=[O:19])=[C:15]([F:25])[CH:14]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CCc1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Agent: CS(N)(=O)=O
Product: CCc1cc(C(=O)NS(=O)(=O)N2CCC2)c(F)cc1OCC12CC3CC(CC(C3)C1)C2

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-ethyl-2-fluorobenzoic acid and methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as colorless solid (0.16 g, 59%): 1H NMR (300 MHz, DMSO-d6) δ 11.60 (s, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.94 (d, J=13.0 Hz, 1H), 4.08-4.01 (m, 4H), 3.62 (s, 2H), 2.59 (q, J=7.5 Hz, 2H), 2.22-2.12 (m, 2H), 1.99 (br s, 3H), 1.75-1.64 (m, 12H), 1.15 (t, J=7.5 Hz, 3H); MS (ES+) m/z 451.2 (M+1); MS (ES−) m/z 449.3 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].O=C1CCC(=O)N1O[C:26](=O)[CH:27]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:28][CH3:29].CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[NH:30][CH:27]([C:26]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:17])[N:1]=1)[CH2:28][CH3:29])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cccc(N)c1C(=O)Nc1ccccc1
Reactant: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCC(NC(=O)OCc1ccccc1)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
Compound 15 (1.20 g, 5.30 mmol) was combined with 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester (2.13 g, 6.36 mmol), dimethylaminopyridine (915 mg, 7.49 mmol), and diisopropylethylamine (1.10 mL, 6.36 mmol) in toluene (15 mL). The mixture was heated to 110° C. and stirred at that temperature for 22 hours. After cooling, the reaction was purified by flash chromatography to provide the quinazolinone (16) as a pale yellow solid. MS (ES): m/z 428 (M+H). 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.75 (d, 2H, J=7.9 Hz), 7.32 (t, 2H, J=7.8 Hz), 7.07 (t, 1H, J=7.3 Hz), 7.00 (t, 1H, J=7.8 Hz), 6.58 (d, 1H, J=8.1 Hz), 6.46 (d, 1H, J=7.4 Hz), 4.98 (br. s, 2H), 2.21 (s, 3H). The reaction described above and compound 16 are shown below.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:24]([NH2:26])=[O:25])[CH:19]=[CH:20][CH:21]=1)=[O:14].I[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(NCC)C.C(O)=O>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:17]=[C:18](/[C:22](/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23]\[C:24]([NH2:26])=[O:25])[CH:19]=[CH:20][CH:21]=1)=[O:14]
Reactant: Ic1ccccc1
Reactant: NC(=O)C#Cc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CCNCC
Product: NC(=O)/C=C(/c1ccccc1)c1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Temperature: 75 °C
Yield: 19.9 %

Procedure:
A mixture of 3-{3-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide (31.0 mg, 0.085 mmol), iodobenzene (0.010 mL, 0.089 mmol), diethylamine (0.029 mL, 0.281 mmol), formic acid (0.0083 mL, 0.221 mmol), and bis(dibenzylideneacetone)palladium(0) (3.4 mg, 0.006 mmol) in 1.1 mL EtOAc (degassed) was heated at 75° C. for 16 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed with H2O/brine mixture, brine, dried with anhydrous Na2SO4 and rotary evaporated. The crude material was chromatographed eluting with EtOAc/CHCl3 to give the higher Rf material as an off-white solid. The solid was recrystallized from EtOAc/hexane to give the title compound as a white solid (7.5 mg, 20%). 1H NMR (CD3CN) δ: 8.54-8.58 (m, 1H), 7.89 (s, 1H), 7.71 (d, J=3.2 Hz, 1H), 7.14-7.39 (m, 10H), 6.78-6.82 (m, 1H), 6.39 (s, 1H), 6.14 (br. s, 1H), 5.79 (br. s, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.O[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: OCCN1CCCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCN1CCCC1
Yield: 11.5 %

Procedure:
Using an analogous procedure to that described in Example 15, 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), was reacted with 1-(2-hydroxyethyl)pyrrolidine (0.11 ml, 0.9 mmol) to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)cinnoline (30 mg, 12%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:17]1([CH2:22][CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][C:29]([CH:34]=O)=[CH:28]3)[CH2:21][CH2:20][CH2:19][CH2:18]1.N1CCCCC1>C(O)C>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3=[CH:34][C:29]2[NH:30][C:31]3[C:27]([CH:28]=2)=[CH:26][C:25]([O:24][CH2:23][CH2:22][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:33][CH:32]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(-c3ccccc3)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Temperature: 100 °C
Yield: 60.7 %

Procedure:
A mixture of 5-phenyl-2-oxindole (23 mg, 0.11 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (29 mg, 0.11 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 30 mg (61%) of the title compound as an orange solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH3:2].C[N:20]([CH:22]=O)C.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=O)[CH2:39]Br)=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O.CCOCC>[C:25]12([CH2:24][O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[N:20]=[C:22]([CH2:34][CH:35]([CH3:38])[CH3:36])[N:14]([C:11]5[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])=[CH:9][CH:10]=5)[CH:39]=4)=[CH:34][CH:33]=3)[CH2:30][CH:29]3[CH2:24][CH:25]([CH2:30][CH:27]([CH2:28]3)[CH2:26]1)[CH2:26]2
Reactant: CN(C)C=O
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reactant: CCN(CC)CCCOc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Solvent: O
Product: CCN(CC)CCCOc1ccc(-n2cc(-c3ccc(OCC45CC6CC(CC(C6)C4)C5)cc3)nc2CC(C)C)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol) in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol). The reaction mixture was stirred under nitrogen at rt until completion, as indicated by HPLC. The reaction mixture was then diluted with cold H2O and the product was isolated in Et2O. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product was obtained from 2–7% MeOH/DCM (yield ˜30%).
Reaction SMILES: C(O[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][C:13]=1F)CCCCCCCCC.S(=O)(=O)(O)O>N1C=CC=CC=1.CO>[CH:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:19]#[C:18][C:15]2[CH:14]=[CH:13][CH:12]=[CH:17][CH:16]=2)=[CH:16][CH:17]=1
Reactant: C#Cc1ccc(OCCCCCCCCCC)c(F)c1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: CO
Product: C(C#Cc1ccccc1)#Cc1ccccc1
Temperature: 25 °C
Yield: 225.9 %

Procedure:
To a 50 ml round bottom flask equipped with a magnetic stirrer and reflux condenser was added 300 mg 4-decyloxy-3-fluorophenylacetylene and 43 mg cupric acetate in 40 ml 1:1 pyridine/MeOH. The reaction mixture was refluxed for 2 hrs, allowed to cool to room temperature and then added dropwise into a stirred 9M aqueous sulfuric acid solution at ice bath temperature. The resulting cream-like suspension was extracted with ethyl ether and sequentially washed with water (3×) and brine and dried with anhydrous magnesium sulfate yielding 289 mg of a yellow-brown solid. Flash chromatography (1% ethyl acetate/hexane) and recrystallization of the residue from 95% ethanol afforded 248 mg diphenyldiacetylene (5), 4,4'-didecyloxy-3,3'-difluoro diphenyldiacetylene, as pale yellow needles.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]2[CH2:24][O:23][B:22]([OH:25])[C:21]=2[CH:26]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[F:15][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][C:8]=1[S:11](=[O:13])(=[O:12])[NH:16][C:17]1[CH:18]=[CH:19][C:20]2[CH2:24][O:23][B:22]([OH:25])[C:21]=2[CH:26]=1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(F)c1
Yield: 73.8 %

Procedure:
A solution of 4-acetamido-2-fluorobenzene-1-sulfonyl chloride (1.47 g, 5.84 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (0.870 g, 5.84 mmol), triethylamine (8.2 mL, 58.4 mmol), and N,N-dimethylformamide (30 mL) was stirred for one hour at room temperature. The solution was then made to pH 5 using 6 N hydrochloric acid. The solution was then extracted using ethyl acetate and water. The organic layer was washed five times with water, and then washed with brine. The organic layer was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give N-(3-fluoro-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetamide (1.57 g, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 2.04 (s, 3H), 4.85 (s, 2H), 7.17 (dd, J=2.1 Hz, J=8.2 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.30 (dd, J=1.8 Hz, J=8.7 Hz, 1H), 7.45 (d, J=1.7 Hz, 1H), 7.65-7.70 (m, 2H), 9.19 (s, 1H), 10.41 (s, 1H), 10.44 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>[Ni].CO>[NH2:10][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(CO)cc1N

Procedure:
A mixture of 8.3 parts of 4-amino-3-nitrobenzaldehyde in 200 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After a calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 8.5 parts of 3,4-diaminobenzenemethanol as an oily residue.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:12])=[CH:5][C:6](=[O:11])[C:7]=1[N+:8]([O-:10])=[O:9].C1C(=O)N([I:20])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(O)(=O)C>[I:20][C:5]1[C:6](=[O:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[NH:3][C:4]=1[CH3:12]
Reactant: Cc1cc(=O)c([N+](=O)[O-])c(C)[nH]1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1[nH]c(C)c([N+](=O)[O-])c(=O)c1I
Temperature: 105 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a suspension of 2,6-dimethyl-3-nitropyridin-4(1H)-one (0.44 g, 2.62 mmol) in acetic acid (13 mL) was added NIS (0.765 g, 3.40 mmol). The mixture was heated at 105° C. for 2 h, at which time it was poured into ice water (100 mL). The mixture was stirred for 15 min and cooled in a freezer for 15 min. To the cooled mixture was added 0.1M Na2S2O3 (1-2 mL) with swirling The solids were filtered, washed with water, air dried for 5 min, and further dried in a vacuum oven for 4 h to give 3-iodo-2,6-dimethyl-5-nitropyridin-4(1H)-one (596 mg, 1.824 mmol, 69.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.28-2.31 (m, 3 H) 12.32 (br. s., 1 H). MS(ES) [M+H]+ 294.9.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10]C)=O)[CH2:4][CH2:3]1.O.[NH2:13][NH2:14]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:13][NH2:14])=[O:10])[CH2:4][CH2:3]1
Reactant: COC(=O)C1CCN(C)CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1CCC(C(=O)NN)CC1
Temperature: 120 °C
Yield: 72.5 %

Procedure:
In a 25 mL sealed tube, methyl 1-methylpiperidine-4-carboxylate (0.2 g, 1.0 eq.) was dissolved in ethanol (5 mL) at RT. Hydrazine hydrate (0.127 g, 2 eq.) was introduced dropwise at RT and the reaction mixture was heated at 120° C. for 20 h. The reaction mixture was concentrated under reduced pressure (40° C., 20 mm Hg) to afford the crude 1-methylpiperidine-4-carbohydrazide (0.145 g) which was used without further purification in the following step.