Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:14](I)=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([Cl:23])[CH:22]=1.O1CCOCC1.[Na+].C(O[O-])=O.[Na+].C(O[O-])=O>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.O>[Cl:1][C:2]1[C:14]([C:19]2[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([Cl:23])[CH:20]=2)=[CH:13][C:5]2[NH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[N:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1nc2cc(Cl)c(I)cc2[nH]1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=CO[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1nc2cc(Cl)c(-c3cc(Cl)cc(Cl)c3)cc2[nH]1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Compound number 247 (i.e., 6-chloro-5-(3,5-dichlorophenyl)-2-trifluoromethylbenzimidazole) was prepared as follows. A 100-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen. 5-chloro-6-iodo-2-(trifluoromethyl)-1H-1,3-benzodiazole (200 mg, 0.58 mmol, 1.00 equiv), (3,5-dichlorophenyl)boronic acid (110 mg, 0.58 mmol, 2.00 equiv), dioxane (15 mL), Pd(PPh3)4 (66.8 mg, 0.06 mmol, 0.10 equiv), water (5 mL) and sodium methaneperoxoate sodium (183.8 mg, 1.72 mmol, 3.00 equiv) was placed in the flask. The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). The crude product (100 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-2): Column, C18 silica gel; mobile phase, water increasing to acetonitrile within 40 min; Detector, UV 254 nm. 47.7 mg product was obtained. This resulted in 47.7 mg (23%) of 6-chloro-5-(3,5-dichlorophenyl)-2-trifluoromethylbenzimidazole as a white solid.
Reaction SMILES: Cl[S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3].[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(Cl)Cl>[CH3:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3]
Reactant: CNc1ccccc1
Reactant: COC(=O)CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N(C)c1ccccc1

Procedure:
Chlorine gas was passed through a suspension of 230 g of ice, CH2Cl2 (457 ml) and methyl thioglycolate (86 ml, 942 mmol), cooling with an ice/water bath to maintain an internal temperature below 30° C. After approximately six hours, the yellow/green color of the dissolved chlorine persisted for 30 minutes after gas flow was stopped and passing additional chlorine gas was no longer exothermic. The cooling bath was then removed and the biphasic mixture was allowed to stir at ambient temperature for 1 h before being sparged with nitrogen for 20 minutes. The layers were then separated and the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the intermediate methyl (chlorosulfonyl)acetate (160 g, 927 mmol) as a yellow oil. A portion of the intermediate methyl (chlorosulfonyl)acetate (100 g, 579 mmol) was added dropwise as a solution in CH2Cl2 (290 ml) to a stirring −15° C. solution of N-methylaniline (124 g, 1159 mmol) dissolved in CH2Cl2 (290 ml). The rate of addition was adjusted to maintain the internal temperature below 5° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature over the course of 2 h and 1 M HCl (1000 mL) was added and the aqueous phase was extracted with dichloromethane (2×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting oil was seed crystallized to afford a brown solid. Recrystallization from hot ethanol (320 mL) provided the title compound as an off-white solid. 1H NMR (600 MHz, DMSO-D6) δ 7.40 (m, 4H); 7.31 (m, 1H); 4.30 (s, 2H); 3.65 (s, 3H); 3.26 (s, 3H). LRMS (APCI) calculated for C25H21N4O3S [M+H]+, 244.1; found 244.0.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=O)[N:6]=1)([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].[NH2:23][N:24]1[C:28](=[O:29])[CH2:27][S:26][C:25]1=[S:30]>C(O)(=O)C.C(O)C.O>[CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[N:8]=[C:7]([CH:16]=[C:27]2[S:26][C:25](=[S:30])[N:24]([NH2:23])[C:28]2=[O:29])[N:6]=1)([CH3:3])[CH3:4]
Reactant: NN1C(=O)CSC1=S
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1nc(C=C2SC(=S)N(N)C2=O)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.1 %

Procedure:
A mixture of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde (1.00 g, 4.23 mmol), sodium acetate (1.36 g, 16.6 mmol), and 3-aminorhodanine (0.63 g, 4.3 mmol) in glacial acetic acid (15 mL), under nitrogen atmosphere, is warmed to reflux and refluxed 7 hours. This mixture is then cooled to room temperature and stirred 16 hours. After stirring, the reaction mixture is diluted with a 1:2 mixture of ethanol and water and extracted with ethyl acetate. The combined organic extracts are washed with water, aqueous 0.2N hydrochloric acid solution, and brine. The organic phase is dried over magnesium sulfate, concentrated, and purified by flash chromatography (SiO2, 20% ethyl acetate/hexane) followed by recrystallization from methanol and water to give 0.42 g (27%) of the title compound, mp 194°-196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:21])=[CH:5][C:6]([OH:20])=[C:7]2[C:12](=[O:13])[CH:11]=[C:10]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:9][C:8]=12.[CH2:22]=O.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CO>[OH:20][C:6]1[C:5]([CH2:22][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:4]([OH:21])[C:3]([O:2][CH3:1])=[C:8]2[C:7]=1[C:12](=[O:13])[CH:11]=[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:9]2
Reactant: C1CNCCN1
Reactant: C=O
Reactant: COc1c(O)cc(O)c2c(=O)cc(-c3ccccc3)oc12
Solvent: CO
Product: COc1c(O)c(CN2CCNCC2)c(O)c2c(=O)cc(-c3ccccc3)oc12
Temperature: 55 °C
Reaction time: 4 h

Procedure:
The mixture of Wogonin (28.4 g), methanol (350 ml), 37% formaldehyde solution (8.1 ml), piperazine (8.6 g) was stirred under for 4 hours at 55° C., then precipitates were removed by filtration and washed several times with methanol, after drying under reduced pressure at 65° C. to get the product as yellow solid 36.1 g of purity 99.1%. MS: (API-ES) m/z 383.5[M+H]+; 1H NMR (DMSO-d6, 400 MHz) δ 8.13˜8.14 (m, 2H, Ar-2′,6′-H), 7.64˜7.66 (m, 3H, Ar-3′,4′,5′-H), 7.14 (s, 1H, 3-H), 4.43 (s, 2H, CH2), 3.98 (s, 3H, 8-OCH3), 3.36 (s, 4H, CH2), 3.56 (s, 4H, CH2), 1.25 (s, 1H, NH).
Reaction SMILES: [C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=4[CH2:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:39].C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)C>[ClH:39].[C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][C:20]=4[CH2:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1CC)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1CC)n2C)c1ccccc1
Yield: 61 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-ethylphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 61% of theory, C30H34N6O3 (526.6); EKA mass spectrum: (M+H)+=527; (M+H+Na)++=275; (M+2H)++=264.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].Br[C:34]#[N:35]>C1COCC1.O.C(Cl)Cl>[NH2:35][C:34]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)[C:3]2=[N:4][C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]2[N:1]=1
Reactant: N#CBr
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3N)cc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(N)nc4c(C)cc(C)nc43)cc2)cc1
Yield: 70.9 %

Procedure:
To a stirred solution of N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (300 mg, 0.66 mmol) in THF (6 ml) was added a solution of BrCN (175 mg, 1.65 mmol) in water (2 ml). The resultant mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2 and washed with brine. The organic layer was dried over MgSO4 and filtered. After concentration in vacuo, the residue was purified by preparative TLC (CH2Cl2/MeOH=10/1) to afford 224 mg (71%) of the title compound.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O.CO>O.O.O.O.O.O.[Ni](Cl)Cl.C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH2:24][CH2:25]3)[CH2:18][CH2:19]2)[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
NaBH4 (2.64 g, 69.8 mmol) was added carefully in portions to a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-[2-(methylsulfonyl)-ethyl]piperazine (9.9 g, 23.3 mmol), nickel(II)chloride hexahydrate (1.66 g, 7 mmol), MeOH (120 mL) and THF (60 mL) at 0° C. The ice bath was removed and the reaction mixture was stirred at rt overnight (˜16 h). The reaction mixture was concentrated onto silica gel and flash chromatography afforded the title compound of step B (6.24 g, 68%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 6.49-6.44 (m, 2H), 6.26 (dd, J=8.4, 2.6 Hz, 1H), 4.18 (bs, 2H), 3.71 (s, 3H), 3.43-3.36 (m, 2H), 3.25 (t, J=6.8 Hz, 2H), 3.00 (s, 3H), 2.65 (t, J=6.8 Hz, 2H), 2.47-2.36 (m, 4H), 2.23-2.15 (m, 1H), 1.82-1.75 (m, 2H), 1.54-1.43 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([OH:31])=O)[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.[CH2:33]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH2:33]([N:40]1[CH2:45][CH2:44][N:43]([C:29](=[O:31])[CH2:28][O:27][C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[C:20]([C:9]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)[C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]=2)=[O:32])[CH2:42][CH2:41]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCN(Cc5ccccc5)CC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (103.5 mg, 0.22 mmol) in 8 ml of methylene chloride was added 1.0 equivalent of N-benzylpiperazine, 1.05 equivalent of HBTU and 4 equivalent of triethylamine. The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was extracted with ethyl acetate and water. The organic phase was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded on a preparative HPLC for purification to give 1-{3-[2-(4-Benzyl-piperazin-1-yl)-2-oxo-ethoxy]-benzoyl}-6,7-dimethoxy-isoquinoline-4-carboxylic acid as a fluffy solid (43 mg, 35%). ES-MS calcd for C32H31N3O7 (m/e) 569.6, obsd 570.3 (M+H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1.[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]>C(Cl)Cl>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][CH2:3][CH:23]([C:22]([O:25][CH2:26][CH3:27])=[O:24])[C:22]([O:25][CH2:26][CH3:27])=[O:24])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCSc1ncc(CCCl)n1Cc1ccccc1Cl
Reactant: CCOC(C)=O
Agent: Cl
Solvent: ClCCl
Product: CCCSc1ncc(CCC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Yield: 71 %

Procedure:
The procedure of Example 3(iv) was followed using 5-(2-chloro)ethyl-1-[(2-chlorophenyl)methyl]-2-propylthio-1H-imidazole hydrochloride in place of 5-chloromethyl-1-[(2-chlorophenyl)methyl]2-propylthio-1H-imidazole hydrochloride. The title compound was obtained in 71% yield after chromatography over silica gel with a gradient of ethyl acetate in methylene chloride.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.CN(C)C(N(C)C)=N.[CH2:20]([OH:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29].[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([N+]([O-])=O)[C:35]=1[C:36]#[N:37])([O-:33])=[O:32]>>[OH:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:38]1[CH:39]=[CH:40][CH:41]=[C:34]([N+:31]([O-:33])=[O:32])[C:35]=1[C:36]#[N:37]
Reactant: OCCCCCCCCCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCCCCCCCCCO)cccc1[N+](=O)[O-]
Yield: 30.7 %

Procedure:
Prepared as in Example 274c (except DBU was replaced with 1,1,3,3-tetramethylguanidine) from 1,9-nonanediol and 2,6-dinitrobenzonitrile in 30.7% yield. MS 307 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:19])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:22]1([OH:28])C=CC=CC=1.C(Cl)(Cl)Cl.Cl>C(O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:22]=[O:28])[C:6]=1[OH:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
2-t-butyl-4-t-octylphenol (140 g, 0.53 mole) was dissolved in 420 ml of absolute ethanol in a 3 L round bottom flask equipped with a water-cooled condenser. Sodium hydroxide (213 g, 5.3 moles) was dissolved in 200 ml water and added while still hot to the solution of phenol. Chloroform (127 g, 1.06 mole) was added in 2 to 3 ml portions over a 1 hour period. The resulting yellow-brown mixture was stirred for 1 hour while it cooled to ambient temperature. The mixture was diluted into 500 ml of 5M hydrochloric acid. The organic layer was isolated in a separatory funnel and dried over anhydrous magnesium sulfate. The mixture was filtered and rotoevaporated to a thick syrup to yield 26% crude product with an IR spectrum having the characteristic aldehyde carbonyl stretching frequency. The product was used without further purification.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH:9]1[C:36]2[C:31](=[C:32]([Br:37])[CH:33]=[CH:34][CH:35]=2)[C:11]2([CH2:16][CH2:15][N:14]([C:17](=[O:30])/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:13][CH2:12]2)[CH2:10]1.CCN(C(C)C)C(C)C.[CH3:47][N:48]=[C:49]=[O:50]>C(Cl)Cl>[Br:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[C:11]1([CH2:16][CH2:15][N:14]([C:17](=[O:30])/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:27])([F:28])[F:29])[CH2:13][CH2:12]1)[CH2:10][CH:9]2[NH:8][C:49]([NH:48][CH3:47])=[O:50]
Reactant: CN=C=O
Reactant: NC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)NC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A vial equipped with a flea stirbar was charged with (±)-(E)-1-(3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one TFA salt (9 mg, 0.015 mmol), i-Pr2NEt (0.01 mL) and CH2Cl2 (1 mL). MeNCO (0.05 mL, 0.085 mmol) was added. The mixture was stirred at rt for 3 h and evaporated to dryness. The residue was purified by prep HPLC to afford (±)-(E)-1-(7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-3-methylurea (2.9 mg, 59%). LC-MS Method 1 tR=1.77, min, m/z=536, 538.
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.CCCC[N+](CCCC)(CCCC)CCCC.[OH-].O.CC1C=CC2C(=C([OH:63])C=CC=2)N=1>CS(C)=O.[Cu]I>[NH2:25][C@@H:20]([CH2:21][CH:22]([CH3:23])[CH3:24])[CH2:19][O:18][C:17]1[C:2]([OH:63])=[CH:3][C:4]2[C:13]3[C:8](=[CH:9][N:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[CH:16]=1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Reactant: Cc1ccc2cccc(O)c2n1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)C[C@H](N)COc1cc2c(cc1O)c1ccncc1c(=O)n2C
Temperature: 120 °C
Reaction time: 14 h
Yield: 55 %

Procedure:
A mixture of (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.05 g, 0.099 mmol) (as prepared in Ex. 3, Part A), tetra-N-butylammonium hydroxide. 30H2O (0.463 g, 1.784 mmol) and water (1.5 mL) was added over 0.1 h to a stirred solution of copper(I) iodide (1.89 mg, 9.91 μmol) and 2-methyl 8-quinolinol (3.16 mg, 0.020 mmol) in DMSO (1 mL). The reaction mixture was heated to 120° C. and stirred for 14 h. The resulting mixture was cooled to room temperature. The crude product was purified by reverse phase HPLC (10 mM ammonium acetate) to afford a (S)-8-((2-amino-4-methylpentyl)oxy)-9-hydroxy-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (0.004 g, 0.011 mmol, 12% yield) as a brown solid. LC/MS (ESI) m/e 342.2 [(M+H)+, calcd for C19H24N3O3, 342.2]; HPLC retention time (method F): tR=1.62 min. HPLC retention time (method B): tR=5.88 min. 1H NMR (400 MHz, CD3OD) δ 9.39 (s, 1H), 8.62 (d, J=6.00 Hz, 1H), 7.96 (d, J=5.60 Hz, 1H), 7.56 (s, 1H), 6.73 (s, 1H), 3.80 (s, 3H), 3.67-3.70 (m, 1H), 3.49-3.59 (m, 2H), 1.81-1.85 (m, 1H), 1.56-1.63 (m, 2H), 1.05 (d, J=6.80 Hz, 3H), 0.98 (d, J=6.80 Hz, 3H).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]=O)[C:9]2[CH:10]=[CH:11][CH2:12][O:13][C:8]=2[C:7]=1[O:18][CH3:19].[CH2:20]([O:22][CH2:23][CH2:24][C:25]#[N:26])C>CO.O.C(OCC)C>[CH3:4][O:5][C:6]1[CH:15]=[C:14]([CH:16]=[C:24]([CH2:23][O:22][CH3:20])[C:25]#[N:26])[C:9]2[CH:10]=[CH:11][CH2:12][O:13][C:8]=2[C:7]=1[O:18][CH3:19]
Reactant: CCOCCC#N
Reactant: COc1cc(C=O)c2c(c1OC)OCC=C2
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COCC(C#N)=Cc1cc(OC)c(OC)c2c1C=CCO2
Yield: 73.6 %

Procedure:
A mixture of sodium methoxide (7.02 g, 0.13 mole), 7,8-dimethoxy-5-formyl-2H-1-benzopyran (57 g, 0.26 mole) and 3-ethoxypropanenitrile (28.35 g, 0.286 mole) in methanol (150 mL) was heated at reflux for 4 hr, allowed to cool and diluted with water (150 mL) and ethylether (500 mL). The layers were separated and the ether portion was washed with water (3×250 mL and 1×100 mL) and dried over magnesium sulfate. The ether solution was concentrated to give 55 g (73%) of an amber oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=3)[C:9]([CH3:19])=[C:8]2[CH3:20])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH2:28].ON1C2C=CC=CC=2N=N1.N=C=N.[N-]=C=O>CN(C)C=O.C(N(CC)CC)C>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][NH:28][C:16]([C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=1)[C:8]([CH3:20])=[C:9]2[CH3:19])=[O:18]
Reactant: CN(C)CCCN
Reactant: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)O)cc12
Agent: N=C=N
Agent: On1nnc2ccccc21
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccc(F)cc2)c2ccc(C(=O)NCCCN(C)C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 8.9 mg portion of 1-(4-fluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid, 3.1 mg of N,N-dimethylpropane-1,3-diamine, 4.1 mg of 1-hydroxybenzotriazole (HOBt) and 0.0083 ml of triethylamine were dissolved in 1.0 ml of N,N-dimethylformamide, and 100 mg of PS-Carbodiimide (Argonaut Technologies, Inc., USA) was added, followed by overnight stirring at room temperature. Then, 50 mg of MP-Carbodiimide (Argonaut Technologies, Inc., USA) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc., USA) was added to the reaction liquid at room temperature, followed by stirring for 4 hours. Then, the reaction liquid was filtered. By concentrating the filtrate under a reduced pressure, 9.5 mg of N-[3-(dimethylamino)propyl]-(4-fluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CS(O[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([CH3:12])=[C:4]([CH:3]=1)[O:13][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: COC(=O)c1cc(Cl)cc(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 75 °C
Yield: 81.5 %

Procedure:
A mixture of methyl 5-chloro-3-hydroxy-2-methylbenzoate (1.25 g, 6.23 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.66 g, 13.08 mmol) and cesium carbonate (5.08 g, 15.58 mmol) in DMF (25 mL) was heated at 75° C. for 18 h. The reaction was allowed to cool to ambient temperature and poured into ice/water (200 mL) with stirring. The mixture was extracted with EtOAc (3×100 mL), dried over magnesium sulfate, and concentrated in vacuo. The light yellow residue was purified by flash chromatography (5-50% EtOAc/hexanes) to give tert-butyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylate (1.95 g, 5.08 mmol, 82% yield) as a solid. 1H NMR (DMSO-d6) δ 7.37 (d, J=2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 4.71 (dt, J=7.4, 3.8 Hz, 1H), 3.83 (s, 3H), 3.54-3.63 (m, 2H), 3.22-3.31 (m, 2H), 2.28 (s, 3H), 1.83-1.93 (m, 2H), 1.51-1.63 (m, 2H), 1.41 (s, 9H).