Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[S:23][C:22]([C:24]([O:26]CC)=O)=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:32][CH2:31]1.C[Al](C)C>ClCCCl>[NH3:4].[CH:1]1([N:4]([CH2:18][C:19]2[S:23][C:22]([C:24]([N:39]3[CH2:38][CH2:37][N:36]([CH:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH2:41][CH2:40]3)=[O:26])=[N:21][N:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1nnc(CN(C2CC2)S(=O)(=O)c2c(C)cc(OC)cc2C)s1
Reactant: CN1CCC(N2CCNCC2)CC1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nnc(C(=O)N3CCN(C4CCN(C)CC4)CC3)s2)C2CC2)c(C)c1
Product: N

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3,4-thiadiazole-2-carboxylate (30 mg, 0.07 mmol), 1-(1-methylpiperidin-4-yl)piperazine (26 mg, 0.14 mmol) and trimethylaluminium (2 M in toluene, 0.07 mL) in DCE (5 mL). The crude product was purified using FCC, eluting with 95:4.5:0.5 DCM:MeOH:NH3, to afford the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[C:5]([NH:20][C:21]([NH2:23])=[NH:22])=[N:4][CH:3]=1>[Pd].CO>[NH3:4].[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:8]2[CH:7]=[C:6]3[C:11]([CH:2]=[CH:3][N:4]=[C:5]3[NH:20][C:21]([NH2:23])=[NH:22])=[CH:10][CH:9]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(-c2ccc3c(Br)cnc(NC(=N)N)c3c2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-c2ccc3ccnc(NC(=N)N)c3c2)cc1
Product: N
Temperature: 23 °C
Reaction time: 72 h
Yield: 160 %

Procedure:
A solution of (4-bromo-7-(4-methoxyphenyl)isoquinolin-1-yl)guanidine (38 mg, 0.1 mmol) in industrial methylated spirits (2.0 mL) containing 5% Pd-C (10 mg) was stirred under an atmosphere of H2 (3.5 atmospheres) at 23° C. for 3 days. The mixture was filtered through Arbocel™ with ethanol rinsing, the filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:3:0.3) as eluant to give (7-(4-methoxyphenyl)isoquinolin-1-yl)guanidine (24 mg, 0.08 mmol) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([NH:34][CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[N:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:35])=[CH:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Reactant: CNCc1ccccc1
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(C)Cc3ccccc3)c2c1

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with benzyl-methyl-amine to give 100 mg of [4-(benzyl-methyl-carbamoyl)-6,8-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C26H31N3O5+H 466.5; found 466.0.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>CCO>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1)=[O:4])[CH3:18]
Reactant: CCNCC
Reactant: COc1cc(C(=O)CBr)cc(OC)c1OC
Solvent: CCO
Product: CCN(CC)CC(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
To 100 mL of EtOH is added 28.9 g (0.1 mol) of 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone and 9.0 g (0.2 mol) of diethylamine. Reflux the reaction mixture and monitor by thin-layer chromatography. Upon completion of the reaction remove the solvent in vacuo and add 100 mL of 5% Na2CO3 solution and extract with Et2O. Dry the organic layer with Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][CH:6]=[N:5][C:4]=2[C:3]=1[Cl:12].C[O-].[Na+].[CH3:16][O:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH3:27])=[O:25])[C@H:19]1[CH2:28][C:29](=[O:32])[CH2:30]Br.N1C2C=CS(=O)C=2C=NC=1>CO>[Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH2:30][C:29](=[O:32])[CH2:28][C@H:19]3[C@H:18]([O:17][CH3:16])[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([O:26][CH3:27])=[O:25])[CH:6]=[N:5][C:4]=2[C:3]=1[Cl:12]
Reactant: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: O=c1[nH]cnc2c(Cl)c(Cl)sc12
Agent: C[O-]
Agent: O=S1C=Cc2ncncc21
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2c(Cl)c(Cl)sc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen in a flame dried round bottom flask with magnetic stirring, a solution of 0.440 g (0.002 moles) of 6,7-dichlorothieno[3,2-d]pyrimidin-4(3H)-one [M. Robba, J-M. Lecomte, and M. Cugnon de Sevricourt, Bull. soc. chim. France, 1970, 3630-3636], 5 ml of methanol, and 2.0 ml of 1.0N sodium methoxide in methanol was treated with a solution of 0.002 moles of methyl trans-3-methoxy-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate and 2 ml of methanol. A colorless precipitate formed almost immediately; the reaction mixture was stirred for two hours at room temperature. The solid matter was some starting thienopyrimidinone, and was filtered. The filtrate was evaporated under reduced pressure to afford a greenish oil which was chromatographed under moderate pressure ("flash" chromatography) on a column of silica gel (Woelm 32-63 micrometers, i.d. 5 cm×height 18 cm); the eluant was initially 1% ethanol in chloroform but was changed to 2% ethanol later on. There was obtained the title compound: m.p. 58°-62° C.; yield 0.270 g (30%); mass spectrum peaks at 447 (molecular ion), 415 (-32, --CH3OH), 195 (parent) among others; 13C-nmr delta (CDCl3) 19.05 ppm, 23.42, 39.33, 40.81, 50.53, 52.93, 53.62, 56.35, 76.01, 119.92, 121.68, 149.62, 152.19, 155.49, 157.01, 199.22; 1H-nmr (CDCl3) delta 3.36 ppm (OCH3), 3.66 (CO2CH3) among others.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].[Mg]>O1CCCC1>[CH2:1]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COc1ccccc1Br
Reactant: CCCCCCCCCCCCCCCCI
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCc1ccccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 102 %

Procedure:
To a refluxing solution of about 35.3 g of hexadecyl iodide in tetrahydrofuran was added a solution of about 37.4 g of bromoanisole and about 4.86 g of magnesium in tetrahydrofuran which had been refluxed for about 2 hours. An about 10 ml portion of about 0.1M lithium cupric chloride was added, the mixture was refluxed about 2 hours and stirred at room temperature for about 16 hours giving about 34 g of the desired reagent.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[OH-].[Na+].[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1/[CH:17]=[CH:18]/[C:19](=[O:21])[CH3:20]>CS(C)=O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C@@H:17]1[CH2:2][C@H:18]1[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)/C=C/c1ccc(Cl)cc1Cl
Reactant: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(=O)[C@@H]1C[C@H]1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask equipped with magnetic stirrer, nitrogen inlet and additional funnel was charged with trimethylsulfoxonium iodide (0.61 g, 2.78 mmol), DMSO (10 ml) and powdered sodium hydroxide (97 mg, 2.44 mmol). The suspension was stirred for 1.0 hour at ambient temperature to yield a solution. So prepared solution was added drop wise at ambient temperature to a solution of (E)-4-(2,4-dichloro-phenyl)-but-3-en-2-one (0.50 g, 2.32 mmol) prepared as described in example P30 in DMSO (10 ml). The reaction mixture was stirred for 0.5 hours, poured onto ice water (100 ml) and extracted with ether (3×25 ml). Combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (25 g) (eluent: n-hexane/ethyl acetate 10:1) to afford 0.33 g (62% of theory) of trans 1-[2-(2,4-dichloro-phenyl)-cyclopropyl]-ethyanone in form of an oil.
Reaction SMILES: O[NH:2][N:3]=[CH:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13](=[O:34])[C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:33])[C@@H:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:7][CH2:6]1.[N-:35](C#N)[C:36]#N.[Na+]>CCCCO>[C:36]([NH:2][N:3]=[CH:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13](=[O:34])[C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:33])[C@@H:20]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:7][CH2:6]1)#[N:35]
Reactant: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC1CCN(C=NNO)CC1
Reactant: N#C[N-]C#N
Agent: [Na+]
Solvent: CCCCO
Product: CS(=O)(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCC1CCN(C=NNC#N)CC1
Yield: 57 %

Procedure:
To a stirred solution of Example 3 Part D compound (220 mg, 0.40 mmol) in 3.0 mL of n-BuOH was added sodium dicyanamide (99.0 mg, 1.00 mmol). The reaction mixture was heated to reflux for 14 h and concentrated in vacuo. This was purified by preparative HPLC to give 124 mg (57%) of title compound.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[ClH:1].[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[O:11])=[CH:5][CH:4]=2)=[CH:24][CH:23]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: O=C(Nc1ccc(Br)cc1)C1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CSc1ccc(-c2ccc(NC(=O)C3CN4CCC3CC4)cc2)cc1

Procedure:
90 mg (0.26 mmol) of N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide hydrochloride, 50 mg (0.31 mmol) of 4-(methylsulfanyl)phenylboronic acid, 190 mg (0.57 mmol) of cesium carbonate and 20 mg (0.03 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride are reacted in 1 ml of 1,2-dimethoxyethane by the general method. 21.6 mg (21% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1C=O.[CH3:11][N:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].[C:19]([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:7]([CH:19]=[C:18]2[N:12]([CH3:11])[C:13](=[O:14])[NH:15][C:16]2=[O:17])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)[O-]
Reactant: CN1CC(=O)NC1=O
Reactant: COc1ccccc1C=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(C=C2C(=O)NC(=O)N2C)c1
Yield: 18.2 %

Procedure:
A mixture of 2-methoxybenzaldehyde (3.8 g, 28 mmoles), 1-methyl hydantoin (3.0 g 26 mmoles), sodium acetate (8.4 g, 102 mmoles), acetic anhydride (10 ml), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 24 hours the mixture is stirred into water (350 ml), stirred, and the resulting gum is isolated and washed by decantation, then crystallized from isopropanol. Recrystallization from acetonitrile gave the pure product (1.1 g), mp 195°-197° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[C@H:7](N)[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[CH2:7][C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
2.16 g 6-amino-penicillanic acid were added to 20 ml methylene chloride cooled to +5° C. Then, 2 g triethylamine were added and the mixture was stirred for 2 hours at +5° C. Then, at 0° C. 10 ml methylene chloride were added, in which 2.6 g compound of formula (III) obtained in Example 6 were dissolved. Then, the mixture was stirred for 30 minutes at +5° C., the solvent was vacuum evaporated and the residue was dissolved in 10 ml methyl-ethyl-ketone. Then, 1.9 g para-toluensulphonic acid dissolved in 10 ml methyl-ethyl-ketone were added. The solid thus formed was filtered and crystallized from a mixture acetone-water.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH2:8])=[NH:7].[Cl:18][C:19]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:20]=1[CH:21]=[C:22]([C:25]#[N:26])[C:23]#[N:24]>>[NH2:26][CH2:25][C:22]1[C:23]([NH2:24])=[N:7][C:6]([C:5]2[CH:4]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:9]=2)=[N:8][C:21]=1[C:20]1[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:19]=1[Cl:18]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: N=C(N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: NCc1c(N)nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc1-c1ccc(Cl)cc1Cl

Procedure:
The title compound, MS: m/e=481.2 (M+H+), was prepared from 3,5-bis-trifluoromethyl-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([NH2:20])=[N:18][N:19]=2)[N:16]=1>>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([NH2:20])=[N:18][N:19]=2)[N:16]=1
Reactant: OCC(F)(F)F
Reactant: Nc1nnc2ccc(Cl)nn12
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Nc1nnc2ccc(OCC(F)(F)F)nn12

Procedure:
2,2,2-Trifluoroethanol (1 ml), sodium hydride (86 mg) and 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001, 100 mg) were reacted according to W1.004. 87 mg of the title compound were obtained in solid form.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 4-phenoxy-phenol (169 g, 0.9 mol) in pyridine (500 mL) was treated with acetic anhydride (90 mL). The reaction mixture was stirred at room temperature overnight. The mixture was partitioned between DCM and 10% HCl solution, and the resulting mixture was stirred for 1 h. The organic phase was washed with 10% HCl and water until pH=7. The organic layer was dried and the solvent was evaporated to afford acetic acid 4-phenoxy-phenyl ester (200 g, 97%). 1H-NMR (CDCl3): 2.21 (s, 3H), 6.94 (m, 6H), 7.04 (m, 1H), 7.28 (m, 2H).
Reaction SMILES: [C:1]1(=[O:16])[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4](=[O:15])[CH:3]=[CH:2]1.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29](Br)Br.[I-].[Na+]>CN(C)C=O>[CH:27]1[C:28]2=[C:19]3[C:20](=[CH:21][CH:22]=[C:23]2[CH:24]=[CH:25][CH:26]=1)[CH:29]=[C:2]1[C:3]([C:4](=[O:15])[C:5]2[C:14]([C:1]1=[O:16])=[CH:13][C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH:6]=2)=[CH:18]3
Reactant: BrCc1c(C(Br)Br)ccc2ccccc12
Reactant: O=C1C=CC(=O)c2cc3ccccc3cc21
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cc3ccccc3cc2C(=O)c2cc3c(ccc4ccccc43)cc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In an atmosphere of argon, 6.9 g (33 mmole) of 1,4-anthraquinone, 9.8 g (25 mmole) of 1-(bromomethyl)-2-(dibromomethyl)naphthalene and 25 g (660 mmole) of sodium iodide were dissolved into 85 ml of dry dimethylformamide. After the exothermic reaction was completed, the reaction solution was heated to 70° C. and stirred for 8 hours. After the reaction was completed, the formed crystals were separated by filtration and washed with methanol and water and light yellow needle crystals of 8,15-benzo[a]pentacenequinone were obtained in the quantitative amount.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)([O-:3])=[O:2].[H-].[Na+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[C:18]([F:17])([F:27])[F:28])[CH:8]=2)([O-:3])=[O:2]
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: O=[N+]([O-])c1cnc2cc(O)ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
In dimethylformamide (DMF, 9 mL) was dissolved 3-nitro-7-hydroxyquinoline (800 mg, 4.24 mmol.). To the solution were added subsequently sodium hydride (168 mg, 4.24 mmol.) and 2-trifluoromethylbenzyl chloride (816 mg, 4.24 mmol.) under chilling with ice. The resulting mixture was stirred overnight at room temperature. After the completion of reaction was confirmed, ethyl acetate and aqueous sodium sulfate were added. The ethyl acetate portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 790 mg of the desired compound as a white crystalline product, yield 53%.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:11]=O.[C:13]([OH:16])(=[O:15])[CH3:14]>>[C:1]12([OH:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:13]12([OH:16])[CH2:14][CH:7]3[CH2:6][CH:5]([CH2:10][C:1]([OH:11])([CH2:8]3)[CH2:2]1)[CH2:4]2
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: CC(=O)O
Reactant: O=O
Product: OC12CC3CC(C1)CC(O)(C3)C2
Product: OC12CC3CC(CC(C3)C1)C2
Yield: 13 %
Yield: 48 %

Procedure:
To 25 ml of acetic acid were added 10 mmol of adamantane, 0.8 mmol of NHPI and 0.6 mmol of acetylacetonatocobalt(II)Co(AA)2 , and the resultant mixture was stirred in an oxygen atmosphere at a temperature of 75° C. for 3 hours. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, adamantane was converted into 1-adamantanol (yield: 48%) and 1,3-adamantanediol(yield: 13%) with the adamantane conversion of 65%.
Reaction SMILES: CC([N:5]([C@H:9]([CH3:31])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:29])=[N:27][O:28][C:24]=3[CH:23]=[C:22]([CH3:30])[CH:21]=2)=[CH:15][CH:14]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:29][C:26]1[C:25]2[C:20]([O:19][C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH3:31])[NH2:5])=[CH:18][CH:17]=3)=[CH:21][C:22]([CH3:30])=[CH:23][C:24]=2[O:28][N:27]=1
Reactant: Cc1cc(Oc2ccc(NC(=O)[C@@H](C)N(C(=O)[O-])C(C)(C)C)cc2)c2c(C)noc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Oc2ccc(NC(=O)[C@@H](C)N)cc2)c2c(C)noc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-dimethylethyl[(1R)-2-({4-[(3,6-dimethyl-1,2-benzisoxazol-4-yl)oxy]phenyl}amino)-1-methyl-2-oxoethyl]carbamate) (Intermediate 22, 74 mg) was dissolved in 3.0 ml of dichloromethane. TFA (1.5 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. After removal of the volatiles, the residue was purified with a SCX cartridge and eluted with DCM/MeOH/NH3 (2.0 M solution in MeOH). The evaporation of the volatiles, afforded 54 mg of the title compound.
Reaction SMILES: C([O:3][CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=O)C.C(O)(=O)C.[CH:20]([NH2:22])=[NH:21]>C(O)C.C(OCC)(=O)C.Cl>[NH:22]1[C:4](=[O:3])[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][N:21]=[CH:20]1
Reactant: N=CN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc[nH]c1=O
Temperature: 25 °C
Yield: 39.6 %

Procedure:
Diethyl ethoxymethylenemalonate (10.1 mL, 50 mmole) and formamidine acetate (10.4 g, 100 mmole) were refluxed in ethanol (10 mL) for 24 hours. The reaction mixture was allowed to cool to room temperature overnight, and suspended in ethyl acetate (30 mL) and 1.0N HCl (20 mL). The suspension was filtered, and the filter cake was washed with 1.0N HCl, followed by water, then ethyl acetate, and air dried affording the title compound as an tan solid (3.33 g, 40% yield). Rf=0.21 (silica gel, 10% methanol in dichloromethane). m.p. 187-188° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].[CH2:15]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)=[O:19])[CH3:16].CCN=C=NCCCN(C)C>CCO.[Pd]>[CH2:15]([O:17][C:18]([CH:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32](=[O:33])[NH:12][C:9]3[CH:10]=[C:11]4[C:6]([CH:5]=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:7][CH:8]=3)=[CH:30][CH:31]=2)[CH2:24][CH2:25]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCn1ccc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc4ccn(CC)c4c3)cc2)CC1
Reaction time: 8 h
Yield: 34.8 %

Procedure:
A slurry of 1-ethyl-6-nitro-1H-indole (100 mg, 0.52 mmol) and 10% Pd/C (21 mg) in EtOH was hydrogenated under 1 atm of H2 for 2 h. The mixture was filtered and concentrated and the intermediate amine was dissolved in CH2Cl2 (5 mL) and treated with 1-(4-carboxy-phenyl)-piperidine-4-carboxylic acid ethyl ester (110 mg, 0.39 mmol) and EDCI (228 mg, 1.19 mmol). After stirring overnight the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was collected, filtered and concentrated. The residue was chromatographed with 20-60% EtOAc in hexanes to afford the product (57 mg, Yield: 34%). HRMS m/z calcd for C25H29N3O3 [M+H]+: 420.2282. Found: 420.2280.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]2[NH:7][C:8]([CH:10]3[CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)=[N:9][C:5]=2[CH:4]=1.CO>O1CCOCC1>[NH:12]1[CH2:13][CH:10]([C:8]2[NH:7][C:6]3[CH:21]=[CH:22][C:3]([Cl:2])=[CH:4][C:5]=3[N:9]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Clc1ccc2[nH]c(C3CNC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
Hydrochloric acid, 4.0 m solution in 1,4-dioxane (16.25 mL, 65.0 mmol) was added to a solution of tert-butyl 3-(5-chloro-1H-benzo[d]imidazol-2-yl)azetidine-1-carboxylate (2 g, 6.50 mmol) in dioxane (20 ml) under argon. MeOH (20 mL) was added to the resulting suspension to make a solution and the mixture was stirred for 2 h at RT, at which time it turned back to a suspension. The mixture was filtered and the collected solid was washed with dioxane and air dried to give product as a white solid (840 mg). The filtrate was then concentrated and then dissolved in a minimum of MeOH. Et2O was added slowly and the resulting suspension was filtered and dried to give an additional 560 mg product as a light grey solid.