Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][CH:7]=[CH:6][CH:5]=2.N1C=CC=CC=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>ClCCl>[C:33]([O:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: C[Si](C)(C)CCCCCCCCCC1=C(O)C(=O)c2ccccc2C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)OC1=C(CCCCCCCCC[Si](C)(C)C)C(=O)c2ccccc2C1=O
Reaction time: 0.05 h

Procedure:
To a stirred solution of 2-hydroxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone, Example 12, (100 mg, 0.27 mmol) in dry dichloromethane (10 ml) at room temperature was added pyridine (0.5 ml) and, after 3 minutes, propanoyl chloride (62 mg, 0.67 mmol). The reaction was stirred for 2 h before diluting with dichloromethane (50 ml), washing with water (2×30 ml), dilute hydrocholic acid (30 ml), saturated sodium chloride solution (30 ml) and dried (MgSO4). Filtration and evaporation of the solvent under reduced pressure and chromatography, eluent hexane/ether, gave 2-propanoyloxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone (112 mg). m. pt. 41-43° C. NMR peaks at: 184.6, 178.2, 151.2, 139.8, 134.0, 133.7, 132.1, 130.9, 126.7, 126.5, 33.6, 29.7, 29.4, 29.4, 29.3, 29.3, 28.5, 24.3, 23.9, 16.7, -1.6; 171.6, 27.3, 9.1 (COCH2CH3).
Reaction SMILES: [OH:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][C:7]#[CH:8])=[O:4].[CH:10](O)=[O:11].CNC1(NC)C=CN=CC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCCl>[CH:10]([O:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][C:7]#[CH:8])=[O:4])=[O:11]
Reactant: O=CO
Reactant: C#CCOC(=O)C(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC1(NC)C=CN=CC1
Solvent: ClCCCl
Product: C#CCOC(=O)C(C)OC=O
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
19.96 g (156 mmol) of the obtained 2-propynyl 2-hydroxypropionate, 7.17 g (156 mmol) of formic acid, and 15.23 g (125 mmol) of 4,4-dimethylaminopyridine (nucleating agent) were dissolved in 100 g of 1,2-dichloroethane (solvent), and a mixed solution of 35.35 g (171 mmol) of N,N′-dicyclohexylcarbodiimide (dehydrating agent) and 50 g of 1,2-dichloroethane was added thereto at 10° C., taking 30 minutes. These were reacted at room temperature for 4 hours, and the absence of the starting materials was confirmed through gas chromatography. Subsequently, the reaction liquid was filtered to remove N,N′-dicyclohexylurea, and the filtrate was concentrated. The concentrate was purified through silica gel column chromatography, and from the fraction taken with hexane/ethyl acetate=4/1, 20.78 g (yield 85%) of 2-propynyl 2-(formyloxy)propionate was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][C:17]([Cl:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C>[Pt]=S.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:19]([NH2:20])=[CH:18][C:17]([Cl:23])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Cl)cc2[N+](=O)[O-])CC1
Agent: S=[Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Cl)cc2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A round bottom flask is charged with 5% platinum sulfide on carbon (0.20 g, 0.039 mmol). The flask was evacuated and refilled with argon three times. To the flask is added 4-(5-chloro-3-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.80 g, 8.17 mmol) as a solution in a 1:1 mixture of ethyl acetate:methanol (100 mL). The mixture is placed under an atmosphere of hydrogen and stirred overnight at room temperature. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to provide 2.0 g of 4-(3-amino-5-chloro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester as a dark solid in 80% yield.
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].C(N(CC)CC)C.[S:29](Cl)([CH3:32])(=[O:31])=[O:30]>C(Cl)Cl>[S:29]([O:21][CH2:1][CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4])(=[O:31])(=[O:30])[CH3:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOS(C)(=O)=O
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
Phytanol (20.0 g, 66.7 mmol), triethylamine (18.6 mL, 133 mmol) and a stir bar were added to a 1000 mL round bottom flask. The flask was sealed and flushed with nitrogen Anhydrous DCM (250 mL) was added, and the mixture cooled to −15° C. (Ice and NaCl). Mesyl Chloride (10.4 mL, 133 mmol) was added slowly via syringe over a 30 minute period, and the reaction stirred at −15° C. for a further 1.5 hours. At this point TLC showed that the starting material had been used up. The solution was diluted with DCM (250 mL) and washed with saturated NaHCO3 (2×200 mL). The organic phase was then dried (MgSO4), filtered and concentrated (rotovap). The crude product was purified by column chromatography. Yield 21.5 g, 85.7%.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCCCCCCCn1ccc([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
3-Nitro-1-octyl-1H-pyrazole (134 mg, 0.60 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The reaction was passed through a plug of celite and concentrated in vacuo to afford 1-octyl-1H-pyrazol-3-ylamine (48 mg, 41%) as a golden oil: ESI-LRMS m/e calcd for C11H21N3 [M+] 195.18, found 196.2 [M+H+].
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)[C@@H:10]([CH3:13])[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P([N:68]=[N+:69]=[N-:70])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:68]([CH2:11][C@H:10]([CH3:13])[C@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15]1)[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:69]=[N-:70]
Reactant: C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)O1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of (2S,3R)-3-(tert-butyldimethylsilyloxy)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropan-1-ol (1.0 equiv.), DIAD (2.0 equiv.), and PPh3 (2.0 equiv.) in THF (0.18 M) was added DPPA (1.0 equiv., 1M solution in THF). The reaction mixture was stirred at room temperature overnight. Upon removal of the volatiles under vacuo, the residue was purified by silica gel column chromatography (2-3-5% EtOAc/n-heptanes) yielding ((1R,2S)-3-azido-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropoxy)(tert-butyl)dimethylsilane (62%). 1H-NMR (400 MHz, CDCl3): δ 4.04-4.10 (m, 1H), 3.94 (dd, J=8.0, 6.4, 1H), 3.72 (d, J=7.2, 1H), 3.53 (t, J=8.0, 1H), 3.36 (dd, J=12, 8.0, 1H), 3.19 (dd, J=12.0, 6.7, 1H), 1.52-1.60 (m, 1H), 1.41 (s, 3H), 1.34 (s, 3H), 0.92 (d, J=7.2, 3H), 0.90 (s, 9 H), 0.12 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[O:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25](CC2C=CC(OC)=CC=2OC)[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])=[C:17]([F:43])[CH:16]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[O:14][C:15]1[C:20]([F:21])=[CH:19][C:18]([S:22]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)(=[O:23])=[O:24])=[C:17]([F:43])[CH:16]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnnc3N)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 74.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-2-(3-aminopyridazin-4-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (45 mg, 0.073 mmol) prepared in Example 82f, triethylsilane (0.06 mL), trifluoroacetic acid (0.08 mL) and dichloromethane (0.76 mL), to yield the title compound (25 mg, 74%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[NH4+:17]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([C:8]2[CH:7]=[N:17][CH:13]=[CH:14][C:10]=2[O:11][CH3:12])=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: [NH4+]
Reactant: N#Cc1cc(Br)c(-c2ccco2)nc1N
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccncc1-c1cc(C#N)c(N)nc1-c1ccco1
Yield: 56 %

Procedure:
A solution of 2-amino-5-bromo-6-(2-furyl)nicotinonitrile (1.80 g, 6.82 mmol), 2-methoxy-5-(1,1,1-tributylstannyl)pyridine (5.20 g, 13.1 mmol) and dichlorobis(triphenylphosphine) palladium (II) (480 mg, 0.634 mmol) in N,N-dimethylformamide (18 ml) was stirred at 80° C. for 2 hours in a nitrogen atmosphere. After cooling as it was, the reaction solution was diluted with ethyl acetate and an aqueous saturated solution of ammonium chloride. The organic layer was washed with an aqueous saturated solution of ammonium chloride (×2), then dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane, hexane:ethyl acetate=8:1, 4:1), and then suspended in diethyl ether. The resulting solid was collected by filtration and washed with diethyl ether, to give the title compound (1.12 g, 56%) as a yellow solid.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[C:30]1([CH2:36][CH:37]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:29][O:28][C:18]1[CH:17]=[C:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C@@H:5]([NH:4][CH2:37][CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:6][CH:7]([CH3:8])[CH3:9])[N:11]=2)[CH:21]=[CH:20][C:19]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: O=CCc1ccccc1
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Agent: Cl
Product: COc1cc(Nc2nc([C@H](CC(C)C)NCCc3ccccc3)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 32 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 27 mg (0.22 mmol) phenylacetaldehyde yielding 44 mg (46%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-((S)-3-methyl-1-phenethylamino-butyl)-thiazol-2-yl]-amine as a yellow solid. MS ISP (m/e): 476.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.34 (s, 1H), 7.87 (s, 1H), 7.65 (s, 1H), 7.24-7.13 (m, 6H), 7.02 (s, 1H), 7.00 (d, 1H), 6.64 (s, 1H), 3.76 (s, 3H), 3.59 (br t, 1H), 2.72-2.59 (m, 4H), 2.14 (s, 3H), 1.59-1.48 (m, 3H), 0.87 (d, 3H), 0.82 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH3:35])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:20].[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:21][C:22]1[C:23]([NH:34][CH3:35])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2
Reactant: CNc1nc2ccc(OC)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 6 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1.01 mmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-methylquinolin-2-amine hydrochloride SLA 28154 (276 mg, 1.01 mmol) followed by a 2 N aq. LiOH solution (1.01 mL, 2.02 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with a CH2Cl2:MeOH=9:1 mixture (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided, after evaporation and drying, 39 mg of 6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.40 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to give 6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 48 as a yellow solid (31 mg, 6% yield).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCc1ccc(C#N)nc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccc(-c2nc(=O)c3ccccc3s2)nc1
Yield: 97.8 %

Procedure:
tert-Butyl 3-(6-cyano-3-pyridyl)propanoate (0.46 g, 1.97 mmol) and methyl thiosalicylate (0.50 g, 2.96 mmol) were dissolved in toluene (30 ml), and triethylamine (0.55 ml, 3.94 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.71 g, 98%) as white crystals.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:28])[NH:26][NH2:27])=[CH:20][CH:19]=1)[CH2:16][CH3:17]>>[CH2:15]([C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:28])[NH:26][N:27]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])=[CH:22][CH:23]=1)[CH2:16][CH3:17]
Reactant: CCCc1ccc(NC(=O)NN)cc1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: CCCc1ccc(NC(=O)NN=c2c(=O)c3ccccc3c2=O)cc1

Procedure:
ninhydrin, 4-(4-propylphenyl)-semicarbazide hydrochloride
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:21](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:18][CH3:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Cc2ccccc2)ccc2ccccc12
Reaction time: 17 h
Yield: 98.3 %

Procedure:
A mixture of 2-phenylmethyl-1-naphthol (40.0 g, 0.17 mole), methyl iodide (36.4 g, 0.26 mole), potassium carbonate (35.9 g, 0.26 mole) and acetone (1000 mL) was heated at reflux with stirring for 17 hours, then cooled and filtered. The acetone was removed under vacuum, and the residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. The residual oil was distilled in a short-path distillation apparatus at approximately 160°-180°/0.2 torr to provide the title compound (41.5 g, 98%) as an off-white solid, mp 56°-59°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[CH:18]=[C:19]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])[CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:31])([F:32])[F:15])[CH:18]=4)=[CH:24][C:25](=[O:26])[NH:14][C:5]=23)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(-c2c(C)n[nH]c2N)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(C)nn3c(-c4cccc(C(F)(F)F)c4)cc(=O)[nH]c23)cc1
Temperature: 25 °C
Yield: 65.9 %

Procedure:
3-Methyl-4-(4-methylphenyl)-1H-pyrazol-5-a mine (300 mg) and ethyl 3-(3-(trifluoromethyl)phenyl)-3-oxopropanoate (500 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield 405 mg of the target compound.
Reaction SMILES: [CH2:1]([C:8]1([NH:14][CH:15]=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCCCCC.CCOC(C)=O>[O:11]1[CH2:12][CH2:13][C:8]2([CH2:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:15]=[N:14]2)[CH2:9][CH2:10]1
Reactant: O=CNC1(Cc2ccccc2)CCOCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C1=NC2(CCOCC2)Cc2ccccc21

Procedure:
Formamide 19 (1.00 g, 4.57 mmol) from the previous experiment is cyclized according to general procedure C to give the imine 21 as a yellow oil after FC (1:1 hexane/EtOAc, then EtOAc). The yield is 0.38 g (41%). 1H NMR (CDCl3) 8.35(s,1), 7.45-7.30(m,3), 7.16(d,1,J=7.0), 4.05-3.95(m,2), 3.80-3.70(m,2), 2.75(s,2), 1.80-1.60(m,4); 13C NMR (CDCl3) 158.21, 134.50, 131.33, 128.25, 128.05, 127.18, 127.13, 63.72, 53.85, 37.29, 37.13; MS(MW=201.3, EI, eE=70 eV) m/z 201(M+), 200, 186, 170, 156 (base peak), 144, 118, 115, 102, 89, 77, 63, 51, 41.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]1>>[C:29]([N:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:15]2[C:16](=[O:19])[CH2:17][CH2:18][N:12]([C:10](=[O:11])/[CH:9]=[CH:8]/[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:14]2)[CH2:24][CH2:25]1)(=[O:31])[CH3:30]
Reactant: O=C1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCN1
Reactant: CC(=O)N1CCN(CCCl)CC1
Product: CC(=O)N1CCN(CCN2CCN(C(=O)/C=C/c3cccc(Cl)c3)CCC2=O)CC1

Procedure:
In analogy to the procedure described in intermediate 4A, 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 3A]) and 1-[4-(2-chloro-ethyl)-piperazin-1-yl]-ethanone gave the title compound as off-white foam. MS: 433.2 (MH+, Cl).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH:26][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1)[CH3:22]
Reactant: CC1(C)OB(c2ccc(OCCCBr)cc2)OC1(C)C
Reactant: CCN(CC)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)CCNCCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Yield: 52.6 %

Procedure:
A solution of 2-[4-(3-bromopropoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mL, 2.02 mmol), N1,N1-diethylethane-1,2-diamine (0.87 mL, 6.1 mmol), and potassium carbonate (550 mg, 4.0 mmol) in acetonitrile (15 mL) was heated to 50° C. for 3 h. The reaction mixture was cooled, filtered and the filtrate was concentrated to afford the desired product (400 mg, 53%) as a yellow oil: ESI MS m/z 377 [C21H37BN2O3+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(OCC)(=O)C.CCCCCCC>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: O=C(CCl)CCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nc(CCl)co2)cc1
Temperature: 25 °C

Procedure:
At 120° C., 31 g (123 mmol) of p-fluorobenzamide and 33 g (123 mmol) of 1,3-dichloroacetone were stirred in the absence of a solvent for 2 hours. After cooling to room temperature, the product was dissolved in 250 ml of ethyl acetate. This solution was diluted with 400 ml of n-heptane and washed 3 times with saturated NaCl solution. The organic phase was filtered through 250 ml of silica gel, and the filter pad was then washed with 200 ml of n-heptane/ethyl acetate (4:1). The solvent was distilled off, giving 4-chloromethyl-2-(4-fluorophenyl)oxazole 1 as crude product. This was dissolved in 650 ml of acetone, and 90 g of NaI were then added. The mixture was then heated at reflux for 16 hours, most of the solvent was then removed and the solid residue was suspended in 200 ml of n-heptane/ethyl acetate (1:1) and filtered through 200 ml of silica gel. The precipitate was washed with 500 ml of n-heptane/ethyl acetate (1:1), and the organic phase was concentrated. On concentration, the iodide 2 began to crystallize as white crystals. TLC n-heptane/ethyl acetate (6:1) Rf 0.4 for 2 and Rf=0.35 for 1. C10H7FINO (303.08) MS(ESI): 304 (M+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([N:19]1[CH2:20][CH2:21][C:16]2([O:15][C:14]3[C:24]4[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=3[S:23][CH2:22]2)=[CH:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:25]=4)[CH2:17][CH2:18]1)=[O:33]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 64 was synthesized using 9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. Mp.: 240-241° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.01 (d, J=1.6 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.87 (dd, J=1.6, 7.6 Hz, 1H), 7.83-7.76 (m, 2H), 7.60-7.46 (m, 6H), 7.41 (dt, J=1.6, 7.6 Hz, 1H), 4.32 (br, 1H), 3.49 (br, 2H), 3.14 (s, 2H), 3.35-3.28 (m, 1H), 2.15 (br, 1H), 2.03 (br, 1H), 1.90 (br, 2H); LCMS: 516 [M+H].