Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[CH2:11](O)[CH3:12]>S(=O)(=O)(O)O>[CH2:11]([O:9][C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH2:7])[NH2:1])[CH3:12]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H](N)CCCCN
Temperature: 90 °C
Yield: 76.5 %

Procedure:
A solution of 2.2 g of L-lysine in 13.0 ml of ethyl alcohol and 1.6 ml of conc. sulfuric acid was heated under reflux at 90° C. for 5 hours, obtaining L-lysine ethyl ester in a yield of 76.5%. Separately, L-methionine ethyl ester was prepared from 0.8 g of L-methionine in the same manner as in Example 1. After 66 mg of papain and 6.6 mg of L-cysteine were dissolved in a solution of 1.8 g of sodium carbonate and 0.52 g of sodium hydrogen carbonate in 20 ml of water, 20 g of wheat gluten in limited amounts was added to the solution and mixed therewith. The previously prepared reaction solutions of L-lysine and L-methionine ethyl esters were all added to the protein system of wheat gluten, and the system was kept at 37° C. for 24 hours to effect plastein reaction. The rates of incorporation of L-lysine and L-methionine were 62.7% and 81.6%, respectively. At the end of the reaction, the reaction solution was diluted with water to a volume of 300 ml and adjusted to pH 7 with hydrochloric acid before it was subjected to repeated concentration operations for desalting and purification using a reverse osmosis membrane equipped small experimental apparatus (equipped with a DRS-10 flat membrane, manufactured by Daicell Chemical K.K.) under an operating pressure of 15 kg/cm2. The concentrate resulting from the reverse osmosis treatment was again diluted with water to a volume of 400 ml and adjusted to pH 2.0 with phosphoric acid. After 0.4 g of pepsin was added to the solution, the hydrolytic reaction was carried out for 3 hours. Thereafter, 0.4 g of orientase was added and the hydrolytic reaction was continued for an additional 30 hours. The reaction solution was heated to 90° C. for 10 minutes and then centrifuged under 2000G to remove the solids. The supernatant was freeze dried to yield 18.3 g of a low-molecular weight peptide mixture. This product had an average molecular weight of 350 and contained 8.9% of free amino acids, and the gel filtration showed that it contained 86.2% of compounds with a molecular weight of 700 or lower. Table 2 shows the amino acid composition of the starting protein, wheat gluten and the low-molecular weight peptide mixture produced therefrom. As seen from Table 2, the low-molecular weight peptide mixture had the increased contents of L-lysine and L-methionine as compared with the starting protein.
Reaction SMILES: [CH2:1](C(CO)(CO)CC)[OH:2].C[CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=O)[CH3:12]>>[CH2:20]([CH:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:11][CH3:12])[CH2:1][OH:2])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)CCCCCCCCCCCCC(=O)O
Reactant: CCC(CO)(CO)CO
Product: CCCCCCCCC(CO)CCCCCC

Procedure:
The ester oil of claim 1 being the triisopalmitic acid ester of trimethylolpropane, said isopalmitic acid being obtained by the oxidation of 2-hexyldecanol formed from n-octanol by the Guerbet synthesis.
Reaction SMILES: [OH2:1].C1(=O)[N:6]([CH2:7][CH2:8][O:9][CH2:10][N:11]2[CH:19]=[N:18][C:17]3[C:16](=[O:20])[NH:15][C:14]([NH2:21])=[N:13][C:12]2=3)C(=O)C2=CC=CC=C12.NN>C(O)C>[OH2:9].[C:16]([OH:20])(=[O:1])[CH3:17].[NH2:6][CH2:7][CH2:8][O:9][CH2:10][N:11]1[CH:19]=[N:18][C:17]2[C:16](=[O:20])[NH:15][C:14]([NH2:21])=[N:13][C:12]1=2
Reactant: Nc1nc2c(ncn2COCCN2C(=O)c3ccccc3C2=O)c(=O)[nH]1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(=O)O
Product: NCCOCn1cnc2c(=O)[nH]c(N)nc21
Reaction time: 1 h
Yield: 112.7 %

Procedure:
A dispersion of N-(2-hydroxyethyl)phthalimide (19.1 g) and paraformaldehyde (3.0 g) in 1,2-dichloroethane (250 ml) was cooled in an ice-salt-acetone bath and saturated with dry hydrochloric acid with stirring. After 4 hours the mixture was dried over calcium chloride, filtered and evaporated under reduced pressure to give N-(2-chloromethoxyethyl)phthalimide (21.9 g), m.p. 69°-72° C. To a stirred solution of tris trimethylsilylguanine (16.5 g) in toluene (50 ml) was added N-(2-chloromethoxyethyl)phthalimide (17.0 g) and triethylamine (23 ml). The reaction mixture was heated at reflux under nitrogen for 29 hours, cooled and evaporated under reduced pressure giving a dark brown oil. The oil was digested in ethanol (400 ml) on a steam bath for 40 minutes, giving a solid which was collected and washed with ethanol and ether. It was recrystallized from 2-methoxyethanol to give 9-(2-phthalimidoethoxymethyl)guanine hydrate (14.4 g), m.p.>240° C. (dec.). A mixture of 9-(2-phthalimidoethoxymethyl)guanine hydrate (0.94 g), hydrazine (2 ml) and ethanol (100 ml) was heated at reflux with stirring for one hour. The reaction mixture was filtered hot, and the filtrate was cooled and evaporated under reduced pressure. Ethanol was added and the mixture re-evaporated. This was repeated three times. The residual solid was stirred with 3% aqueous acetic acid (50 ml) for 30 minutes and filtered. The solids were washed with water (15 ml), and the wash and filtrate combined. The combined wash and filtrate was evaporated under reduced pressure at<35° C. to a small volume, diluted with ethanol and evaporated to dryness. The pasty, white solid was dispersed in a small amount of ethanol and diluted with a few ml ether to give a granular solid which was collected, washed with ethanol and dried. Recrystallization from ethanol-water gave 9-(2-aminoethoxymethyl)guanine acetate monohydrate (0.43 g), m.p. (~135° C. melts and resolidifies) 174°-176° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[NH2:21][C:22]1[CH:23]=[C:24]([CH:31]=[CH:32][CH:33]=1)[O:25][CH2:26][C:27]([NH:29][CH3:30])=[O:28]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:23]=[C:24]([CH:31]=[CH:32][CH:33]=2)[O:25][CH2:26][C:27]([NH:29][CH3:30])=[O:28])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: CNC(=O)COc1cccc(N)c1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)COc1cccc(Nc2nc(Cl)nc3[nH]ccc23)c1
Temperature: 100 °C
Yield: 56.6 %

Procedure:
To a solution of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.062 g, 0.33 mmol) in DMSO (1 mL) was added DIPEA (0.117 mL, 0.66 mmol) and 2-(3-aminophenoxy)-N-methylacetamide (0.095 g, 0.49 mmol). After heating at 100° C. for 15 h, it was diluted with EtOAc, washed with saturated NaHCO3, brine, dried and concentrated to give 2-(3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy-N-methylacetamide (0.062 g).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6].[N:20]1([C:24]([C:26]2[CH:31]=[N:30][C:29](Cl)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:18][C:16]3[CH:15]=[C:10]([CH:9]=[C:8]([O:7][C@@H:5]([CH3:6])[CH2:4][O:3][CH:2]([F:19])[F:1])[CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])=[N:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)COC(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@@H](C)COC(F)F)c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 74.7 %

Procedure:
A mixture of methyl 3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxybenzoate (0.28 g, 1.01 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (201 mg, 1.01 mmol) and potassium carbonate (280 mg, 2.03 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours. The reaction mixture was reduced in vacuo, ethyl acetate (50 mL) added and the organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 20 to 70% ethyl acetate in isohexane, to give the desired compound as a colourless oil (330 mg). 1H NMR δ (CDCl3): 1.38 (d, 3H), 2.37 (quin, 2H), 3.90 (s, 3H), 3.93-4.04 (m, 2H), 4.26 (d, 2H), 4.61-4.70 (m, 3H), 6.25 (t, 1H), 6.95 (t, 1H), 7.43-7.44 (m, 1H), 7.49-7.50 (m, 1H), 8.32 (d, 1H), 8.85 (d, 1H); m/z 438 (M+H)+
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:29]=[C:28]([C:27]2[CH:30]=[CH:31][C:24]([CH3:23])=[C:25]([O:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:35][N:34]=3)[CH:26]=2)[N:2]([CH3:1])[N:3]=1
Reactant: Cc1ccc(C#N)cc1Oc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2ccccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nc(-c3ccccc3Cl)nn2C)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 36.5 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-benzohydrazonoyl chloride (1.1 g), 4-methyl-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.00 g), anhydrous iron (III) chloride (0.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.50 g of desired compound.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:35])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[N:9]=[C:8]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)([CH3:3])[CH3:2].Br[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[F:45])[CH:40]=[O:41].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[F:45][C:44]1[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][C:37]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)[N:7]([CH2:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:35])[C:16]2=[O:17]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: COc1cccc(-c2nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3c(=O)n2CC(=O)NC(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2nc3ccc(-c4cc(C=O)ccc4F)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 80 °C
Yield: 26.7 %

Procedure:
To a solution of N-isopropyl-2-[2-(3-methoxyphenyl)-4-oxo-6-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-4H-quinazolin-3-yl]acetamide (70 mg, 0.15 mmol) in DMF (3 mL) was added 3-bromo-4-fluorobenzaldehyde (70 mg, 0.34 mmol), followed by tetrakis(triphenylphosphine)palladium (Pd[P(C6H5)3]4) (24 mg, 0.02 mmol) and 2M K3PO4 (aq.) (0.38 mL, 0.76 mmol). The mixture was heated at 80° C. under argon for 20 h, then cooled to room temperature and DMF evaporated in vacuo. The crude product was purified by preparative thin layer chromatography on silica gel with methanol:dichloromethane (1:9, v/v) as eluent to provide 2-[6-(2-fluoro-5-formylphenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (19.3 mg, 0.04 mmol, 27% yield).
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[CH2:14][C:15]#[N:16])([O-])=O.O.C(O)(=O)C>CCO.[Pd]>[F:13][C:10]([F:11])([F:12])[C:8]1[CH:9]=[C:4]2[C:5]([CH:14]=[CH:15][NH:16]2)=[CH:6][CH:7]=1
Reactant: N#CCc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2cc[nH]c2c1
Yield: 114.6 %

Procedure:
The commercially available (2-nitro-4-trifluoromethylphenyl) acetonitrile (14.0 g, 60.8 mmol) was dissolved in 9:1 EtOH:H2O (50 mL) and glacial acetic acid (1.4 mL). This mixture was hydrogenated over 10% Pd/C (5.0 g) at 50 psi for 16 h at room temperature. The reaction was filtered over celite and evaporated in vacuo. The residue was partitioned between saturated aqueous sodium carbonate and dichloromethane (2×200 mL) and the combined organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (hexanes/ethyl acetate, 20:1, 9:1, 5:1) to afford 12.9 g (65% yield) of 6-trifluoromethyl-1H-indole as a yellow solid: 1H NMR (400 MHz, CDCl3) 8.36, (1H, br s), 7.72 (2H, m), 7.37 (2H, m), 6.63 (1H, m); MS m/e 184 (M−H)−. Anal calcd. for C9H6F3N: C, 58.38; H, 3.26; N, 7.56. Found: C, 58.30; H, 2.92; N, 7.49.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.Cl.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[C:32](=[O:35])([O-:34])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[C:8]([OH:17])(=[O:7])/[CH:9]=[CH:10]/[C:32]([OH:34])=[O:35].[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:4]([CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][CH:26]([C:20]3[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=3)[CH2:31][CH2:30]2)[CH2:5][CH2:6]1
Reactant: BrCCC1CCOc2ccccc21
Reactant: COc1ccc(C2CCNCC2)cc1OC
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(C2CCN(CCC3CCOc4ccccc43)CC2)cc1OC
Product: O=C(O)/C=C/C(=O)O

Procedure:
The B isomer of 1-[2-(3,4-dihydro-1(2H)-benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)piperidine fumarate is prepared by following the procedure of Example 16 but starting with the B isomer of 4-(2-bromoethyl)-3,4-dihydro-(2H)-benzopyran (1.5 g) and 4-(3,4-dimethoxyphenyl)piperidine dihydrochloride (1.78 g), followed by potassium carbonate (1.71 g) and potassium iodide (1.03 g) in 2-butanone (50 cc).
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1.[CH3:20][I:21]>C(Cl)Cl>[I-:21].[CH3:1][N+:2]1([CH3:20])[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1
Reactant: CI
Reactant: CN1CCN2c3ccccc3Cn3cccc3C2C1
Solvent: ClCCl
Product: C[N+]1(C)CCN2c3ccccc3Cn3cccc3C2C1
Product: [I-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of 500 mg of 2-methyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine, 10 ml of methylene chloride and 0.5 ml of methyl iodide is stirred at room temperature for one hour. It is filtered and the residue washed with methylene chloride, to yield the 2,2-dimethyl-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepinium iodide melting at 258°-260° with decomposition.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[CH3:24]C([Si](Cl)(C)C)(C)C.N1C=CN=C1>>[OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:8])([CH3:9])[N:5]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:19]=[CH:20][N:21]=[C:22]([CH3:24])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Product: Cc1cc(C[C@H]2[C@@H](CO)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1

Procedure:
The title compound was synthesized in manner analogous to that described in Example 472, using (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylate in the presence of TBSCl and imidazole, and was used without further purification.
Reaction SMILES: S1C=CC(CC(O)=[O:8])=C1.C(S)CCS.[CH:15]1([N:21]=[C:22]=[N:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CC(C)=O>[CH:24]1([NH:23][C:22]([NH:21][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)Cc1ccsc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: SCCCS
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C

Procedure:
As shown in Reaction 1, 2-(thiophene-3-yl)acetic acid) (1 g, 7.03 mmol), propane-1,3-dithiol (0.753 g, 7.03 mmol), and 4-dimethylaminopyridine (4-DMAP) (2.014 g, 1.75 mol) were dissolved in 80 ml of methylene chloride in a three-neck round bottom flask, after which stirring was performed at 60° C. in a nitrogen atmosphere. The stirred mixture solution was slowly added with N,N′-dicyclohexylcarbodiimide (DCC) (2.89 g, 14.06 mol) dissolved in 20 ml of methylene chloride, and was then allowed to react for 9 hours. The reaction solution was washed using saturated aqueous Na2CO3, dried over MgSO4, and filtered. The remaining solvent was removed by rotary evaporation to obtain a yellowish solution. This solution was diluted with acetone, and cooled to 0° C., to obtain residual 1,3-dicyclohexylurea (“DCU”) as a precipitate. This precipitate was removed by filtration through a paper filter, and addition of acetone and removal of the DCU precipitate were repeated until DCU precipitate was no longer evident in the solution. Finally, the remaining solvent was removed by rotary evaporation, and the crude purified using a silica column eluted with a solution of methylene chloride and methanol (60:1 v/v), thereby producing after collection of the fractions and removal of the solvent, S-3-mercaptopropyl-2-(thiophene-3-yl)ethanethioate (“MTE”) (the monomer) as a pure yellow compound. The characteristic H1-NMR spectrum (in acetone-d6) of the product is shown in FIG. 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].C([O-])([O-])=O.[K+].[K+].Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][N:24]=1>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][N:24]=2)[CH2:14][CH2:15]1)=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)c2ccccc12
Reactant: O=C(c1ccccc1F)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(c1ccccc1F)N1CCN(c2ncc([N+](=O)[O-])c3ccccc23)CC1
Reaction time: 24 h
Yield: 75.8 %

Procedure:
Add (2-fluoro-phenyl)-piperazin-1-yl-methanone (3.16 g, 12.9 mmol) and K2CO3 (8.9 g, 64.5 mmol) to 1-chloro-4-nitroisoquinoline (2.85 g, 13.7 mmol) in acetonitrile (100 mL) and stir for 24 hours. Filter the insoluble solid and wash the cake with AcOEt. Evaporate the solvent under reduced pressure to give a residue. Subject residue to silica gel chromatography eluting with hexane:AcOEt 20-90% to give 3.72 g of (2-fluoro-phenyl)-[4-(4-nitro-isoquinolin-1-yl)-piperazin-1-yl]-methanone as a solid. LCMS ES+(m/z) 381.2 [M+H].
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][NH:3]1.[CH2:18]=O.[CH:20]1[CH:21]=[C:22]2[C:27]3=[C:28]([C:30]([NH:32][C:33](=[O:34])[C:26]3=[CH:25][CH:24]=[CH:23]2)=[O:31])[CH:29]=1>CN(C)C=O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:18][N:32]3[C:33](=[O:34])[C:26]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:27]=4[C:28](=[CH:29][CH:20]=[CH:21]5)[C:30]3=[O:31])[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][NH:3]1
Reactant: O=C1NC(=O)c2cccc3cccc1c23
Reactant: C=O
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Solvent: CN(C)C=O
Product: O=C1c2cccc3cccc(c23)C(=O)N1CN1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
An equimolar mixture of 4-oxo-1-phenyl-1,3,8-triazaspiro-[4.5]decane, aqueous formaldehyde, and 1,8-naphthalimide is suspended in a small amount of dimethylformamide and the mixture is heated until dissolution is complete. The solution is allowed to stand at room temperature and the resulting precipitate is filtered off and dried to yield the titled compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[O:23]1[C:27]2=[CH:28][N:29]=[C:30]([CH:32]=O)[CH:31]=[C:26]2[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].C(Cl)(Cl)[Cl:54]>CO.CO.C(Cl)Cl>[ClH:54].[O:23]1[C:27]2=[CH:28][N:29]=[C:30]([CH2:32][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)[CH:31]=[C:26]2[CH2:25][CH2:24]1
Reactant: ClC(Cl)Cl
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: O=Cc1cc2c(cn1)OCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cn2)OCC3)CC1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A suspension of (2R)-2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(j)) (70 mg, 0.232 mmol) and 2,3-dihydrofuro[2,3-c]pyridine-5-carbaldehyde (for a synthesis see WO2007122258, Example 43(f) (34.6 mg, 0.232 mmol) in chloroform (5 ml) and methanol (0.250 ml) at room temperature under nitrogen was stirred for 0.5 h (the suspension turned into a solution). Sodium triacetoxyborohydride (155 mg, 0.697 mmol) was then added and the reaction was stirred at room temperature. After 3 h there was no starting material left so a saturated aqueous solution of sodium bicarbonate (25 mL) was added followed by 20% methanol/DCM (25 mL) and the aqueous layer was extracted and then separated from the organic layer. The aqueous layer was extracted again twice with 20% methanol/DCM (2×25 mL). The combined organic extracts were dried on sodium sulphate, filtered and evaporated to afford 90 mg of crude product. The crude product was purified by silica chromatography (0-20% MeOH/DCM) to afford the free base of the title compound as a pale yellow solid (77 mg, 76%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]4[C:29]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:23]=5[N:22]([CH3:37])[C:21]=4[N:38]=3)[C:13](=[O:39])[CH:12]=2)=[N:7][CH:8]=1>CO.CCOCC>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]4[C:29]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24][C:23]=5[N:22]([CH3:37])[C:21]=4[N:38]=3)[C:13](=[O:39])[CH:12]=2)=[N:7][CH:8]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc31)CCNCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
1.25 M HCl in MeOH (6.0 mL) was added to tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.12 g, 0.22 mmol) and the resulting solution was stirred under N2 at ambient temperature for 20 h. The resulting suspension was diluted with Et2O (30 mL), and the resulting solids were collected by filtration to provide the title compound (92 mg, 92%) as an off-white solid: mp 238-240° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.43 (s, 2H), 8.62 (d, J=2.0 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.84-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.30 (d, J=8.5 Hz, 1H), 6.19 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 3.73 (s, 3H), 3.40-3.37 (m, 2H), 3.34-3.30 (m, 4H), 3.18-3.14 (m, 2H); ESI MS m/z 420 [M+H]−; HPLC (Method A) 98.8% (AUC), tR=13.5 min.