Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[C:28](O)=[O:29].CCN=C=NCCCN(C)C>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.ClCCl>[CH2:16]([O:15][C@H:3]1[C@@H:2]([NH:1][C:28]([C:24]2[NH:23][CH:27]=[CH:26][N:25]=2)=[O:29])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ncc[nH]2)[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.5 %

Procedure:
tert-Butyl cis(±)-4-amino-3-(benzyloxy)piperidine-1-carboxylate obtained in Example (90d) (0.92 g, 3.0 mmol) was dissolved in DMA (10 mL). 1H-Imidazol-2-ylcarboxylic acid (0.19 g, 1.70 mmol), WSC (0.82 g, 0.43 mmol) and DMAP (60 mg, 0.49 mmol) were added, and the mixture was stirred at room temperature for one hour. The reaction solution was diluted with dichloromethane, washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1, 1/1, 1/3) to obtain 0.31 g of the title compound as a colorless solid (46%).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:17][C:16]1[CH:18]=[CH:19][C:13]([C:12]([F:11])([F:20])[F:21])=[CH:14][CH:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1nc2ccccc2[nH]1
Product: FC(F)(F)c1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration and preparative LCMS to give the title compound as the free base (white solid, mp 199-200° C.). MS(ES+) m/z 278 ([M+1]+, 100).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32]([OH:34])=O.[O:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][NH2:41]>ClCCl>[O:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][NH:41][C:32](=[O:34])[CH2:31][N:15]1[CH2:16][CH2:17][C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:13]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NCc1ncco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1ncco1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.050 g, 0.169 mmol; Example 1C) and oxazol-2-ylmethanamine (0.018 g, 0.186 mmol) were stirred together in dichloromethane (0.5 mL) at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 (Analogix®) column and the product eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (Flow=30 mL/minute) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 7.38-7.19 (m, 10H), 7.05 (s, 1H), 6.68 (s, 1H), 4.48 (d, J=5.6, 2H), 4.08 (s, 2H), 3.53 (t, J=6.5, 2H), 2.83 (t, J=6.5, 2H); MS (ESI+) m/z 376.0 (M+H)+.
Reaction SMILES: C(O[C:4]([NH:6][C:7]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:8]=1[C:9]([O:11]CC)=O)=[O:5])C.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]2)=[CH:20]1>>[OH:18][C:15]1[CH:14]=[C:8]2[C:7](=[CH:17][CH:16]=1)[NH:6][C:4](=[O:5])[N:36]([CH2:35][CH2:34][N:31]1[CH2:30][CH2:29][CH:28]([C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:19][CH:20]=3)[CH2:33][CH2:32]1)[C:9]2=[O:11]
Reactant: CCOC(=O)Nc1ccc(O)cc1C(=O)OCC
Reactant: NCCN1CCC(c2c[nH]c3ccccc23)CC1
Product: O=c1[nH]c2ccc(O)cc2c(=O)n1CCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 200 °C
Yield: 70 %

Procedure:
A mixture of 12.5 parts of ethyl 2-(ethoxycarbonylamino)-5-hydroxybenzoate and 12 parts of 4-(1H-indol-3-yl)-1-piperidineethanamine was stirred in an oil bath at about 200° C. and under nitrogen atmosphere. The formed ethanol was distilled off. The whole was cooled and the solid product was crystallized from a mixture of ethanol and acetonitrile. The product was filtered off and dried, yielding 14.5 parts (70%) of 6-hydroxy-3-[2-[4-(1H-indol-3-yl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione; mp. 258.2° C. (compound 1).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2.[H-].[Na+].[CH:21](I)([CH3:23])[CH3:22].Cl>CN(C=O)C.O>[CH:21]([O:11][C:9]1[CH:8]=[C:7]2[C:2]([CH:3]3[O:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[CH:4]3[CH2:5][O:6]2)=[CH:1][CH:10]=1)([CH3:23])[CH3:22]
Reactant: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Reactant: CC(C)I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc2c(c1)OCC1c3ccccc3OC21
Yield: 50.6 %

Procedure:
Compound 6a,11a-Dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.42 mmol) was dissolved in DMF (5 ml) and NaH (10 mg, 0.42 mmol) was added to the solution at room temperature, followed by isopropyl iodide (149 mg, 0.84 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 3-isopropoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene (60 mg, 51%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:19][C:20]1[C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:22][O:23][C:24]=1[CH3:25]>C1COCC1.C(OCC)(=O)C>[CH3:25][C:24]1[O:23][N:22]=[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]=1[CH2:19][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1onc(-c2ccccc2)c1CCl
Reactant: Nc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1CNc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
To a solution of 2-aminopyridine (109 mg, 1.2 mmol) in THF (2 mL) was added potassium bis(trimethylsilyl)amide (0.9 M in THF, 1.2 mL, 1.1 mmol) at 0° C. under argon. After 10 min, a solution of 4-chloromethyl-5-methyl-3-phenyl-isoxazole (200 mg, 1.0 mmol) in THF (1 mL) was added and the resulting mixture stirred at 0° C. for 1 h. The mixture was then diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The aqueous phase was extracted with ethyl acetate and the combined extracts dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=4:1: to 1:1) afforded the title compound (45 mg, 18%) as an off white solid. MS: m/e=266.2 [M+H]+.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Br.O>C1COCC1>[Br:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: BrCc1ccccc1Br
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccccc1Br)OCC
Reaction time: 0.08 h

Procedure:
Diethyl phosphite (0.77 mL, 6.0 mmol) was dissolved in dry THF (10 mL) in a dry schlenk tube under an argon atmosphere. The solution was cooled on an ice bath and NaH (0.24 g, 60% in oil, 6.0 mmol) was added and stirred for 5 min. 2-bromo-benzylbromide (1.0 g, 4.0 mmol) dissolved in 2 mL dry THF was added and the reaction mixture was refluxed overnight. H2O (20 mL) was added and the water phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a colourless oil.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[Na].Cl[CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]>CO.C[O-].[Na+]>[OH:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: Oc1ccccc1O
Reactant: COC(=O)C(C)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)C(C)Oc1ccccc1O
Yield: 15.3 %

Procedure:
Catechol (55 g) was dissolved in a methanol solution of sodium methoxide prepared from metallic sodium (11.5 g). Methyl 2-chloropropionate (62 g) was added thereto and refluxed. Extraction with ether and purification on a silica gel column afforded 15 g of methyl 2-(2-hydroxyphenoxy)propionate. This product and 3,4-dichlorobenzylcyanide were dissolved in an ethanol solution of sodium ethoxide prepared from metallic sodium (7 g), and the mixture was refluxed with heat for 3 hours. Extraction with ether and purification on a silica gel column afforded 3 g of 2-(3,4-dichlorophenyl)-4-(2-hydroxyphenyl)-3-oxopentanonitrile. This compound (1 g), 2,3-dichloro-5-trifluoromethylpyridine (0.6 g), and potassium carbonate (0.4 g) were dissolved in dimethylformamide, and the mixture was stirred for 2 hours at 120° C. Extraction with ether and purification on a silica gel column afforded 0.6 g of 4-[2-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-2-(3,4-dichlorophenyl)-3-oxopentanonitrile (Compound 18).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH2:3].[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17](=O)[C:18](O)=[O:19])=[C:11]([F:22])[CH:10]=1>CO>[Cl:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[C:18](=[O:19])[N:6]([CH3:7])[C:4](=[S:5])[N:2]([CH3:1])[N:3]=2)=[C:11]([F:22])[CH:10]=1
Reactant: COc1cc(C(=O)C(=O)O)c(F)cc1Cl
Reactant: CNC(=S)N(C)N
Solvent: CO
Product: COc1cc(-c2nn(C)c(=S)n(C)c2=O)c(F)cc1Cl
Yield: 54.3 %

Procedure:
A solution of 2,4-dimethylthiosemicarbazide (0.20 g) and 2-(4-chloro-2-fluoro-5-methoxyphenyl)-2-oxoacetic acid (0.38 g) in methanol (10 ml) was refluxed for 16 hours. Filtration of the reaction mixture afforded 6-(4-chloro-2-fluoro-5-methoxy-phenyl)-2,4-dimethyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine (0.28 g). 1H NMR, CDCl3, 3.77 (3H, s), 3.91 (3H, s), 4.07 (3H, s), 7.08 (1H, d, J=6.09 Hz), 7.25 (1H, d, J=9.22 Hz).
Reaction SMILES: Br[C:2]1[C:21]([O:22][CH3:23])=[CH:20][C:5]2[NH:6][C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[CH3:23][O:22][C:21]1[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])=[CH:3][C:4]2[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[N:9][CH2:8][C:7](=[O:19])[NH:6][C:5]=2[CH:20]=1
Reactant: COc1ccccc1B(O)O
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2
Agent: OB(O)c1ccccc1
Product: COc1ccccc1-c1cc2c(cc1OC)NC(=O)CN=C2c1cccc(C#N)c1
Yield: 88 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 5 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2-methoxy-benzene boronic acid. The title compound (474 mg) was obtained as a pale yellow solid, (yield=88%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]1([CH2:17][C:18](O)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:18](=[O:19])[CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])[CH3:9]
Reactant: O=C(O)Cc1ccccc1
Reactant: CC(=O)c1ccccc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)c1ccccc1NC(=O)Cc1ccccc1
Reaction time: 4 h

Procedure:
A mixture of o-aminoacetophenone (25 g.) and phenylacetic acid (25 g.) in anhydrous methylene dichloride (200 ml.) was prepared. To that mixture was added dicyclohexylcarbodiimide (40 g.) in portions of approx. 10 g. every 5 min. at ambient temperature. When the addition was completed the mixture was stirred for 4 hr. at ambient temperature. The mixture was then filtered, and the filtrate was evaporated in vacuo to dryness. The residue was crystallised from cyclohexane to give o-acetyl-N-(phenylacetyl)aniline, m.p. 78°.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:6]([N+:19]([O-])=O)=[CH:7][C:8]([N+:16]([O-])=O)=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H][H]>[Ni].CCO>[NH2:16][C:8]1[CH:7]=[C:6]2[C:5]([CH:4]=[CH:3][NH:19]2)=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(/C=C/N(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cc2cc[nH]c2cc1N
Yield: 29.4 %

Procedure:
A mixture of (E)-ethyl 5-(2-(dimethylamino)vinyl)-2,4-dinitrobenzoate (15 g, 0.050 mol) and Raney Nickel (5 g) in EtOH (500 mL) was hydrogenated at room temperature under 50 psi of hydrogen for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-5-carboxylate (3.0 g, 30%). 1H NMR (DMSO-d6) δ 10.68 (s, 1H); 7.99 (s, 1H), 7.01-7.06 (m, 1H), 6.62 (s, 1H), 6.27-6.28 (m, 1H), 6.16 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 1.32-1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([NH:1][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][N:5]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1CCC(N2Cc3c(NCc4ccccc4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A stirred mixture of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (518 mg, 2.0 mmol) and benzaldehyde (0.21 ml, 2.0 mmol) in methanol (20 ml) was heated to reflux for 5 h. The solvent was removed in vacuo to give a solid. The solid was re-dissolved in acetic acid (20 ml). The stirred solution was heated to reflux for 1 h, and was then allowed to cool to room temperature. To the stirred solution was added sodium borohydride (90 mg, 2.3 mmol) and stirring continued at room temperature for 18 h. The resulting suspension was filtered and washed with acetic acid (10 ml) and ether (20 ml) to give 3-{1-oxo-4-[benzylamino]isoindolin-2-yl}piperidine-2,6-dione as an off-white solid (420 mg, 60% yield): mp, 257–259° C.; 1H NMR (DMSO-d6) δ 2.01–2.07 (m, 1H, CHH), 2.23–2.30 (m, 1H, CHH), 2.49–2.65 (m, 1H, CHH), 2.85–3.00 (m, 1H, CHH), 4.19 (d, J=17 Hz, 1H, CHH), 4.31 (d, J=17 Hz, 1H, CHH), 4.39 (d, J=5.7 Hz, 2H, CH2), 5.12 (dd, J=5.1, 13 Hz, 1H, NCH), 6.37 (t, J=5.9 Hz, 1H, NH), 6.62 (d, J=8.0 Hz, 1H, Ar), 6.91 (d, J=7.3 Hz, 1H, Ar), 7.19–7.40 (m, 6H, Ar), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.79, 31.25, 45.79, 46.09, 51.56, 110.32, 112.34, 126.72, 127.05, 128.32, 129.07, 132.08, 139.72, 143.33, 168.82, 171.22, 172.90; Anal Calcd for C20H19N3O3: C, 68.75; H, 5.48; N, 12.03. Found C, 68.73; H, 5.41; N, 12.04.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([CH3:10])=[CH:5][C:3]=1[NH2:4].Cl[C:12](OC(Cl)(Cl)Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([CH3:10])=[CH:5][C:3]=1[N:4]=[C:12]=[O:13]
Reactant: Cc1cc(N)c(Cl)cc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(N=C=O)c(Cl)cc1Cl
Yield: 107.9 %

Procedure:
In a manner similar to Kurita, et al., J. Org. Chem., 41, 2070 (1976), incorporated herein by reference, the reaction of 3.43 g (0.0156 mole) of 2,4-dichloro-5-methylaniline and 3.5 g (0.018 mole) of trichloromethyl chloroformate in 50 mL of toluene produced 3.4 g of 2,4-dichloro-5-methylphenyl isocyanate.
Reaction SMILES: [CH2:1]=[CH: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][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(C1C=C(C=C(C(C)(C)C)C=1O)CC1C(C)=C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)C(C)=C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)C=1C)(C)(C)C.[C:78]1(=[O:84])[O:83][C:81](=[O:82])[CH:80]=[CH:79]1>CCCCCCC>[CH:1]([CH:79]1[CH2:80][C:81](=[O:82])[O:83][C:78]1=[O:84])=[CH: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][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CCCCCCCCCCCCCCCCCCC
Agent: Cc1c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c1Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCCCCCC
Product: CCCCCCCCCCCCCCCCCCC=CC1CC(=O)OC1=O
Temperature: 210 °C

Procedure:
In a separate reaction vessel was placed 560 grams of the above isomerized eicosene and 200 ml heptane. The 3.1 grams of tri-(3,5-di-tert-butyl-4-hydroxybenzyl)mesitylene stabilizer was added and the mixture heated to 210° C. Over a 2.5-hour period, 156.8 grams of maleic anhydride was added at about 225° C. Following this unreacted maleic anhydride was distilled out under vacuum at 210° C. leaving isomerized eicosenyl succinic anhydride.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC(=O)[NH:35][C:36]([CH3:49])([CH3:48])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][C:40]=1[F:47])(C)(C)C>>[NH2:35][C:36]([CH3:49])([CH3:48])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:41][C:40]=1[F:47]
Reactant: CC(C)(COc1ccc(C=O)cc1F)NC(=O)OC(C)(C)C
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N)c(F)c2)c1
Yield: 73.6 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and tert-butyl[2-(2-fluoro-4-formylphenoxy)-1,1-dimethylethyl]carbamate (72 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (19 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>C(OCC)(=O)C.[Pd]>[N:15]1[C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[NH:12][C:11]=1[S:10][C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:28]([NH:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:33])([F:31])[F:32])[CH:23]=2)=[S:29])=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: O=[N+]([O-])c1ccc(Sc2nc3ccccc3[nH]2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4ccccc4[nH]3)cc2)ccc1Cl
Yield: 5 %

Procedure:
2-(4-Nitrophenylthio)benzimidazole (5.0 mmoles, 1.37 g) was reduced in ethyl acetate over 1.37 g 5% Pd/C, filtered and condensed and then reacted with 4-chloro-3-trifluoromethylphenylisothiocyanate (5.0 mmoles, 1.0 g) according to procedure C to yield the title compound 0.12 g, 5% product. Mass Spec (FD) 479. Calculated for C21H14ClF3N4 S2 : C, 52.66; H, 2.95; N, 11.70. Found: C, 52.85; H, 3.18; N, 10.47.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]2[N:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][O:29][C:30]4[CH:31]=[CH:32][CH:33]=[C:34]5[C:39]=4[N:38]=[C:37]([CH3:40])[CH:36]=[CH:35]5)[C:22]=3[Cl:41])[CH:18]=[CH:19][CH:20]=2)=[O:13])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN.[CH2:45]([N:47]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:41][C:22]1[C:23]([CH2:28][O:29][C:30]2[CH:31]=[CH:32][CH:33]=[C:34]3[C:39]=2[N:38]=[C:37]([CH3:40])[CH:36]=[CH:35]3)=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[N:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]1[CH:8]=[N:9][C:4]([C:1](=[O:2])[NH:47][CH3:45])=[CH:5][CH:6]=1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(-n4cccc4CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(/C=C/C(=O)NCc2cccn2-c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cn1
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a solution of 2-[(E)-3-(6-carboxypyridin-3-yl)acryloylaminomethyl]-1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]pyrrole (60 mg) and methylamine hydrochloride (7.59 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (19 mg) and 1-hydroxybenzotriazole (20.7 mg) at ambient temperature, and the mixture was allowed to stand for 1 day at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[(E)-3-[6-(methylcarbamoyl)pyridin-3-yl]acryloylaminomethyl]pyrrole (58 mg) as amorphous powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1.C1COCC1>CN(C1C=CN=CC=1)C.C(O)C>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Reactant: Nc1ccc(S)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Sc2cc(-c3ccccc3)c3ccccc3n2)cc1
Yield: 451.6 %

Procedure:
2-Chloro-4-phenylquinoline (4.18 mmoles, 10.0 g), 4-aminothiophenol (41.8 mmoles, 5.2 g) and DMAP (41.8 mmoles, 5.0 g) were stirred in 200 ml ethanol and 50 ml THF for 3 days. The solution was concentrated, ethyl acetate added, washed with water, dried over sodium sulfate and the solvent removed. The product was purified by HPLC over silica gel eluted with 30% ethyl acetate in hexane to yield 2-(4-aminophenylthio)-4-phenylquinoline 6.2 g, 45%. Mass Spec (FD) 328. Calculated for C21H16N2S: C, 76.80; H, 4.91 N, 8.53. Found: C, 77.04; H, 5.00; N, 8.55.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C[N:30](C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.N>CN(C=O)C>[NH2:30][C:14]([C:11]1([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(=O)O)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(N)=O)CC1
Yield: 20.6 %

Procedure:
To a solution of 4-benzyloxycarbonylamino-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.09 g, 5.52 mmol) in DMF (10 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.27 g, 6.63 mmol), 1-hydroxy-7-azabenzotriazole (0.373 g, 2.76 mmol) and triethylamine (0.924 mL, 6.63 mmol), followed by ammonia (0.5 M in MeOH, 13.3 mL, 6.63 mmol). After 18 h the mixture was concentrated and the residue was partitioned between saturated aqueous NaHCO3 and ethyl acetate, the organic layer dried over MgSO4, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 6% methanol:dichloromethane to give the title compound (0.43 g). MS: m/z=378.2 (M+1).