Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][NH:28][N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40]O)[CH2:34][CH2:33]1>>[Cl:1][C:2]1[C:3]([C:26]2[N:30]=[CH:29][N:28]([CH2:40][CH2:39][CH2:38][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[N:27]=2)=[C:4]([NH:7][C:8](=[O:25])[CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:24])[S:5][CH:6]=1
Reactant: CN1CCN(CCCO)CC1
Reactant: O=C(Cn1c(=O)ccc2cc(C(F)(F)F)ccc21)Nc1scc(Cl)c1-c1nc[nH]n1
Product: CN1CCN(CCCn2cnc(-c3c(Cl)csc3NC(=O)Cn3c(=O)ccc4cc(C(F)(F)F)ccc43)n2)CC1

Procedure:
The title compound was prepared from N-(4-chloro-3-(1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide (108 mg, 248 umol) and 3-(4-methylpiperazin-1-yl)propan-1-ol (350 mg, 2.21 mmol) using the procedures described in Example 1.76. HPLC purification gave N-(4-chloro-3-(1-(3-(4-methylpiperazin-1-yl)propyl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)-2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetamide. Method [7] retention time 4.27 min by HPLC (M+=594 and 596). 1H NMR (300 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H), 8.22 (d, J=9.9 Hz, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.17 (s, 1H), 6.87 (d, J=9.3 Hz, 1H), 5.32 (s, 2H), 4.25 (t, J=6.6 Hz, 2H), 2.95 (broad m, 10H), 2.73 (s, 3H), 1.97 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:13]([Li])[CH2:14][CH2:15]C.C(#N)C1C=CC=CC=1>CCCCCC>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:12]([C:11]2[CH:15]=[CH:14][CH:13]=[CH:9][CH:10]=2)=[O:8])[O:4][N:3]=1
Reactant: C1CCOC1
Reactant: [Li]CCCC
Reactant: Cc1cc(C)on1
Solvent: N#Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(CC(=O)c2ccccc2)on1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
The general procedure of Micetich, Can. J. Chem., 48, 2006 (1970) was employed. 3,5-Dimethylisoxazole (4.86 g, 50 mmol) and 100 mL of tetrahydrofuran were placed in a flask under nitrogen and cooled to -70° C. with an ether Dry Ice bath. To this was added with cooling and stirring 20 mL (50 mmol) of 2.5M n-butyl lithium in hexane solution at a rate such that the temperature remained below -50° C. and the mixture was allowed to stir at -70° C. for 1 hr. Benzonitrile (5.67 g, 55 mmol) was then added and stirring at -70° C. was continued for an additional 2-hr period. The resulting mixture was allowed to warm to ambient temperature and was then concentrated by evaporation under reduced pressure. The residue was mixed with 100 mL of hydrochloric acid and extracted with diohloromethane. The organic extract was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a solid residue which was recrystallized from ether to obtain 4.6 g (46 percent of theory) of the title compound as a yellow solid melting at 73°-74 ° C.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:6]=1)(=O)C.N1CCCCC1.[OH:37][CH2:38][CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[ClH:11].[NH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:43]2[CH2:44][CH2:45][CH:40]([CH2:39][CH2:38][OH:37])[CH2:41][CH2:42]2)=[C:7]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=2)[CH:6]=1
Reactant: OCCC1CCNCC1
Reactant: COc1cc(COc2cc(NC(C)=O)c(Cl)cc2C(=O)CCCCCl)cc(OC)c1
Solvent: C1CCNCC1
Product: COc1cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCC(CCO)CC2)cc(OC)c1
Product: Cl

Procedure:
Proceeding as in Example 4, Step (c), but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one with 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzyloxy)phenyl]-5-chloropentan-1-one and piperidine with 4-(2-hydroxyethyl)piperidine, gave 1-[4-amino-5-chloro-2-(3,5-dimethoxy-benzyloxy)phenyl]-5-[4-(2-hydroxyethyl)piperidin-1-yl]pentan-1-one hydrochloride, m.p. 180-183° C.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:20][C:21](=[O:42])[C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[NH:29][S:30]([C:33]1[C:38]2=[N:39][S:40][N:41]=[C:37]2[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.N1SN=C2C(S(NC3C=C(I)C=CC=3C(O)=O)(=O)=O)=CC=CC=12.COC(=O)[C@@H](N)C(C1C=CC(Cl)=CC=1)C1C=CC(Cl)=CC=1>>[N:41]1[S:40][N:39]=[C:38]2[C:33]([S:30]([NH:29][C:23]3[CH:24]=[C:25]([I:28])[CH:26]=[CH:27][C:22]=3[C:21]([NH:20][C@@H:4]([CH:5]([C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=3)[C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:3]([OH:43])=[O:2])=[O:42])(=[O:31])=[O:32])=[CH:34][CH:35]=[CH:36][C:37]=12
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: COC(=O)[C@@H](N)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Product: O=C(N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)c1ccc(I)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 84 %

Procedure:
(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodo-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester. The title compound (49 mg, 84%) was prepared from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-iodobenzoic acid (Example 101, Part D) and (S)-2-amino-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester (Example 106, Part H) as in Example 1, Part C. 1H NMR (500 MHz, CDCl3): 11.16 (s, 1H), 8.36 (dd, J=7.0, 1.0, 1H), 8.23 (dd, J=8.8, 1.0, 1H), 8.03 (d, J=1.6, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.32-7.27 (m, 4H), 7.24 (dd, J=8.2, 1.6, 1H), 7.21-7.15 (m, 4H), 6.71 (d, J=8.3, 1H), 6.22 (br d, J=8.8, 1H), 5.48 (t, J=8.5, 1H), 4.48 (d, J=8.3, 1H), 3.62 (s, 3H).
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].C(OC(=O)[N:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31](N)=[CH:30][CH:29]=1)[CH:20]=[CH:19]2)C)(C)(C)C.[CH3:36][C:37]1[CH:38]=[C:39](S(N)(=O)=O)[S:40][CH:41]=1>>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:7][C:5]([NH:4][S:1]([C:39]3[S:40][CH:41]=[C:37]([CH3:36])[CH:38]=3)(=[O:3])=[O:2])=[O:6])=[CH:32][CH:33]=1)[CH:20]=[CH:19]2
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Reactant: NC(=O)N=S(=O)=O
Reactant: Cc1csc(S(N)(=O)=O)c1
Product: Cc1csc(S(=O)(=O)NC(=O)Nc2ccc(-n3ccc4cc(N)c(F)cc4c3=O)cc2)c1

Procedure:
An analogous sulfonylurea coupling and de-protection procedure to that described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 4-methylthiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl]amino}carbonyl)-4-methylthiophene-2-sulfonamide. ES-MS (M+H)+=487.1.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:16])=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:16])=[O:4]
Reactant: CNC(=O)c1c(C)[nH]c2cc(OC)ccc12
Agent: BrB(Br)Br
Product: CNC(=O)c1c(C)[nH]c2cc(O)ccc12

Procedure:
This material was prepared from 6-methoxy-2-methyl-1H-indol-3-carboxylic acid methylamide 24a by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (300 MHz, CD3OD) δ 7.52 (1H, d, J=8.7 Hz), 6.72 (1H, d, J=2.3 Hz), 6.65 (1H, dd, J=2.3, 8.7 Hz), 2.93 (3H, s), 2.55 (3H, s). LCMS (ESI+) [M+H]/z Calc'd 205. found 205.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:13]([NH:19][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and hexylamine as starting materials to give the aimed compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(N([CH2:12][CH3:13])CC)C.O1C[CH2:17][CH2:16][CH2:15]1>>[C:2]1(=[O:3])[CH:13]2[CH:6]([CH2:15][CH2:16][CH2:17][CH2:12]2)[CH2:5][O:4]1
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Product: O=C1OCC2CCCCC12
Temperature: 12 °C
Reaction time: 0.5 h

Procedure:
At -5° C. and over a few minutes, a solution of 256 mg of ethyl chloroformate in 0.6 ml of tetrahydrofuran was added to a solution of 440 mg of the product of Step B'2 and 239 mg of triethylamine in 3.3 ml of tetrahydrofuran. The mixture was stirred for 30 minutes and then the precipitate was filtered off. The filtrate was added dropwise to a suspension of 235 mg of 95% sodium borohydride in 2.3 ml of water maintained at about 12° C. which was then left for 3 hours 30 minutes at ambient temperature. It was then cooled, acidified with 2N hydrochloric acid and extracted with methylene chloride. The extracts were dried, evaporated to dryness, purified by chromatography over silica (eluent: cyclohexane ethyl acetate, 65-35) to obtain 228 mg of (3a S, cis) hexahydro 1-(3H)-isobenzofuranone with a specific rotation of [α]D20 =-47° (c=0.6% in chloroform).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[NH3:5].[C:6](=[O:8])=[O:7]>O>[NH2:1][C:2]([NH2:4])=[O:3].[C:6](=[O:7])([O-:8])[NH2:5].[NH4+:1]
Reactant: O=C=O
Reactant: N
Agent: NC(N)=O
Solvent: O
Product: NC(=O)[O-]
Product: [NH4+]

Procedure:
This invention relates to an improved process for making urea from ammonia and carbon dioxide. The process is carried out in a reaction vessel which has a zone in which the ammonia and carbon dioxide are reacted to form urea, ammonium carbamate and water, and which also has a zone in which the carbamate is decomposed to ammonia and carbon dioxide. Liquid ammonia is passed in indirect heat exchange relationship with the mixture in the reaction zone, whereby the mixture is cooled and liquid ammonia is vaporized. Ammonia vapor thus produced is passed into the zone in which carbamate is decomposed into ammonia and carbon dioxide to assist in the decomposition of the carbamate. Ammonia and carbon dioxide vapors produced by the decomposition of the carbamate are returned to the reaction zone. A stoichiometric excess of ammonia (that is, more than two moles of ammonia per mole of carbon dioxide and generally from 2.5 to 10 moles of ammonia per mole of carbon dioxide) is introduced into the reaction vessel, and, optionally, means are provided for the recycle of excess ammonia which passes through the reaction vessel unconverted.
Reaction SMILES: [CH2:1]=O.[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:10][C:11]1[C:12]([NH2:26])=[N:13][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[N:15][CH:16]=1>C(Cl)Cl>[F:10][C:11]1[C:12]([NH:26][CH2:3][N:4]2[CH2:9][CH2:8][N:7]([CH3:1])[CH2:6][CH2:5]2)=[N:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[N:15][CH:16]=1
Reactant: CN1CCNCC1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: C=O
Solvent: ClCCl
Product: CN1CCN(CNc2nc(OCc3ccc(F)cc3)ncc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
To a magnetically stirred mixture of paraformaldehyde (0.24 g, 8 mmol) in CH2Cl2 (20 mL) was added N-methylpiperazine (0.80 g, 8.0 mmol). The suspension was stirred overnight at ambient temperature on an orbital shaker, and then 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.47 g, 2.0 mmol) was added. The resulting mixture was stirred over the weekend at RT. The solvent was evaporated and the crude residue was washed twice with 50% ether/petroleum ether and dried under a stream of N2 to give 0.21 g (30%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl](4-methylpiperazin-1-ylmethyl)amine as a beige solid: mp 125-126° C.; 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=2.3 Hz, 1H), 7.43 (m, 2H), 7.03 (t, J=8.5 Hz, 2H), 5.40 (bs, 1H), 5.27 (s, 2H), 4.41 (d, J=6.8 Hz, 2H), 2.63 (bs, 4H), 2.47 (bs, 4H), 2.30 (s, 3H); HPLC-MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.Cl.[NH2:15][OH:16].O>N1C=CC=CC=1>[C:10]1(=[N:15][OH:16])[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: ON=C1CCCc2ccccc21

Procedure:
A solution of 7-methoxy-1-tetralone (10 g; 56.8 mmol) in pyridine (28 ml) and hydroxylamine hyrochloride (9 g; 130.6 mmol) was refluxed for 12 hours. The mixture was poured into water and extracted with CH2Cl2. The organic phase was washed with 1N HCl and 0.5N NaHC3, dried over MgSO4 and evaporated to give 7-methoxy-,1,2,3,4-tetrahydronaphthalen-1-one oxime as a brown solid (10 g; 92.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[S:5][CH:6]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([N:25]=[N+:26]=[N-:27])=[O:11])[S:5][CH:6]=1
Reactant: O=C(O)/C=C/c1cc(Br)cs1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of (E)-3-(4-bromo-thiophen-2-yl)-acrylic acid (3.0 g, 12.9 mmol) in anhydrous acetone (20 ml) was cooled in an ice-bath to 0° C. and treated with triethylamine (2.15 ml, 15.4 mmol) and ethyl chloroformate (1.24 ml, 15.4 mmol). The reaction was left to stir for 0.5 h before being treated with a solution of sodium azide (1.0 g, 15.4 mmol) in distilled water (4 ml). After stirring for 1 h at 0° C., the reaction was further diluted with distilled water (40 ml) and extracted with DCM (3×25 ml). The organic layer was dried (MgSO4) and filtered for direct use in the next reaction.
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[C:56]([O:57][CH2:58][CH2:59][CH2:60][O:61][C:62]2[C:63]([O:80][CH3:81])=[CH:64][C:65]3[C:71](=[O:72])[N:70]4[CH:73]=[C:74](/[CH:76]=[CH:77]/[CH3:78])[CH2:75][C@H:69]4[CH:68]=[N:67][C:66]=3[CH:79]=2)=[CH:55][C:12]2[N:13]=[CH:14][C@@H:15]3[CH2:21][C:20](/[CH:22]=[CH:23]/[CH2:24][NH:25][C:26](=[O:54])[C@@H:27]([NH:29][C:30](=[O:53])[C@@H:31]([NH:35]C(=O)OCC4C5C=CC=CC=5C5C4=CC=CC=5)[CH:32]([CH3:34])[CH3:33])[CH3:28])=[CH:19][N:16]3[C:17](=[O:18])[C:11]=2[CH:10]=1>CN(C=O)C.C(Cl)Cl>[NH2:35][C@@H:31]([CH:32]([CH3:34])[CH3:33])[C:30]([NH:29][C@@H:27]([CH3:28])[C:26]([NH:25][CH2:24]/[CH:23]=[CH:22]/[C:20]1[CH2:21][C@H:15]2[CH:14]=[N:13][C:12]3[CH:55]=[C:56]([O:57][CH2:58][CH2:59][CH2:60][O:61][C:62]4[C:63]([O:80][CH3:81])=[CH:64][C:65]5[C:71](=[O:72])[N:70]6[CH:73]=[C:74](/[CH:76]=[CH:77]/[CH3:78])[CH2:75][C@H:69]6[CH:68]=[N:67][C:66]=5[CH:79]=4)[C:9]([O:8][CH3:7])=[CH:10][C:11]=3[C:17](=[O:18])[N:16]2[CH:19]=1)=[O:54])=[O:53]
Reactant: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC6c7ccccc7-c7ccccc76)C(C)C)C[C@H]4C=N5)cc3N=C[C@@H]2C1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](N)C(C)C)C[C@H]4C=N5)cc3N=C[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Piperidine (0.04 mL, 4.1 mmol, 13.7 eq.) was added to a stirring mixture of Fmoc amine 19c (0.030 g, 0.0295 mmol, 1 eq.) in anhydrous DMF (0.5 mL) and the mixture was stirred at ambient temperature. After 20 minutes, LCMS showed reaction was completed so the reaction mixture was diluted with DCM (75 mL) and washed with water (3×75 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Co-evaporation with n-hexanes afforded the product as a brown oil, and the material was not subjected to further purification (0.023 g, assumed 100%). LC/MS (1.868 min (ES+)), m/z: 794.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:17][N:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnnc1-c1cnc2ccccn2c1=O
Yield: 50.4 %

Procedure:
A mixture of 4.28 g (0.02 moles) of 3-(1H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine; 100 ml of dimethylformamide, 2.76 g (0.02 moles) of anhydrous potassium carbonate and 25 ml (0.04 moles) of methyl iodide was stirred at 75°-80° C. for 1 hour. The yellow suspension gradually dissolved and at the end of the reaction an orange-colored solution was obtained. The warm reaction mixture was filtered, cooled down and the precipitating crystals were collected. 2.3 g (50.4%) of the title compound were obtained, and crystallized from dimethylformamide to obtain white crystals, m.p.: 280°-282° C. (under decomposition).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[F:11][B-](F)(F)F.F[B-](F)(F)F.F[N+]12CC[N+](O)(CC1)CC2>CO>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:10])[CH2:9][F:11])[CH:5]=[CH:4][CH:3]=1
Reactant: F[B-](F)(F)F
Reactant: CC(=O)c1cccc(Br)n1
Agent: O[N+]12CC[N+](F)(CC1)CC2
Solvent: CO
Product: O=C(CF)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(6-Bromopyridin-2-yl)ethanone (2 g, 10.0 mmol) and 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (9.65 g, 15.0 mmol) were combined in MeOH (100 mL) and heated to reflux for 3 days. After cooling to room temperature, the white solid (alumina) was removed by filtration and filtrate was concentrated in vacuo. The residue was taken up in EtOAc and water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was stirred in a combination of 6 N HCl and Et2O overnight. The organic phase was separated and the aqueous phase extracted with Et2O. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (0-20% EtOAc-hexanes) gave the title compound as a white solid.
Reaction SMILES: ClCCl.[CH3:4][C:5]1([CH3:12])[C:9]([CH3:11])([CH3:10])[O:8][BH:7][O:6]1.[CH3:13][O:14][C:15]([C:17]1[O:18][C:19]([CH3:31])=[C:20]([CH2:22][S:23][C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)[CH:21]=1)=[O:16]>O1CCCC1.O1CCOCC1>[CH3:13][O:14][C:15]([C:17]1[O:18][C:19]([CH3:31])=[C:20]([CH2:22][S:23][C:24]2[CH:29]=[CH:28][C:27]([B:7]3[O:8][C:9]([CH3:11])([CH3:10])[C:5]([CH3:12])([CH3:4])[O:6]3)=[CH:26][CH:25]=2)[CH:21]=1)=[O:16]
Reactant: CC1(C)OBOC1(C)C
Reactant: COC(=O)c1cc(CSc2ccc(Br)cc2)c(C)o1
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc(CSc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Temperature: 100 °C

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (30 mg) and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.34 ml of a 1M solution in tetrahydrofuran) were added to a degassed solution of 4-(4-bromo-phenylsulphanylmethyl)-5-methyl-furan-2-carboxylic acid methyl ester (150) (400 mg, 1.17 mmoles) in 1,4-dioxan (120 ml). The mixture was heated at 100° C., under an argon atmosphere, for 20 hours, cooled and evaporated. The residue was partitioned between ethyl acetate and water, and the organic phase washed with brine and dried (MgSO4). After evaporation of the solvent the residue was purified by flash chromatography, using heptane/ethyl acetate 9:1 v/v as eluent, to afford compound 151 (212 mg) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([C:34]([NH:36][NH2:37])=[O:35])=[CH:32][CH:33]=2)=[O:28])=[CH:20][CH:19]=1.O>CN(C)C=O>[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]2[S:30][C:31]([C:34]([NH:36][N:37]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:35])=[CH:32][CH:33]=2)=[O:28])=[CH:20][CH:19]=1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NCCc2ccncc2)s1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCc2ccncc2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reaction time: 5 h
Yield: 66 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (0.11 g, 0.38 mmol) and 5-hydrazinocarbonylthiophene-2-carboxylic acid (2-pyridin-4-yl)ethylamide (0.10 g, 0.34 mmol) prepared in Reference Synthetic Example 17 were suspended in N,N-dimethylformamide (2.0 mL) and left at 100° C. for 5 hours and then at room temperature for 20 hours. Water (0.20 mL) was added with stirring, and the precipitated solid was recovered by filtration, washed with chloroform and dried to give the desired product, 5-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophen-3-yl]ethylidenehydrazinocarbonyl}thiophene-2-carboxylic acid 2-(pyridin-4-yl)ethylamide (yield 66%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([OH:15])=[C:10]([C:12](=O)[CH3:13])[CH:11]=2)[CH2:3][CH2:2]1.BrC[C:18](=[O:22])[CH:19]([CH3:21])[CH3:20].[C:23](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[O:15][C:13]([C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[C:12]([CH3:23])[C:10]=3[CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)C(=O)CBr
Reactant: CC(=O)c1cc(OCC2CC2)ccc1O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)C(C)C)oc2ccc(OCC3CC3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
A solution of 2′,5′-dihydroxyacetophenone (25.0 g), bromomethylcyclopropane (24.43 g), potassium carbonate (27.2 g) in acetonitrile (400 mL) was stirred with heating under reflux for 2.5 hr. Bromomethylcyclopropane (4.4 g) was added to the mixture, and the mixture was further stirred with heating under reflux for 14 hr. The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0-10:90, v/v) to give 1-[5-(cyclopropylmethoxy)-2-hydroxyphenyl]ethanone (35.5 g) as a yellow oil at purity 70%. A solution of the obtained 1-[5-(cyclopropylmethoxy)-2-hydroxyphenyl]ethanone (35.5 g), 1-bromo-3-methylbutan-2-one (35.5 g) synthesized above and potassium carbonate (66.3 g) in N,N-dimethylformamide (350 mL) was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. 1,8-Diazabicyclo[5.4.0]undec-7-ene (22.5 mL) and N,N-dimethylformamide (300 mL) were added to the obtained residue, and the mixture was stirred at 100° C. for 30 min. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (300 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0-90:10, v/v) to give the title compound (19.91 g, 45%) as a colorless solid.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12.C1C[O:21][CH2:20]C1>>[C:1]1([CH:20]=[O:21])[S:2][CH:3]=[C:4]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12
Reactant: c1ccc2c(c1)c1ccccc1c1cscc21
Reactant: C1CCOC1
Product: O=Cc1scc2c3ccccc3c3ccccc3c12
Yield: 85.9 %

Procedure:
Phenanthro[9,10-c]thiophene (H. C. Pars Pharmaceutical Laboratories, Inc.) was formylated using the procedure of A. Rieche et al., Chem. Ber. 93, 88 (1960) to give a 85.9% yield of phenanthro[9,10-c]thiophene-1-carbaldehyde, mp 198°-199°, (C,H,S), (THF/95% EtOH).