Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[C:19]2[N:20]=[CH:21][S:22][C:18]=2[CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[S:7]([O:12][CH2:13][CH:14]1[C:19]2[N:20]=[CH:21][S:22][C:18]=2[CH2:17][CH2:16][CH2:15]1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCc2scnc21
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCCc3scnc32)cc1
Temperature: 10 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
9.95 g (52 mmoles) p-toluenesulfonyl chloride are added portionwise to a mixture of 8 g (47 mmoles) of the above derivative (IV) and 15 g anhydrous pyridine, while maintaining the temperature at 10° C. After stirring for 24 hrs at room temperature, the mixture is hydrolyzed and is then extracted with ethyl acetate. The combined organic phases are washed with water, dried and evaporated. The residual oil crystallizes slowly. The product is recristallyzed from boiling isopropyl oxide, on cooling. Yield: 72%. M.p.=64°-65° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21]C1C=CC(B(O)O)=CC=1>>[Cl:21][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C1NCCc2c(-c3ccc(Cl)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 4-chlorophenylboronic acid (195 mg, 1.24 mmol) were coupled to yield 2-(4-chloro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 223 mg (66%) as an off-white solid: m.p. 250-252° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.04 (m, 2H), 3.39 (m, 2H), 7.23 (app t, J=7.5 Hz, 1H), 7.58 (m, 3H), 7.68 (m, 3H), 8.10 (br t, 1H), 11.66 (br s, 1H). MS (FAB, MH+) 297. Anal. (C17H13ClN2O.0.8 H2O) C, H, N.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[CH:20]1([C:23]([NH2:25])=[O:24])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C(OCC)(=O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7]1[C:6]([OH:19])=[C:5]2[C:10]([CH:11]=[C:2]([NH:25][C:23]([CH:20]3[CH2:22][CH2:21]3)=[O:24])[N:3]=[CH:4]2)=[CH:9][N:8]=1
Reactant: Oc1c(-c2ccccc2Cl)ncc2cc(Cl)ncc12
Reactant: NC(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2cnc(-c3ccccc3Cl)c(O)c2cn1)C1CC1
Temperature: 90 °C
Yield: 39.6 %

Procedure:
A mixture of 7-chloro-3-(2-chlorophenyl)-2,6-naphthyridin-4-ol (75 mg, 0.26 mmol), cyclopropanecarboxamide (66 mg, 0.77 mmol), chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-i-pr-1,1′-biphenyl)][2-(2-aminoethyl) Ph]Pd(II) (40 mg, 0.05 mmol), (dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-i-pr-1,1′-biphenyl (28 mg, 0.05 mmol), and cesium carbonate (250 mg, 0.77 mmol) in tetrahydrofuran (2 mL) was heated at 90° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1.0M citric acid in water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (35 mg, 40%). 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.51 (d, J=6.6 Hz, 1H), 8.82 (s, 1H), 8.53 (s, 1H), 7.55 (m, 1H), 7.46 (m, 4H), 2.15-2.04 (m, 1H), 0.88 (m, 4H). LCMS (Method E): RT=3.746 min, M+H+=340.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])C1C2C(=CC=CC=2)C=CC=1.COC1C=C(C=CC=1)C(O)[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:17])[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1
Reactant: COc1cccc(C(O)c2ccc3ccccc3c2)c1
Reactant: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Product: COc1cccc(C(Cl)c2ccc3ccccc3c2)c1

Procedure:
The compound 7 was prepared by following the synthesis procedure as described for compound 2, but substituting compound 1 for compound 6.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][C:3]=1S(O)(=O)=O.[CH3:23][NH:24]C=O.[C-]#N.[Na+].[N+](C1C=CC=CC=1)([O-])=O.C([O-])(=O)C.[Na+]>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH2:18])=[CH:4][C:3]=1[C:23]#[N:24]
Reactant: Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Reactant: CNC=O
Agent: CC(=O)[O-]
Agent: [C-]#N
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Product: N#Cc1cc(N)c2c(c1N)C(=O)c1ccccc1C2=O
Reaction time: 8 h

Procedure:
A mixture of 174 g of 91.2 percent pure 1,4-diamino-anthraquinone-2-sulphonic acid (as the Na salt), 1,200 ccs of N-methyl-formamide, 63.7 g of sodium cyanide, 62.0 g of nitrobenzene and 41 g of sodium acetate is heated to 80°-85° C., whilst stirring, until, according to the TLC, the starting material has reacted without trace, that is to say for about 8 hours. The reaction mixture is worked up as described in Example 1. After drying, 133 g of a dark blue, crystalline product which, according to analysis, contains 85.5% of 1,4-diamino-2,3-dicyano-anthraquinone and no 1,4-diamino-2-cyanoanthraquinone are obtained. This corresponds to a yield of 78.9% of the pure product.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([O:13][CH3:14])[C:5](=[O:12])[C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH3:11].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([O:13][CH3:14])[C:5](=[O:12])[C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][Br:15]
Reactant: CON=C(OC)C(=O)c1ncsc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CON=C(OC)C(=O)c1ncsc1CBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 106 g (0.5 mol) of the methylthiazol (cis-isomer from Example 3 c), 100 g (0.56 mol) of N-bromosuccinimide and 1 g of azobisisobutyronitrile in 1 l of carbon tetrachloride is refluxed for 3 hours. 20 g (0.11 mol) of N-bromosuccinimide are also added and heating is carried out for a further 2 hours. The reaction mixture is cooled to room temperature and the precipitated succinimide is filtered off under suction. The filtrate is extracted with water, dried over MgSO4 and evaporated down. The residue is purified by column chromatography using hexane/ethyl acetate mixtures. The products brominated in the nucleus and polybrominated products are obtained in the first fraction, followed by 58 g of the cis-isomer (about 90% purity; 0.18 mol, 36%) and 11 g of the trans-isomer (about 90% purity, 34 mmol, 7%) of the title compound as yellow oils.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:28][C:29](=[O:31])[NH2:30])=[O:25])[C@@H:21]([CH3:23])[OH:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:42]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:43]([C:48](ON1C(=O)CCC1=O)=[O:49])[C@H:44]([CH2:46][CH3:47])[CH3:45].C1C=CC2N(O)N=NC=2C=1.C(N1CCOCC1)C>CN(C=O)C>[NH:42]([C:58]([O:60][C:61]([CH3:63])([CH3:62])[CH3:64])=[O:59])[C@H:43]([C:48]([NH:8][C@H:9]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C:32]([NH:34][C@H:35]([C:38]([O:40][CH3:41])=[O:39])[CH2:36][OH:37])=[O:33])[CH2:28][C:29](=[O:31])[NH2:30])=[O:25])[C@@H:21]([CH3:23])[OH:22])=[O:18])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:49])[C@H:44]([CH2:46][CH3:47])[CH3:45]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccccc1)[C@@H](C)O
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)OC)[C@@H](C)O
Yield: 85.9 %

Procedure:
A solution cooled on an ice bath of 5.14 g of TFA, H-Phe-Thr-Asn-Ser-OMe (8.78 mM) in 100 ml of DMF has 3.17 g of Boc-Ile-OSu (9.66 mM), 1.30 g of HOBt (9.62 mM) and N-ethyl morpholine added thereto until a pH of 7 is obtained. After 20 hours of reaction at ambient temperature, the solution is concentrated under reduced pressure and the residue taken up in ether gives a precipitate which is filtered and dried in vacuo. 5.24 g of product are obtained.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C@@H:8]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:9]([CH3:12])[CH2:10][OH:11].Br[CH2:23][C:24]([OH:26])=[O:25].[I-].[Na+]>C1COCC1>[C:16]([O:15][C:14]([N:13]([CH3:21])[C@H:8]([C:4]1[O:3][CH:7]=[CH:6][CH:5]=1)[C@H:9]([CH3:12])[CH2:10][O:11][CH2:23][C:24]([OH:26])=[O:25])=[O:20])([CH3:17])([CH3:19])[CH3:18]
Reactant: C[C@H](CO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](COCC(=O)O)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 79.7 %

Procedure:
To a suspension of NaH (60%, 134.0 mg, 3.4 mmol, 3.0 equiv) in THF (2.2 mL) at 0° C. was added 2.6.1a (300.0 mg, 1.1 mmol), bromoacetic acid (464.0 mg, 3.4 mmol, 3.0 equiv) and sodium iodide (167.0 mg, 1.1 mmol) successively. After stirring for 7 hours at room temperature, the reaction mixture was quenched with water at 0° C., diluted with EtOAc, and acidified with aqueous 1.0 N HCl aq. solution. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give [(2S,3S)-3-(tert-butoxycarbonyl methylamino)-3-furan-2-yl-2-methyl-propoxy]acetic acid (287.0 mg) which was used for the next step without further purification. MS m/z (M+Na) 350.0
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][C:15](=[O:17])[CH3:16])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].CC(OC(C)=O)=O.[N+:25]([O-])([OH:27])=[O:26]>O1CCOCC1>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:25]([O-:27])=[O:26])[C:13]=1[NH:14][C:15](=[O:17])[CH3:16])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1OC(C)=O
Reactant: O=[N+]([O-])O
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(OC(C)=O)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 89.9 %

Procedure:
Compound 102 (1.00 g, 4.21 mmol) was suspended with stirring in a mixture of Ac2O (8.33 mL, 8.99 g, 88.2 mmol) and dioxane (6.6 mL). This was cooled to 0° C., and a cold solution of the nitrating mixture made from Ac2O (3.33 mL, 3.59 g, 35.2 mmol) and concentrated HNO3 (3.33 mL) was slowly added to the mixture containing 102. The reaction mixture was then warmed to 30°-35° C. until the reaction was complete as evidenced by TLC. The reaction mixture was poured onto ice/water (100 mL), extracted with EtOAc (4×50 mL), dried (NaSO4), and concentrated to dryness on a rotary evaporator to give crude 104 (1.05 g, 89.9%) as an oil. Trituration with CHCl3 gave a solid: mp 196°-201° C. (dioxane/hexane).
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])=[CH:13][CH:12]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1.CO>[CH2:1]([N:8]([CH2:9][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]2[CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:28]2)=[O:19])=[CH:13][CH:12]=1)[CH2:29][CH2:30][CH2:31][N:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(C(=O)N(CCCN2CCOCC2)Cc2ccccc2)cc1)N1Cc2ccccc2C1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CN(CCCN2CCOCC2)Cc2ccccc2)cc1)N1Cc2ccccc2C1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of N-(4-{benzyl[3-(morpholin-4-yl)propyl]carbamoyl}phenyl)-1,3-dihydro-2H-isoindole-2-carboxamide (0.028 g, 0.056 mmol) in THF (1.1 ml) was added 1M borane tetrahydrofuran complex (0.225 ml, 0.225 mmol) dropwise. The mixture was heated at 60° C. for 5 hours. Additional borane complex (0.084 mL) was added and reaction was heated at 60° C. for 1 hour. The reaction was cooled to ambient temperature and 0.3 mL of 1.25 M HCl in methanol was added. The quenched reaction was stirred 30 min and concentrated. The title compound was isolated after flash chromatography. 1H NMR (400 MHz, pyridine-d5, Temp=90° C.) δ ppm 8.05 (s, 1H), 7.88-7.82 (m, 2H), 7.47-7.38 (m, 4H), 7.36-7.29 (m, 2H), 7.26-7.15 (m, 5H), 4.85 (bs, 4H), 3.68-3.59 (m, 8H), 3.48-3.35 (m, 1H), 2.59 (t, J=7.0 Hz, 2H), 2.38-2.29 (m, 6H), 1.79-1.65 (m, 3H); MS (ESI(+)) m/e 485 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH2:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])[OH:15].[OH-].[Na+]>O>[CH2:1]([O:8][C:9]([NH:12][CH2:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])[OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)OCc1ccccc1

Procedure:
Benzyloxycarbonyl chloride was added dropwise to 3.7 kg of 1-amino-1-desoxy-D-glucitol (about 70% pure) in 7 liters of H2O, whilst stirring vigorously, and the pH was kept at 8-9 with 2 N sodium hydroxide solution. The batch was allowed to warm to 40°-50° C. during this operation. The batch was then further stirred overnight at room temperature and the precipitate was filtered off, washed with acetone and recrystallised from water.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)c(F)c1
Temperature: 75 °C
Reaction time: 12 h
Yield: 76.5 %

Procedure:
A mixture of 1,2-difluoro-4-nitrobenzene (1.0 g, 6.29 mmol), 2-morpholinoethanol (1.0 g, 7.62 mmol) and Cs2CO3 in DMF (10 mL) was stirred at 75° C. for 12 h. 30 mL of water was then added and the resulting mixture was extracted with DCM (30 mL×2). The combined organic phases were washed with brine (30 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as yellow oil (1.30 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=[O:31]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(O)c1ccccn1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4ccccn4)nc3cc21

Procedure:
Pyridine-2-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and picolinic acid (109 mg, 0.89 mmol). The title compound was obtained as orange powder (121 mg, 36%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]([CH2:20][CH2:21]O)[CH2:17][CH2:18]O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:15][N:16]1[CH2:20][CH2:21][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])([C:11]([O:13][CH3:14])=[O:12])[CH2:18][CH2:17]1
Reactant: COC(=O)CS(=O)(=O)c1ccccc1
Reactant: CN(CCO)CCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C1(S(=O)(=O)c2ccccc2)CCN(C)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
2-(Phenylsulfonyl)acetic acid, methyl ester (205 mg, 0.95 mmol) was dissolved in THF (20 ml), then treated with N-methyl-diethanolamine (111 μl, 0.97 mmol), 1,1′-(azodicarbonyl)-dipiperidine (483 mg, 1.91 mmol) then tributylphosphine (197 μl, 1.91 mmol). After 10 minutes the mixture was warmed to 40° C. After stirring for 3 hours the solvents were removed and the residue purified by flash column chromatography on silica gel eluted with 25-75% ethyl acetate in hexanes to give N-(N-methyl-4-(phenylsulfonyl)-isonipecotic acid, methyl ester (47 mg).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17]O)[CH2:13][O:14]2)=[C:9]([F:19])[CH:8]=1.[Br-:30].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:4]=1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][Br:30])[CH2:13][O:14]2)=[C:9]([F:19])[CH:8]=1
Reactant: [Br-]
Reactant: OCC1=Cc2c(F)cc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)cc2OC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Fc1cc(OCc2ccc(C(F)(F)F)cc2C(F)(F)F)cc2c1C=C(CBr)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of (7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methanol (200 mg) in MeCN (5 mL) was added triphenylphosphine dibromide (240 mg). The reaction liquid was stirred at room temperature for 2 hours and concentrated under reduced pressure. To the residue were added EtOAc and IPE, the resulting solid was removed by filtration, and the filtrate was concentrated to obtain 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(bromomethyl)-5-fluoro-2H-chromene (230 mg) as a brown liquid. 60% sodium hydride (24 mg) was added to a DMF solution (5 mL) at 0° C., and subsequently, ethyl 1H-pyrazole-4-carboxylate (76 mg) was added thereto. The mixture was stirred at room temperature for 0.5 hours, and a solution of 7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-3-(bromomethyl)-5-fluoro-2H-chromene (220 mg) in DMF (5 mL) was added thereto at 0° C. The reaction liquid was stirred at room temperature for 13 hours, quenched with a saturated NH4Cl solution, and then extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 70:30) to obtain ethyl 1-[(7-{[2,4-bis(trifluoromethyl)benzyl]oxy}-5-fluoro-2H-chromen-3-yl)methyl]-1H-pyrazole-4-carboxylate (111 mg) as a pale yellow solid.
Reaction SMILES: C(=S)=S.[CH2:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[CH:10]=1)[CH3:5].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Sn](Cl)(Cl)(Cl)Cl>O>[C:17]([C:10]1[C:9]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:8]=2[O:7][C:6]=1[CH2:4][CH3:5])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCc1cc2ccc(OC)cc2o1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: S=C=S
Product: CCc1oc2cc(OC)ccc2c1C(=O)c1ccc(OC)cc1

Procedure:
Dried carbon disulfide solution (20 ml) of 2-ethyl-6-methoxy-benzofuran (2.76 g, 15.6 mmol) and p-anisoyl chloride (3.48 g, 20.3 mmol) was cooled on ice, to which tin chloride (IV) was dropped (5.25 g, 20.3 mmol) while stirring. The mixture was stirred at a temperature in a range of 5 to 10° C. for 3 hours and then poured into water. The organic layer was washed with diluted hydrochloric acid and water, dried over MgSO4, and concentrated under reduced pressure. Crude product thereof was purified by HPLC (silica gel, ethyl acetate: hexane=2:8) and a target product in pale yellow oily state (2.98 g, 9.60 mmol, 58%) was obtained.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:18](=[O:19])[C:17](=[O:20])[C:16]=2OC)[N:9]=1)[C:2]([NH2:4])=[NH:3]>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:16]2[C:17](=[O:20])[C:18](=[O:19])[C:15]=2[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]2[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COc1c(NCCCCc2csc(NC(=N)N)n2)c(=O)c1=O
Solvent: CO
Product: N=C(N)Nc1nc(CCCCNc2c(NCCCCc3csc(NC(=N)N)n3)c(=O)c2=O)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-quanidino-4-(4-aminobutyl)thiazole (0.105 g) and 1-[4-(2-guanidinothiazol-4-yl)butylamino]-2-methoxycyclobutene-3,4-dione (0.16 g) in dry methanol (5 ml) was stirred for 18 hours at room temperature. The white solid was filtered off, washed with methanol and dried in vacuo to give 1,2-bis[4-(2-guanidinothiazol-4-yl)-butylamino]cyclobutene-3,4-dione, 0.16 g., m.p. 228°-229° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=O)[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:4]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:7]1[N:8]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2cccc(C(F)(F)F)c2)cc(C(F)(F)F)[nH]1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(Cl)n2)c1

Procedure:
The title compound was prepared from 6-trifluoromethyl-4-(3-trifluoromethyl-phenyl)-1H-pyrimidin-2-one (7.85 g, 25.5 mmol) and phosphoroxychloride (85 mL) according to the general procedure I. Obtained as a yellow solid (5.33 g, 64%). MS (EI) 326.1 [(M)+]; mp 65° C.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=[O:2].[OH2:18]>CC(C)=O>[C:1]([C:3]1[S:7][C:6]([C:8]2[S:9][C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)([OH:18])=[O:2]
Reactant: O
Reactant: O=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Solvent: CC(C)=O
Product: O=C(O)c1ccc(-c2ccc(-c3cccs3)s2)s1
Temperature: 15 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
0.27 g of 5-formyl-2,2':5',2"-terthiophene was dissolved in 50 ml of acetone and the temperature thereof was maintained at 15° C. CrO3 /H2O/H2SO4 solution (0.9 g/12 ml/0.2 ml) was dropped in slowly and stirred for 4 hours at 40° C. Then 50 ml of water was dropped in slowly, and the solution was filtered, washed with water, dried and a yellowish solid was thus obtained. After washed with chloroform, 150 mg of product was obtained and the melting point thereof was 239°-240° C. (yield: 51%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH:26]=[O:27])[CH3:25])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].Cl>CN(C)C=O>[CH:26]([N:24]([CH2:23][C:20]1[CH:19]=[C:15]2[C:16]([O:18][C:1](=[O:2])[NH:13][C:14]2=[CH:22][CH:21]=1)=[O:17])[CH3:25])=[O:27]
Reactant: CN(C=O)Cc1ccc(N)c(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C=O)Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 1 h

Procedure:
There was suspended, in 15.2 mL of N,N-dimethylformamide, 3.82 g of 1,1′-carbonyl-diimidazole (CDI) and the resulting suspension was cooled to 5° C. To this slurry, there was added 4.0 g of 2-amino-5-(N-formyl-N-methylamino-methyl)benzoic acid in two portions, followed by the stirring of the same for one hour. After the confirmation of the disappearance of the starting material by HPLC, seed crystals were added to the slurry while dropwise adding 40.3 mL of a 1M hydrochloric acid aqueous solution to separate out solid and the resulting solid was isolated through filtration under reduced pressure. After washing the solid with 120 mL of water, it was dried at 70° C. for 13 hours under reduced pressure to thus give 3.20 g of the title compound as a white solid.