Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][NH:3][C:4]([CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].[Li]CCCC.[O:31]1[C:35]2=[N:36][CH:37]=[C:38]([CH:40]=O)[CH:39]=[C:34]2[CH:33]=[CH:32]1>C1COCC1>[O:31]1[C:35]2=[N:36][CH:37]=[C:38]([CH:40]=[CH:6][C:4]([NH:3][CH3:2])=[O:5])[CH:39]=[C:34]2[CH:33]=[CH:32]1
Reactant: O=Cc1cnc2occc2c1
Reactant: CNC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)C=Cc1cnc2occc2c1
Reaction time: 5 h
Yield: 95.1 %

Procedure:
To a solution of 0.25 g of methylcarbamoylmethyl-triphenyl-phosphonium chloride (J. Med. Chem. 2003, 46, 399) in 1 ml of THF was added 0.88 ml of n-BuLi (1.6M) at −60° C. After stirring for 1 h at −60° C. a solution of 0.1 g of furo[2,3-b]pyridine-5-carbaldehyde in 1 ml of THF was added and the resulting reaction mixture was stirred for 5 h reaching slowly rt. The reaction mixture was poured over ice. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC using EtOAc as eluant yielded 0.13 g of 3-furo[2,3-b]pyridin-5-yl-N-methyl-acrylamide as a mixture of E/Z isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34](O)[CH:33]=1)[CH3:29].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH2:28]([O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH:33]=1)[CH3:29]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1ccc(C)c(O)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: CCOC(=O)c1ccc(C)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 3-hydroxy-4-methyl-benzoic acid ethyl ester and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (16%). MS (Turbo Spray): m/z=539.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.C([O:17][CH:18]=[CH:19][C:20](OCC)=O)C.C1(C)C(C)=CC=CC=1>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][CH:20]=[CH:19][C:18](=[O:17])[N:6]2[N:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC=CC(=O)OCC
Reactant: Nc1nnc(SCc2ccccc2)s1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=c1ccnc2sc(SCc3ccccc3)nn12
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Fifteen point five (15.5) grams of 2-amino-5-benzylthio-1,3,4-thiadiazole, 10 g of ethyl 3-ethoxypropenoate, 15 g of polyphosphoric acid and 15 ml of xylene were mixed and vigorously stirred for 30 minutes. After the reaction was finished, the reaction mixture was cooled. Water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and water respectively and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was recrystallized from an ethanol/hexane mixture, and thus 10.3 g of 2-benzylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 54%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH:29]3[CH2:31][CH2:30]3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:6][CH:7]=1.C([O-])(=O)C.[NH4+:38]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:38][C:11]([CH:12]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([CH:29]4[CH2:31][CH2:30]4)(=[O:27])=[O:28])=[CH:24][CH:25]=3)[CH2:13][CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(Br)cn1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1)C1CC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
To a solution (10 mL) of 1-(5-bromopyridin-2-yl)-5-[4-(cyclopropylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.29 g) in acetic acid (10 mL) was added ammonium acetate (3.00 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.12 g, yield 96%) was obtained as a white amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 517 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)([O-])=O.[Cl-].[Ca+2].[Cl-].O>C(O)C.[Zn]>[N:6]1[N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=[C:4]([NH2:1])[CH:5]=1
Reactant: O=[N+]([O-])c1cnn2ccccc12
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1cnn2ccccc12
Yield: 77.2 %

Procedure:
To a mixture of 3-nitropyrazolo[1,5-a]pyridine (2.35 g, 14.4 mmol) and zinc (28.2 g, 432 mmol) in 78% ethanol (75.0 mL) was added a solution of calcium chloride (0.8 g, 7.2 mmol) in a minimum amount of water. The resulting mixture was refluxed for 2 h and filtered in hot and washed with hot ethanol. The filtrate was concentrated in vacuo to dryness and the residue was subjected to column chromatography (EtOAc) to give an orangish solid as the desired product (1.48 g, 77%): 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=7.0 Hz, 1H), 7.69 (s, 1H), 7.44 (d, J=9.0 Hz, 1H), 7.01–6.96 (m, 1H), 6.68–6.64 (m, 1H), 2.90 (br, 2H); MS (EI) m/z 134 (M++H).
Reaction SMILES: C(=O)([O-])O.[Na+].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.CN(C=O)C.Cl[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:36]=[CH:35][C:27]([CH:28]=[C:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1>O>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:36]=[CH:35][C:27]([CH:28]=[C:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(C)=Cc1ccc(OCCCCl)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)=Cc1ccc(OCCCNc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
Sodium hydrogen carbonate (3.5 g), 4-chloroaniline (10.45 g) and DMF (50 ml) were added to methyl 4-(3-chloropropoxy)-α-methylcinnamate (11 g), and the mixture was stirred at 100° C. overnight. After the reaction mixture was allowed to cool, water (200 ml) was added thereto, and further the mixture was stirred at room temperature for 30 minutes. The insoluble product was collected by filtration, washed well with water, and was added cold methanol (20ml) thereto, and the mixture was stirred. The resulting crystal was collected by filtration to give methyl 4-[3-[N-(4chlorophenyl)amino]propoxy]-α-methylcinnamate (8 g). mp. 62°-64° C.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[OH:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: BrCc1ccccc1
Reactant: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Product: Brc1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Yield: 79.8 %

Procedure:
Following the basic procedure of Example 11, by reacting 12.5 g (35 mmol) of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene with 5 ml (42 mmol) of benzyl bromide, 12.5 g (80%) of the expected compound of melting point 150°-151° C. were obtained.
Reaction SMILES: [CH2:1]=[CH:2]Cl.[CH3:4][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH2:6]>>[C:7]([O:9][CH2:10][CH:2]=[CH2:1])(=[O:8])[C:6]1[C:5](=[CH:4][CH:6]=[CH:5][CH:4]=1)[C:7]([O:9][CH2:10][CH:2]=[CH2:1])=[O:8]
Reactant: C=CCl
Reactant: C=C(C)C(=O)OC
Product: C=CCOC(=O)c1ccccc1C(=O)OCC=C

Procedure:
Polyvinyl chloride resin of 35 mass % and carbon nanofibers of 1.4 mass % having an average grain diameter of 0.1 μm and a length of 5 μm as amorphous carbon source and PMMA as a pore opening member to form pores were mixed together to form a composition and diallyl phthalate monomer as a plasticizer was added to this composition, the composition was then dispersed using a Henschel mixer, kneaded repeatedly a sufficient number of times using a pressure kneader to obtain a kneaded composition, which was then pelletized using a pelletizer to obtain a composition for molding. The pellet of this composition for molding was transformed into a sheet-like molded product having a thickness of 400 μm through extrusion molding, further graphite (SP270 manufactured by Nippon Graphite industries, ltd.) of 5 mass % and having an average grain diameter of on the order of 4 μm was dispersed on furan resin, both sides of which were coated with a liquid containing a hardener and hardened to be transformed into a multilayered sheet. The multilayered sheet was processed in an air oven of 200° C. for five hours to be a carbon precursor. The multilayered sheet was then heated in a nitrogen gas at a temperature rising rate of 20° C./h and left for three hours at 1000° C. The multilayered sheet was naturally cooled and then kept under a vacuum at 1500° C. for three hours, naturally cooled, carbonization completed and a composite carbon vibration plate was thus obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][CH:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:11]2)[CH2:30][CH2:29]1
Reactant: CCCCc1cc(CCC=O)n(Cc2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCC1=NN(Cc2ccccc2)C(CCCN2CCN(c3ccccc3F)CC2)C1

Procedure:
180 mg (84.2%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-benzyl-3-butyl-1H-pyrazol-5-yl)propanal (133 mg, 0.492 mmol), 1-(2-fluorophenyl)piperazine (155 mL, 0.984 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [OH:1][CH:2]([C:17]1([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[CH2:20][CH2:19][CH2:18]1)[C:3]1[C:8]([NH:9]C(=O)OC(C)(C)C)=[CH:7][CH:6]=[CH:5][N:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:9][C:8]1[C:3]([CH:2]([C:17]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[CH2:20][CH2:19][CH2:18]2)[OH:1])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C(O)C1(c2cccc(C(F)(F)F)c2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccnc1C(O)C1(c2cccc(C(F)(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 120D (96 mg, 0.229 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred at room temperature for about 2 hours, and concentrated in vacuum. The residue was treated with saturated NaHCO3 and extracted with ethyl acetate three times. Combined organic phases were washed with water and brine sequentially, dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC (Column: BOSTON-C18 20×250 mm 10 μm, eluent: water (0.05% NH4HCO3): acetonitrile, 1:1 to 5:95) (60 mg, 30%) to provide the title compound. LC-LC-MS: m/z (M+H) 323. 1H NMR (400 MHz, CDCl3): δ 7.78-7.80 (m, 1H), 7.35-6.99 (m, 4H), 6.82-6.86 (m, 1H), 6.58-6.61 (m, 1H), 4.77 (s, 1H), 3.00 (b, 3H), 2.69-2.82 (m, 2H), 2.14-2.27 (m, 2H), 1.65-1.95 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[C:17]([F:24])[CH:16]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[S:23][C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:17]([F:24])[CH:16]=1
Reactant: CCOC(=O)Cc1cccnc1Cl
Reactant: Fc1cc(Br)ccc1N=C=S
Product: CCOC(=O)c1c(Nc2ccc(Br)cc2F)sc2ncccc12

Procedure:
Prepared from ethyl (2-chloropyridin-3-yl)acetate (D. H. Bremner et al., Synthesis, 1997, 949) (500 mg, 2.5 mmol) and 4-bromo-2-fluorophenyl isothiocyanate (580 mg, 2.5 mmol) by the method of Example 1. Title compound obtained as an off-white solid (390 mg, 40%). δH (DMSO-d6) 10.37 (1H, br s), 8.25 (1H, dd, J 1.4, 8.1 Hz), 8.19 (1H, d, J 4.8 Hz), 7.69 (1H, dd, J 1.8, 10.2 Hz), 7.56-7.45 (2H, m), 7.32 (1H, dd, J 4.5, 8.1 Hz), 4.35 (2H, q, J 7.1 Hz), 1.37 (3H, t, J 7.1 Hz). LCMS (ES+) RT 4.66 minutes, 395 (M(79Br)+H)+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C:17]([CH3:18])=[O:19])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reaction time: 0.75 h
Yield: 79.5 %

Procedure:
A solution of tert-butyldimethylsilyl chloride (13.6 g) in DMF (50 ml) was added dropwise to stirred solution of 4-hydroxyphenylacetone (12.5 g) and imidazole (9.0 g) in DMF (150 ml) at 20° under N2. After 0.67 h additional tert-butyldimethylsilyl chloride (4.7 g) was added and the reaction stirred for 0.75 h. The reaction mixture was concentrated in vacuo and the residue partitioneed between Et2O and water. The organic phase was washed with water, brine, dried (MgSO4) and evaporated to dryness. The residue was purified by chromatography on a Biotage (90 g) eluting with cyclohexane-Et2O (9:1) to give the title compound (17.5 g), ES+ve 282 (M+NH4)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][C:25]=2[CH3:26])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:34]>O1CCOCC1>[ClH:34].[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([C:27]([F:28])([F:29])[F:30])=[CH:24][C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
A N-[(1,1-dimethylethoxyl)carbonyl]-4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester (253 mg, 0.54 mmol) was treated with 4 N HCl solution in dioxane (4.0 mL) at room temperature. The solution was stirred for 2 h as a white solid was formed. The mixture was concentrated and the residue was dissolved in methanol. After removal of methanol, the residue was dried under high vacuum to obtain 221 mg (100% yield) of 4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt as an amorphous white solid. ES-LRMS m/z 369.3 (M+H), 410.3 (M+CH3CN).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6](Br)[CH:7]=1.[C:11]([C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[C:23]=2[CH3:37])=[O:20])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([C:24]2[C:23]([CH3:37])=[C:22]([NH:21][C:19](=[O:20])[C:18]3[CH:17]=[CH:16][C:15]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:39][CH:38]=3)[CH:27]=[CH:26][CH:25]=2)[CH:7]=1
Reactant: Cn1cc(Br)cc(N)c1=O
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(N)c(=O)n(C)c1
Temperature: 95 °C
Yield: 71.9 %

Procedure:
A 48-mL seal tube equipped with a magnetic stirring bar was charged with 3-amino-5-bromo-1-methyl-1H-pyridin-2-one (2) (0.10 g, 0.50 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (0.24 g, 0.70 mmol), and Pd(PPh3)4 (0.030 g, 0.025 mmol) in DME (10 mL) and 1N Na2CO3 (5 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane and the phases were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10% MeOH in dichloromethane/ether (1/1), to afford 0.14 g (68%) of N-[3-(5-amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (3) as a solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>ClCCl>[CH2:27]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH2:22][CH2:23]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
34.1 g (0.12 mol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid chloride, dissolved in 300 ml of dichloromethane, are added dropwise at 15 to 20° C. to a solution of 22.43 ml (0.11 mol) of 4-amino-1-benzyl-piperidine and 42.97 ml (0.31 mol) of triethylamine in 600 ml of dichloromethane. The mixture is stirred for 14 hours at ambient temperature. The reaction solution is diluted with 300 ml of dichloromethane and extracted with a mixture of 1N sodium hydrogen carbonate solution and 1N sodium hydroxide solution. The organic phase is dried over sodium sulphate and the solvent is eliminated. The residue is recrystallised from 650 ml ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][C:10](=[O:22])[C:11]=3[N:12]2C(OC(C)(C)C)=O)=[CH:4][C:3]=1[F:23].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][C:10](=[O:22])[C:11]=3[NH:12]2)=[CH:4][C:3]=1[F:23]
Reactant: CC(C)(C)OC(=O)n1c2c(c3cc(F)c(Cl)cc31)CCCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCc2c1[nH]c1cc(Cl)c(F)cc21
Temperature: 0 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
tert-Butyl 7-chloro-6-fluoro-1-oxo-3,4-dihydro-1H-carbazole-9(2H)-carboxylate (0.55 g, 1.6 mmol) was dissolved in DCM (10 mL), cooled to 0° C., and TFA (1 mL) was added slowly. The reaction mixture was brought to room temperature and stirred for 5 h, neutralized with saturated NaHCO3 (10 mL) and extracted with DCM (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to obtain the title compound (0.35 mg, 92%) which was used in the next step with out any purification. 1H NMR (200 MHz, DMSO-d6, δ in ppm) 11.84 (bs, 1H), 7.76 (d, J=9.8 Hz, 1H), 7.52 (d, J=6.2 Hz, 1H), 2.95 (t, J=6.0 Hz, 2H), 2.60 (t, J=5.8 Hz, 2H), 2.20 (m, 2H).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]1([N:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]3[N:38]=[N:39][NH:40][CH:41]=3)=[C:31]([O:42][CH3:43])[C:30]2=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:23]1([N:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]3[N:38]=[N:39][NH:40][CH:41]=3)=[C:31]([O:42][CH3:43])[C:30]2=[S:10])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 121.1 %

Procedure:
To a stirring solution of Lawesson's reagent (0.075 g, 0.185 mmol) in toluene (10 mL), was added starting material 158a (0.10 g, 0.33 mmol). Reaction mixture was heated to reflux temperature. After overnight reaction, solvent was evaporated under reduced pressure. Crude product was dissolved in small amount of CH2Cl2 to load onto preparative-TLC and eluted with CHCl3:Acetone:EtOH (10:1:0.2) to give pure yellow solid 160 (0.07 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=7.4 Hz, 2H), 7.56 (s, 1H), 7.35 (t, J=7.5 Hz, 2H), 7.28 (m, 1H), 6.97 (d, J=6.6 Hz, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.37 (m, 1H), 5.13 (t, J=5.6 Hz, 2H), 5.03 (t, J=5.6 Hz, 2H), 3.86 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 171.92, 158.94, 147.52, 132.68, 129.92, 128.69, 128.14, 125.43, 120.96, 111.72, 110.22, 56.72, 56.63, 46.38. HRMS (EI) calcd for C16H16N4OS [M]+ 312.104. found 312.1039.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[O:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:21][CH2:20][N:19]([CH:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)[CH2:24][CH2:23]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCN(C3CCOCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (750 μL), 1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride (2.1 g), potassium carbonate (3.2 g), and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. To the reactant was added water, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 1-(4-nitrophenyl)-4-(tetrahydro-2H-pyran-4-yl)piperazine (1.83 g).
Reaction SMILES: Cl[CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>O>[OH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:2][P:3]([OH:6])(=[O:5])[OH:4]
Reactant: O=P(O)(O)CCl
Reactant: NCCCCCCCCCN
Solvent: O
Product: NCCCCCCCCCNCP(=O)(O)O
Yield: 157.2 %

Procedure:
Chloromethanephosphonic acid (4.0 g, 30.6 mmoles) and 1.9-diaminononane (20.1 g, 127.2 mmoles) were dissolved in water (100 cm3) and the resultant solution heated under reflux for 20 hours. The water was then distilled off and methanol (80 cm3) added to the residue. The solid was filtered off, washed with methanol (2×50 cm3) and dried in a vacuum oven at 60° C. for three hours to yield the crude N-(9-aminononyl)aminomethanephosphonic acid monohydrate (6.5 g, 78.5%), having a melting point of 240°-241° C.