Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][N:12]1[C:18]2=[C:19]3[C:24](=[N:25][C:26]4[CH2:27][CH2:28][CH2:29][CH:16]([C:17]=42)[S:15][CH2:14][C:13]1=O)[CH:23]=[CH:22][CH:21]=[CH:20]3.[OH-].[Na+].[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37]>O1CCCC1>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]\[C:36]([OH:38])=[O:37].[CH3:11][N:12]1[C:18]2=[C:19]3[C:24](=[N:25][C:26]4[CH2:27][CH2:28][CH2:29][CH:16]([C:17]=42)[S:15][CH2:14][CH2:13]1)[CH:23]=[CH:22][CH:21]=[CH:20]3
Reactant: CN1C(=O)CSC2CCCc3nc4ccccc4c1c32
Agent: O=C(O)/C=C\C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN1CCSC2CCCc3nc4ccccc4c1c32
Reaction time: 1 h
Yield: 73 %

Procedure:
To 1M lithium aluminum hydride in tetrahydrofuran (14.1 ml), diluted with tetrahydrofuran (50 ml) was added aluminum chloride (1.9 g), followed by 1,3,4a,5,6,7-hexahydro-1-methyl-2H-quino-[4,3,2-ef][1,4]benzthiazepin-2-one (3.42 g). After stirring for 1 hr, the reaction mixture was poured into iced sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic extracts were washed with water, saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in methanol and treated with maleic acid (1.1 eq). Crystallization with ethyl ether followed by recrystallization from methanol/ethyl ether gave 3.17 g (73.0%) of product, mp 200°-201° C. (dec).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C@H:14]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][CH:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:11][N:10]3[CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)(Cl)Cl>[CH3:29][O:30][CH2:31][C:32]([N:13]1[CH:12]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:11][N:10]2[CH:28]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]2[C@@H:14]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:33]
Reactant: COCC(=O)Cl
Reactant: c1ccc(C[C@@H]2NC(c3ccccc3)Cn3cc(-c4ccccc4)nc32)cc1
Solvent: ClC(Cl)Cl
Product: COCC(=O)N1C(c2ccccc2)Cn2cc(-c3ccccc3)nc2[C@@H]1Cc1ccccc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-2,6-diphenyl-8(S)-phenylmethyl-imidazo[1,2-a]pyrazine (29 mg) in chloroform were successively added morpholinom thylpolystyrene resin (Novabiochem, loading=3.51 mmol/g, 50 mg, 2eq) and methoxyacetylchloride (10 mL, 1.3 eq). After about 3 hours of stirring at about 20° C., chloroform was added to the mixture followed by aminomethylpolystyrene resin (Novabiochem, loading=1.2 mmol/g, 132 mg, 2 eq). The reaction mixture was stirred for another 2 hours and then filtered. The filtrate was concentrated under reduced pressure to afford 23 mg of the title compound (yield=68%). NMR (1H, 100 MHz, CDCl3): 7.9-7.0 (m, 16H, arom. H), 6.6 (m, 1H, H8), 5.3 (m, 1H, H6), 4.6 (dd, 1H, 2J=13 Hz, H5), 4.35 (dd, 1H, 2J=13 Hz, 3J=5 Hz, H5′), 3.7-2.9 (m, 5H, CH2Ph, OCH3).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][C:14](N)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.S(=O)(=O)(O)[OH:22]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][C:14]([OH:22])=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2
Reactant: O=S(=O)(O)O
Reactant: NC(=O)Cc1ccc2c(c1)CCc1ccccc1C2=O
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A suspension of (5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)acetamide (17.4 g.) in a mixture of concentrated sulphuric acid (d = 1.83; 70 cc.) and water (70 cc.) is heated with vigorous stirring for 3 hours at 100°C. After cooling, the product which precipitates is filtered off and then added to 2N sodium hydroxide solution (200 cc.). The alkaline solution is extracted with diethyl ether and then acidified by adding 2N sulphuric acid (250 cc.). The product which precipitates is filtered off, dried and then recrystallised from ethyl acetate (100 cc.) to give (5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)acetic acid (11.5 g.) melting at 154°C.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[C:8]1[CH:9]=[C:10]([C:14]2[N:22]3[C:17]([CH:18]=[N:19][C:20](O)=[N:21]3)=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[C:30]2[CH:31]=[CH:32][C:33]([NH2:35])=[CH:34][C:29]=2[NH:28][CH:27]=1>>[N:26]1[C:30]2[CH:31]=[CH:32][C:33]([NH:35][C:20]3[N:19]=[CH:18][C:17]4=[CH:16][CH:15]=[C:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([CH3:25])([CH3:24])[O:6][SiH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=5)[N:22]4[N:21]=3)=[CH:34][C:29]=2[NH:28][CH:27]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: Nc1ccc2nc[nH]c2c1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(-c2ccc3cnc(Nc4ccc5nc[nH]c5c4)nn23)c1

Procedure:
(3H-Benzoimidazol-5-yl)-{7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl}-amine was prepared from 7-[3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3H-benzimidazol-5-ylamine in an analogous manner to Example 1052a. Product isolated as an orange solid (129 mg, 81%). m.p.=70-75° C.; LCMS (m/e) 471 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.20-10.10 (m, 1H), 8.73 (s, 1H), 8.67-8.39 (m, 2H), 7.97 (s, 1H), 7.86-7.62 (m, 2H), 7.51-7.42 (m, 1H), 7.32 (d, 1H, J=7.5 Hz), 7.09-6.92 (m, 3H), 6.86 (d, 1H, J=4.7 Hz), 4.97 (s, 2H), 0.96 (s, 9H), 0.16 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:35]2[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:36]2=[O:43])[CH:5]=[C:6]([CH3:34])[C:7]=1/[CH:8]=[CH:9]/[S:10]([N:13]1[CH2:33][CH2:32][C:16]2([N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[NH:18][C:17]2=[O:31])[CH2:15][CH2:14]1)(=[O:12])=[O:11]>FC(F)(F)CO.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1[CH:3]=[C:4]([N:35]2[C:39]([CH3:40])([CH3:41])[C:38](=[O:42])[NH:37][C:36]2=[O:43])[CH:5]=[C:6]([CH3:34])[C:7]=1[CH2:8][CH2:9][S:10]([N:13]1[CH2:33][CH2:32][C:16]2([N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=3)[NH:18][C:17]2=[O:31])[CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(c1cccc(C(F)(F)F)c1)NC2=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: OCC(F)(F)F
Product: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cccc(C(F)(F)F)c1)NC2=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 61.8 %

Procedure:
A mixture of (E)-1-(3,5-dimethyl-4-(2-((4-oxo-2-(3-(trifluoromethyl)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl)sulfonyl)vinyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (195 mg, 0.316 mmol) and palladium hydroxide/carbon (20% Pd) (wetted with approximately 50% water) (195 mg, 0.139 mmol) in 2,2,2-trifluoroethanol (6 mL) was stirred at room temperature for 14 hours under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford 1-(3,5-dimethyl-4-(2-((4-oxo-2-(3-(trifluoromethyl)phenyl)-1,3,8-triazaspiro[4.5]deca-1-en-8-yl) sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (121 mg, 62%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7](C=O)[CH2:6][C:5]2([CH3:15])[CH3:14].O1[CH2:20][CH2:19][CH2:18]C1.C([Mg]Br)C.C(OCC)(=O)C>C(OCC)C.CCCCCC>[CH:18]1([CH:8]2[C:9]3[C:4](=[CH:3][C:2]([OH:1])=[CH:11][CH:10]=3)[C:5]([CH3:14])([CH3:15])[CH2:6][NH:7]2)[CH2:19][CH2:20]1
Reactant: CC1(C)CN(C=O)Cc2ccc(O)cc21
Reactant: C1CCOC1
Agent: CC[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)CNC(C2CC2)c2ccc(O)cc21
Temperature: 55 °C
Yield: 63 %

Procedure:
A stirred, cooled (0° C.)solution of 6-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline-2-carbaldehyde (Intermediate 20, 2.3 g, 11.21 mmol) anhydrous tetrahydrofuran (40 mL) under argon was treated with titanium tetra-iso-propoxide (8.28 mL, 28 mmol) followed by 3M solution of ethyl magnesium bromide in diethyl ether (18.7 mL) and the reaction mixture was then heated at 55° C. overnight. It was then cooled in an ice-bath, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a yellow oily solid. Flash column chromatography over silica gel (230-400 mesh) using 10-20% ethyl acetate in hexane as the eluent afforded the title compound as a pale yellow solid (1.55 g, 63%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2ncsc2c1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2ncsc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 36 %

Procedure:
The title compound is prepared from benzothiazole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 36% of theory; LC (method 4): tR=1.94 min; Mass spectrum (ESI+): m/z=335 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:16][C:17]2([C:20]([O:22]C)=O)[CH2:19][CH2:18]2)[C@@H:9]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10]2)[C:5]([N+:24]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:24][C:20](=[O:22])[C:17]3([CH2:19][CH2:18]3)[CH2:16][N:8]([C@@H:9]3[CH2:13][CH2:12][C:11]([F:14])([F:15])[CH2:10]3)[C:6]=2[N:7]=1
Reactant: COC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])[C@@H]2CCC(F)(F)C2)CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N([C@@H]2CCC(F)(F)C2)CC12CC2
Temperature: 70 °C
Yield: 59.5 %

Procedure:
A mixture of (R)-methyl 1-(((2-chloro-5-nitropyrimidin-4-yl)(3,3-difluorocyclopentyl)amino)methyl)cyclopropane-carboxylate (3.90 g, 9.98 mmol) and iron powder (1.143 g, 20.46 mmol) in glacial acetic acid (50 mL) was heated to 70° C. for 2 hours. The reaction mixture was filtered hot and the cake was further washed with acetic acid. The mother liquors were concentrated in vacuo. The residue was taken up in a 15% solution of methanol in dichloromethane and filtered through a path of silica gel rinsing with more methanol-dichloromethane solution. The mother liquors were concentrated in vacuo. The residue was triturated with methanol and the solid was filtered to afford the desired compound as a light pink solid (1.953 g, 60% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:20]([O-])=O)[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19])[CH2:9][CH2:8][CH2:7]2.[H][H]>O1CCCC1.C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19])[CH2:9][CH2:8][CH2:7]2
Reactant: CN1CCCC1CCN1CCCc2cc([N+](=O)[O-])cc(F)c21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1CCCC1CCN1CCCc2cc(N)cc(F)c21
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a stirred solution of 8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-nitro-1,2,3,4-tetrahydroquinoline (660 mg, 2.147 mmol) in tetrahydrofuran (6 ml) and ethanol (6.00 ml) was added palladium on carbon, 10 wt % (229 mg, 0.215 mmol). The suspension was stirred under balloon pressure of hydrogen and monitored by TLC. After 4 h, the reaction was complete. The mixture was then filtered through a pad of celite which was washed with methanol. The filtrate was then concentrated and dried on a high vacuum pump. The residue (8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (590 mg, 2.127 mmol, 99% yield)) was used directly in the subsequent reaction. 1H NMR (DMSO-d6) δ 6.16 (dd, J=14.7, 2.4 Hz, 1H); 6.04 (m, 1H), 4.70 (brs, 1H), 2.99-2.93 (m, 3H), 2.88-2.82 (m, 2H), 2.57-2.53 (m, 2H), 2.24 (s, 3H), 2.15-2.05 (m, 2H); 1.93-1.87 (m, 2H), 1.69-1.60 (m, 4H), 1.44-1.35 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO.C(=O)([O-])O.[Na+]>CO>[CH3:34][C:33]1[C:28]([N:25]2[CH2:24][CH2:23][N:22]([C:20]([C:17]3[CH:16]=[CH:15][C:14]([N:10]4[C:11](=[O:13])[CH2:12][NH:8][CH2:9]4)=[CH:19][CH:18]=3)=[O:21])[CH2:27][CH2:26]2)=[N:29][CH:30]=[C:31]([CH3:35])[CH:32]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CN(C(=O)OC(C)(C)C)CC4=O)cc3)CC2)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CNCC4=O)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.9 %

Procedure:
To 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-oxoimidazolidine-1-carboxylic acid tert-butyl ester (200 mg) described in Example 634 were added methanol (3 mL) and 2N hydrogen chloride/methanol (1.05 mL), and the mixture was stirred at room temperature for 8 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (33 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1.[NH:16]1[C:20](=[O:21])[CH2:19][CH:18]2[CH2:22][CH2:23][CH2:24][N:17]12.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:10]1([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([N:16]3[C:20](=[O:21])[CH2:19][CH:18]4[CH2:22][CH2:23][CH2:24][N:17]34)=[N:3][CH:4]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(C#Cc2ccccc2)cn1
Reactant: O=C1CC2CCCN2N1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1CC2CCCN2N1c1ccc(C#Cc2ccccc2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 9.7 %

Procedure:
(150 mg, 0.58 mmol) 2-Bromo-5-phenylethynyl-pyridine (Example 10, step 1) was dissolved in toluene (2 ml) and (RS)-tetrahydro-pyrrolo[1,2-b]pyrazol-2-one [CAS 1159091-93-6] (73 mg, 0.58 mmol, 1.0 equiv.), cesium carbonate (280 mg, 0.87 mmol, 1.5 equiv.), xantphos [CAS 161265-03-8] (14 mg, 0.02 mmol, 0.04 equiv.) and Pd2(dba)3 (11 mg, 0.01 mmol, 0.02 equiv.) were added under nitrogen. The mixture was stirred for 3 hours at 100° C. The crude product was purified by flash chromatography by directly loading the toluene mixture onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired (RS)-1-(5-phenylethynyl-pyridin-2-yl)-tetrahydro-pyrrolo[1,2-b]pyrazol-2-one (17 mg, 9% yield) was obtained as a light brown solid, MS: m/e=304.1 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)(=[O:9])=[O:8].[NH3:17]>CO>[NH2:17][C:13]1[N:12]=[CH:11][C:10]([S:7]([NH:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: N
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Cl)nc1
Solvent: CO
Product: Nc1ccc(S(=O)(=O)Nc2nccs2)cn1

Procedure:
6-Chloro-pyridine-3-sulfonic thiazol-2-ylamide (200 mg, 0.0007 mol) in 7 M of Ammonia in methanol (5.00 mL) was heated at 160° C. in a pressure bottle for ˜6 h. The reaction had to be stopped because the pressure was too high and some of the reaction solution was leaking. By LC/MS, reaction show ˜30% conversion. The reaction solution was concentrated and then purified on Gilson (Prep LC, reverse phase, Phenomenex 250×30 mm, 15 micron C18 column, 40 mL/min. Gradient, 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8). Fractions were checked by LC/MS and dried on a lyophilizer to give the product as a brown oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH2:17]1[S:21](=O)[CH2:20][CH2:19][CH2:18]1.C(OC(C)C)(C)C.C([NH+](CC)CC)C.[C:37]12([C:47]([O:49][C:50]([C:60]([F:63])([F:62])[F:61])([C:56]([F:59])([F:58])[F:57])[CH2:51][S:52]([O-:55])(=[O:54])=[O:53])=[O:48])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O.C(Cl)Cl>[F:1][C:2]([F:15])([F:16])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S+:21]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][CH:6]=1.[C:37]12([C:47]([O:49][C:50]([C:60]([F:63])([F:61])[F:62])([C:56]([F:57])([F:58])[F:59])[CH2:51][S:52]([O-:55])(=[O:53])=[O:54])=[O:48])[CH2:46][CH:41]3[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]3)[CH2:38]1)[CH2:44]2
Reactant: O=S1CCCC1
Reactant: FC(F)(F)COc1cccc2ccccc12
Agent: CC[NH+](CC)CC
Agent: CS(=O)(=O)O
Agent: O=C(OC(CS(=O)(=O)[O-])(C(F)(F)F)C(F)(F)F)C12CC3CC(CC(C3)C1)C2
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)COc1ccc([S+]2CCCC2)c2ccccc12
Reaction time: 8 h

Procedure:
After 233 g of 1-(2,2,2-trifluoroethoxy)naphthalene synthesized in Synthesis Example 1-2 was dispersed in 462 g of Eaton's reagent (diphosphorus pentaoxide-methanesulfonic acid solution) available from Sigma-Aldrich Co., LLC, and 104 g of tetramethylene sulfoxide was added dropwise under ice-cooling and mixed. Aging was carried out at room temperature overnight, 700 g of water and 600 g of diisopropyl ether were added to the mixture under ice-cooling, and the aqueous layer was collected by separation. The aqueous layer was again washed with 600 g of diisopropyl ether, to prepare 4-(2,2,2-trifluoroethoxy)-1-naphthyltetrahydrothiophenium=methanesulfonate as an aqueous solution. To 590 g (corresponding to 0.39 mol) of the aqueous solution were added 160 g of triethyl ammonium=2-(adamantane-1-carbonyloxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate synthesized in Synthesis Example 1-1, 1000 g of methylene chloride and 200 g of water, and the organic layer was extracted from the mixed solution. The extracted organic layer was washed and then concentrated, methyl isobutyl ketone was added to the concentrate, and the mixture was again concentrated. Diisopropyl ether was added to the concentrated solution for recrystallization, and the deposited solid was recovered and dried under reduced pressure to obtain 209 g of 4-(2,2,2-trifluoroethoxy)-1-naphthyltetrahydrothiophenium=2-(adamantane-1-carbonyloxy)-3,3,3-trifluoro-2-trifluoromethylpropane-1-sulfonate (Yield: 93%) which is an objective product as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.ClCCl.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:26][CH:25]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccnc2)cc1
Yield: 20 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(pyridin-3-ylmethyl)benzamide was prepared according to method B with pyridin-3-ylboronic acid (0.029 g; 0.242 mmol), N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.080 g; 0.231 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.018; 0.023 mmol), sodium iodide (0.070 g; 0.461 mmol) and sodium carbonate (0.049 g; 0.461 mmol) in dimethoxyethane (3 mL) and water (1 mL) was irradiated in the microwave at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 75 to 100% ethyl acetate in heptane) furnished 0.018 g (20%) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[C:8]([CH:41]=1)[C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:40])[C:19]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=2[C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[CH2:13][CH2:12]1)=[O:10])([O-])=O>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:42]2[CH:43]=[C:44]([O:52][CH3:53])[C:45]([O:50][CH3:51])=[C:46]([O:48][CH3:49])[CH:47]=2)=[C:8]([CH:41]=1)[C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:40])[C:19]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:20]=2[C:28]2[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: COc1cc(-c2ccc([N+](=O)[O-])cc2C(=O)N2CCCN(C(=O)c3cc([N+](=O)[O-])ccc3-c3cc(OC)c(OC)c(OC)c3)CC2)cc(OC)c1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(-c2ccc(N)cc2C(=O)N2CCCN(C(=O)c3cc(N)ccc3-c3cc(OC)c(OC)c(OC)c3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
Added to a solution of 39 mg (0.050 mmol) of 1,4-bis[5-nitro-2-(3,4,5-trimethoxy-phenyl)benzoyl]hexahydro-1,4-diazepine synthesized by the process described in Example 71 in acetic acid-ethyl acetate (3:2, 2.5 ml) were 39 mg of 10% palladium on carbon, and the mixture was stirred for 2 hours at room temperature under hydrogen. The catalyst was removed from the reaction mixture by suction filtration through Celite, and the filtrate was concentrated under reduced pressure. A chloroform solution of the residue was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel to obtain 32 mg (yield: 90%) of the title compound as a pale yellow amorphous powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([NH2:18])=[NH:17].C[O:20][C:21](=O)/[C:22](/[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[C:23](\O)/[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(OC(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C)(C)C>>[C:27]([O:26][C:24]([C:23]1[C:22]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:21]([OH:20])[N:18]=[C:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Cl:2])[N:17]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: N=C(N)Cc1ccccc1-c1ccccc1Cl
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Yield: 55.8 %

Procedure:
5-Benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-02) (5 g, 55.8%) was synthesized as a brown solid from 2-(2′-chloro-biphenyl-2-yl)-acetamidine hydrochloride salt (5-02) (5 g, 17.82 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (4) (9.4 g, 30.73 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (6-01).