Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=O.[BH4-].[Na+].C(O)(=O)C.O>O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2
Reactant: O=C(CCCl)N1c2ccccc2CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: ClCCCN1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a solution of 3-chloro-1-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propanone (14.0 g, 0.044 mol) in tetrahydrofuran (150 ml) at 0° C., sodium borohydride (6.66 g, 0.176 mol) was added, followed by dropwise addition of glacial acetic acid (10.0 ml). The resulting mixture was stirred at room temperature overnight and then heated at reflux temperature for 2 h. More sodium borohydride (6.50 g, 172 mmol) and then borontrifluoride diethyl etherate (20.0 ml, 0.163 mol) were added and heating at reflux temperature was continued for 20 h. Water (350 ml) was cautiously added and the phases were separated. The aqueous phase was extracted with toluene (3×100 ml). The combined organic phases were washed with brine (3×100 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (100 g) using a gradient of heptane and ethyl acetate (10:0→10:2), to give 4.58 g (38%) of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:14][C:15]1[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:14][C:15]1[C:24]([NH:25][C:9](=[O:11])[C:8]2[C:3]([C:2]([F:1])([F:13])[F:12])=[CH:4][CH:5]=[N:6][CH:7]=2)=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: COC(=O)c1cccc(N)c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)c2cnccc2C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(Trifluoromethyl)nicotinic acid (88; 1.00 g, 5.23 mmol) was taken up in DMF (8 mL) along with methyl 2,3-diaminobenzoate (118; 0.86 g, 5.23 mmol), HATU (2.98 g, 7.84 mmol) and DIEA (1.82 mL, 10.5 mmol). The reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc, washed with water, dried (Na2SO4) and concentrated under reduced pressure to afford crude methyl 2-amino-3-(4-(trifluoromethyl)nicotinamido)benzoate. This material was taken up in 5 mL of glacial acetic acid and stirred at 60° C. for 18 h. The reaction mixture was stirred at 90° C. for an additional 8 h. It was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with EtOAc, washed with dilute aqueous NaHCO3, dried (Na2SO4) and concentrated under reduced pressure to afford crude methyl 2-(4-(trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylate. This material was taken up in MeOH (8 mL) and H2O (8 mL) containing LiOH (0.4 g) and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and neutralized with 6 N HCl. The resulting solids were collected by filtration and dried to afford 570 mg of 2-(4-(trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylic acid (35% yield from methyl 2,3-diaminobenzoate) 119. MS (ESI) calcd for C14H8F3N3O2: 307.06; found: 308 [M+H].
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:16][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1)[CH2:13][CH2:14][CH3:15]
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: CCCCN
Product: CCCCNc1nc(N)c2[nH]cnc2n1
Yield: 30 %

Procedure:
2-Chloroadenine (6.0 g, 35.4 mmol) and n-butylamine (30 ml) were reacted in an autoclave (200 ml) at 130° C. for 150 hours. After the reaction mixture was concentrated under reduced pressure, the residue was poured into water to precipitate the solid. The precipitated solid was successively washed with methylene chloride and methanol to give the captioned compound (2.08 g, yield 30%) as a yellowish orange powdered solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([O:31][CH:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)[CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)=[CH:35][CH:34]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(Cl)cc3)c3ccc4c(c3)CCC4)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-chlorophenol: ESMS m/e: 531.1 (M+H)+.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].[CH2:20]([OH:23])[CH:21]=[CH2:22].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>O.C1(C)C=CC=CC=1>[CH2:20]([O:23][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:21]=[CH2:22]
Reactant: C=CCO
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOCC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 109.4 %

Procedure:
Tetrabutylammonium hydrogenosulfate (470 g, 1.40 mol) is added to a solution of sodium hydroxide (6.6 Kg, 165 mol) in water (14 L) and toluene (14 L) at 20° C. Allyl alcohol (801.5 g, 13.8 mol) is added and the mixture is stirred at 20° C. for 1 h. The mixture is cooled to 5° C., and tert-butyl 2-bromoacetate (4 Kg, 20.5 mol) is added slowly maintaining the internal temperature below 15° C. The reaction mixture is stirred at room temperature for 16 h. The mixture is diluted with water (12 L) and hexanes (12 L) and the organic phase is separated. The aqueous phase is extracted with MTBE (5 L). The combined organic phase is dried over magnesium sulfate, filtered, and concentrated to afford the title compound as colorless oil (2.6 Kg, 100%). ES/MS m/e: 173 (M+1).
Reaction SMILES: Br.S1C=CC=C1C(O)=O.[Br:10][CH2:11][C:12]([C:14]1[CH:15]=[C:16]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[S:17][C:18]=1[CH3:19])=O.[C:26]1([NH:32][C:33]([NH2:35])=[S:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[BrH:10].[CH3:19][C:18]1[S:17][C:16]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:15][C:14]=1[C:12]1[N:35]=[C:33]([NH:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:34][CH:11]=1
Reactant: Cc1sc(C(=O)OC(C)C)cc1C(=O)CBr
Reactant: NC(=S)Nc1ccccc1
Agent: Br
Agent: O=C(O)c1cccs1
Product: Cc1sc(C(=O)OC(C)C)cc1-c1csc(Nc2ccccc2)n1
Yield: 86.7 %

Procedure:
Isopropyl 5-methyl-4-[2-phenylamino)(1,3-thiazol-4-yl)]-thiophene-2-carboxylate hydrobromide: Isopropyl 4-(2-bromoacetyl)-5-methylthiophene-2-carboxylate (64 mg, 0.21 mmol) was allowed to react with phenylthiourea (32.1 mg) as described in Example 154, step (a) to give 80 mg (87% yield) of isopropyl 5-methyl-4-[2-(phenylamino)(1,3-thiazol-4-yl)]-thiophene-2-carboxylate hydrobromide. Mass Spectrum (ESI) m/z calcd. for C18H18N2O2S2, 358.5 (M+H), found 359.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[C:10]1([S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][C:6]1[N:7]=[C:2]([NH:1][C:20]([NH:19][S:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:18])=[O:17])=[O:21])[N:3]=[N:4][C:5]=1[CH3:9]
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: Cc1nnc(N)nc1C
Solvent: ClCCl
Product: Cc1nnc(NC(=O)NS(=O)(=O)c2ccccc2)nc1C
Reaction time: 4 h

Procedure:
To a dry, well stirred mixture of 6 g of 3-amino-5,6-dimethyl-1,2,4-triazine in 100 ml of methylene chloride at ambient temperature and pressure was added 9 g of benzenesulfonyl isocyanate. The mixture was stirred for 4 hours and the precipitated product removed by filtration. After washing with 1-chlorobutane, the product melted at 155°-158°.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:6]=1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:55]1([C:61]2[N:66]=[C:65]3[N:67]=[C:68]([N:70]4[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]4)[S:69][C:64]3=[C:63]([C:76](O)=[O:77])[CH:62]=2)[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C=O)C.O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:4]1[O:3][C:2]([NH:1][C:76]([C:63]2[CH:62]=[C:61]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[N:66]=[C:65]3[N:67]=[C:68]([N:70]4[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]4)[S:69][C:64]=23)=[O:77])=[N:6][N:5]=1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2nc(N3CCCCC3)sc12
Reactant: Nc1nnc(-c2ccco2)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nnc(-c2ccco2)o1)c1cc(-c2ccccc2)nc2nc(N3CCCCC3)sc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
2-Amino-5-(2-furyl)-1,3,4-oxadiazole (76 mg, 0.50 mmol), HOAt (68 mg, 0.50 mmol), HATU (190 mg, 0.50 mmol), and N,N-diisopropylethylamine (97 μL, 0.56 mmol) were added to a solution of commercially available 5-phenyl-2-piperidino-7-thiazolo[4,5-b]pyridinecarboxylic acid (85 mg, 0.25 mmol) in DMF (1 mL), followed by stirring overnight at room temperature in an argon atmosphere. To the reaction solution were added 2-amino-5-(2-furyl)-1,3,4-oxadiazole (76 mg, 0.50 mmol), HOAt (68 mg, 0.50 mmol), HATU (190 mg, 0.50 mmol), and N,N-diisopropylethylamine (97 μL, 0.56 mmol), and the mixture was stirred at room temperature for further 4 days. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and recrystallized from methanol to obtain the title compound (27 mg, 0.06 mmol) (yield: 240).
Reaction SMILES: NC1C=CC=C2C=1C=CN=C2.C(N(CC)CC)C.C(=S)=[S:20].[CH:22]1([N:28]=[C:29]=[N:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[CH:31]1([NH:30][C:29]([NH:28][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[S:20])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: S=C=S
Agent: Nc1cccc2cnccc12
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: S=C(NC1CCCCC1)NC1CCCCC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 5-aminoisoquinoline (14.4 g.) in pyridine (40 cc.) is added dropwise to a solution of triethylamine (10.1 g.) and carbon disulphide (40 cc.) in pyridine (20 cc.), whilst stirring at a temperature of about -10° C. After 1 hour at this temperature, a solution of N,N'-dicyclohexylcarbodiimide (20.6 g.) in pyridine (20 cc.) is added dropwise. Stirring is continued for 3 hours at a temperature changing from -10° to 20° C . and then for 20 hours at a temperature of about 20° C. The N,N'-dicyclohexylthiourea formed is filtered off and washed with methylene chloride (50 cc.); the filtrate is evaporated to dryness under reduced pressure (20 mm. Hg) at 40° C. The solid residue is taken up in methylene chloride (100 cc.); the new insoluble material is filtered off and washed with methylene chloride (30 cc.); the filtrate is evaporated to dryness under reduced pressure (20 mm. Hg) at 40° C. The residue is dissolved in boiling acetonitrile (100 cc.); after cooling, the crystals formed are filtered off and then suspended in diisopropyl ether (180 cc.). After 30 minutes'stirring at a temperature of about 20° C, the insoluble material is filtered off. The filtrate is evaporated to dryness under reduced pressure (20 mm. Hg) at 50° C. The residue is crystalline beige solid (5.9 g.) consisting of 5-isothiocyanatoisoquinoline, melting at 99° C. after recrystallisation from acetonitrile (40 cc.) and at 102° C. after sublimation at 70° C under reduced pressure (1 mm. Hg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.FC(F)(F)S([O-])(=O)=O.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]([I+]C1C=CC=CC=1)=[C:21]2[OH:36]>>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[C:21]2[OH:36]
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1[I+]c1ccccc1
Reactant: CNc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CN(c1ccccc1)c1c(O)c2cc(Br)ccc2[nH]c1=O

Procedure:
The title compound was prepared using N-methylaniline in place of aniline according to the procedure of Intermediate 11, step c except the crude solid was purified by flash column chromatography (silica gel, 50% EtOAc-Heptane), affording the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:20]2[NH:21][C:22]([CH3:33])=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2cccc3c2CC(=O)N3)cn1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(N)nc4)c32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
4-(6-Aminopyridin-3-yl)-1,3-dihydroindol-2-one (56 mg, 0.25 mmol) was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (69 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([O:37][C:38](=O)[NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]3[N:50]([CH3:51])[N:49]=[N:48][N:47]=3)[CH:41]=2)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:38]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]3[N:50]([CH3:51])[N:49]=[N:48][N:47]=3)[CH:41]=2)=[O:37])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 19 h
Yield: 74.8 %

Procedure:
In a dry flask (3R,4R)-4-amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (350 mg, 0.834 mmol) was dissolved in dimethylformamide (5 mL) and [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (285 mg, 0.965 mmol) was added. The reaction mixture was stirred for 19 hours. The reaction mixture was diluted with ethyl acetate and extracted three times with water. The combined aqueous extracts were extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with 70-100% ethyl acetate/hexanes to give a solid (387 mg, 75%). A small amount was further purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (33 mg, 62%). 1H NMR (300 MHz, CDCl3), δ: 7.88 (m, 1H), 7.49 (m, 2H), 7.40 (m, 1H), 7.19 (m, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 6.86 (m, 1H), 4.31 (m, 1H), 4.17 (s, 3H), 4.03 (m, 4H), 3.16 (m, 1H), 3.05 (m, 1H), 2.88 (m, 3H), 2.67 (m, 1H), 2.50 (m, 2H), 2.37 (m, 1H), 1.95 (m, 1H), 1.65 (m, 5H), 1.47 (s, 9H), 1.23 (m ,1H). HRMS (ESI), C32H42FN8O4 m+/z: calc.=621.3313, found=621.3337.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([O:20]C)=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+].CO>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 68.9 %

Procedure:
A mixture of methyl 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylate (trans isomer) (4.05 g) in 1N sodium hydroxide solution (58.3 ml) and methanol (80 ml) was refluxed for 1 hour and evaporated in vacuo. The residue was dissolved in water and washed with chloroform. The aqueous layer was acidified with 1N hydrochloric acid. The resulting precipitates were filtered and recrystallized from isopropyl alcohol to give crystals of 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (2.65 g).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=O>COCCO>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(C(=O)/C=C/N(C)C)cc1
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Solvent: COCCO
Product: Cc1ccc(-c2ccnn2-c2cc(C#N)ccn2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A mixture of 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (124 mg, 0.6 mmol, PREPARATION 3) and (2E)-3-(dimethylamino)-1-(4-methylphenyl)prop-2-en-1-one (95 mg, 0.5 mmol) in 2-methoxyethanol (3 mL) was stirred at 100° C. for 2 h. The reaction mixture was cooled, concentrated, and dissolved in EtOAc and then washed with water and brine. The organic phase was dried, concentrated, triturated with EA/PE (1:10, 5 mL), filtered, and dried to give the title compound (120 mg, 92%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.38 (3H, s), 6.49 (1H, d, J=1.6 Hz), 7.16 (4H, s), 7.38 (1H, dd, J=5.2, 1.2 Hz), 7.76 (1H, d, J=1.2 Hz), 7.90 (1H, s), 8.44 (1H, d, J=5.2 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:7]1([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Reaction time: 4 h

Procedure:
3-Nitroaniline (10 g, 72 mmol)in DMF (100 ml) was added bis(2-chloroethyl) ether (11.7 ml, 100 mmol) and potassium carbonate (27.6 g, 200 mmol). The mixture was heated to reflux for 10 hours. Additional bis(2-chloroethyl) ether (3 ml) was added and reflux was maintained for 18 hours. Addition of bis(2-chloroethyl) ether was repeated and reflux was continued for 4 hours. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was dried and evaporated. The residue was extracted with diethyl ether. The extract was concentrated and purified by column chromatography on silica gel with ethyl acetate/petroleum ether (3:7) as the eluent. Yield 3.4 g. Mp 87°-90° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[NH2:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([Cl:13])[N:7]=1.C(O)C>C(N(CC)CC)C>[NH2:5][C:6]1[N:11]=[C:10]([NH:4][CH2:3][CH2:2][OH:1])[CH:9]=[C:8]([Cl:13])[N:7]=1
Reactant: NCCO
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NCCO)n1
Yield: 59.6 %

Procedure:
To 2-hydroxyethylamine (2.6 g, 42.7 mmol) were added 2-amino-4,6-dichloropyrimidine (7.0 g, 42.7 mmol), ethanol (150 ml) and triethylamine (6.6 ml), and the mixture was refluxed for one day. The solvent was distilled away under reduced pressure and the residue was washed with water, which was followed by recrystallization from chloroform to give yellow prism crystals (4.8 g, 59.6%), m.p. 143-146° C. (chloroform).
Reaction SMILES: Cl.[C:2]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)(=[O:4])[CH3:3].C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>CN(C)C1C=CN=CC=1.C1COCC1>[C:2]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:39](=[O:41])[CH3:40])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)(=[O:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(CN)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a solution of 3-acetyl-2-(4-aminomethylbenzyl)-6-bromo-4-phenyl-2H-isoquinolin-1-one hydrochloride (100 mg) and triethylamine (0.09 ml) and 4-dimethylaminopyridine (24 mg) in THF (5 ml) was added acetic anhydride (0.08 ml) and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure, and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1→1/9) to give the title compound (93 mg, 92%).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([O:6][CH2:7]1)[CH2:4][NH:3]2.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][O:6]3)=[CH:12][CH:11]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1ccc(CN2C[C@@H]3C[C@H]2CO3)cc1
Yield: 76.7 %

Procedure:
(1S,4S)-(+)-2-Aza-5-oxabicyclo[2.2.1]heptane hydrochloride (1.26 g), 4-bromobenzyl bromide (2.32 g) and triethylamine (3.88 ml) were stirred in dimethylformamide (30 nml) for 18 h. The mixture was partitioned between diethyl ether (60 ml) and water (60 ml) and the organic phase was washed further with water (60 ml), dried (MgSO4), concentrated in vacuo and purified by Bondelute® chromatography, eluting with 0–100% ethyl acetate/iso-hexane to give the product as an orange oil (1.91 g).
Reaction SMILES: [CH:1]([Si:4]([CH:15](C)C)([CH:12](C)C)[C:5]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7][CH:6]=1)(C)C.C([O-])(O)=O.[Na+]>O.O.O.[Ru](Cl)(Cl)Cl.COCCO>[CH3:1][Si:4]([CH3:12])([CH3:15])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: CC1=CCC([Si](C(C)C)(C(C)C)C(C)C)=CC1
Agent: Cl[Ru](Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCO
Product: Cc1ccc([Si](C)(C)C)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
In a 150-ml Schlenk flask, 1.18 g (4.5 mmol) of ruthenium chloride trihydrate, 5.6 g (22.5 mmol) of triisopropyl(4-methyl-1,4-cyclohexadienyl)silane, 0.38 g (4.5 mmol) of NaHCO3, and 11 ml of 2-methoxyethanol were added, and the mixture was allowed to react for 9 hours at 130° C. Subsequently, the mixture was left to cool to room temperature, and precipitated crystals were filtered. Thus, 1.4 g of objective [RuCl2 (4-(triisopropylsilyl)toluene)]2 was obtained at a yield of 73.0%.