Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][CH2:7][CH2:8][NH2:9])[CH:2]([CH3:4])[CH3:3].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH:14](=[N:9][CH2:8][CH2:7][CH2:6][P:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:1][CH:2]([CH3:3])[CH3:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)CP(CCCN)CC(C)C
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: CC(C)CP(CCCN=Cc1ccccc1)CC(C)C
Yield: 98 %

Procedure:
Under argon, a solution of 3-diisobutylphosphino-propylamine (428.5 mg, 2.11 mmol) and benzaldehyde (226.9 mg, 2.14 mmol) in ethanol (15 mL) was heated at 65° C. (oil bath) for 4 h. Then, the solvent was removed in-vacuo to give the desired product (>98% by 1H-NMR) as a colourless liquid (614.1 mg, 2.1 mmol, quantitative).
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[C:3]=1[CH3:23].[OH:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([C:31]1[CH:39]=[CH:38][C:34]2[O:35][CH2:36][O:37][C:33]=2[CH:32]=1)=[O:30]>>[O:35]1[C:34]2[CH:38]=[CH:39][C:31]([C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:19]3[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:4]4[C:3]([CH3:23])=[CH:2][CH:10]=[CH:9][C:5]=4[C:6]([OH:8])=[O:7])(=[O:14])=[O:15])=[CH:21][CH:20]=3)=[O:30])=[CH:32][C:33]=2[O:37][CH2:36]1
Reactant: O=C(NCCCO)c1ccc2c(c1)OCO2
Reactant: Cc1ccc(C(=O)O)c(N(C)S(=O)(=O)c2ccc(F)cc2)c1C
Product: Cc1cccc(C(=O)O)c1N(C)S(=O)(=O)c1ccc(OCCCNC(=O)c2ccc3c(c2)OCO3)cc1
Yield: 49 %

Procedure:
The product of Example 2 (0.30 g, 0.92 mmol) was coupled to N-(3-hydroxypropyl)-1,3-benzodioxole-5-carboxamide, prepared according to Example 20, (0.205 g, 0.92 mmol) using the procedure of Example 3 to provide 0.23 g (49% yield) of yellow solid. MP 120° C.; 1H NMR (DMSO-d6): δ1.63 (m, CH2) 1.9 (s, CH3), 3.20 (s, CH3), 3.6 (m, CH2), 4.1 (m, CH2), 6.07 (s, CH2), 6.9-7.1 (m, 5 Ar H), 7.3-7.5 (m, 3 Ar H), 7.88-7.94 (m, 2 Ar H), 8.52 (br s, NH). Electrospray Mass Spec: m/z 527.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5]1.[O:19]1[CH2:21][CH:20]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C.O>[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:21][CH:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[OH:19])[C:7]=2[CH2:6][CH2:5]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: c1cncc(C2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2cccnc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.6 %

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (94 mg, 3.92 mmol) in 5 mL of DMF, 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.3 g, 1.40 mmol) was added and stirred at RT for 5 min. 3-(Oxiran-2-yl)pyridine (254 mg, 1.54 mmol) in DMF (5 mL) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 200 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(pyridin-3-yl)ethanol as the TFA salt.
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OC(=O)C1C=CC(C#CC2C=CC3C(NC4CC4)CCC(C)(C)C=3C=2)=CC=1)C.C([Li])CCC.[Br:55][C:56]1[CH:57]=[C:58]2[C:63](=[C:64]([CH:66]=O)[CH:65]=1)[O:62][C:61]([CH3:69])([CH3:68])[CH2:60][C:59]2([CH3:71])[CH3:70]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[Br:55][C:56]1[CH:57]=[C:58]2[C:63](=[C:64]([CH:66]=[CH2:1])[CH:65]=1)[O:62][C:61]([CH3:69])([CH3:68])[CH2:60][C:59]2([CH3:71])[CH3:70]
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C=O)c2O1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3NC2CC2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=Cc1cc(Br)cc2c1OC(C)(C)CC2(C)C
Yield: 72 %

Procedure:
A solution of methylidene triphenyl phosphorane [generated from methyl triphenylphosphonium bromide (7 g, 20 mmol) and (1 1.8 mL, 19 mmol) of a 1.6M solution of n-butyl lithium in hexanes ] was added 6-bromo-2,2,4,4-tetramethyl chroman-8-carbaldehyde (Intermediate 30, 0.52 g, 1.75 mmol). After 1 h the reaction mixture was diluted with hexane, washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a clear oil which was subjected to flash column chromatography over silica gel (230-400 mesh) using 2% ethyl acetate in hexane as the eluent to afford the title compound as a clear oil (0.37 g, 72%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1.Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C.O>[N:28]1([CH2:27][CH2:26][CH2:25][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: ClCCCN1CCCCC1
Reactant: c1c[nH]c(-c2ccc(OCCCN3CCCCC3)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(-c2ccc(OCCCN3CCCCC3)cc2)n(CCCN2CCCCC2)c1
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a stirred suspension of sodium hydride (0.051 g) in DMF (3 mL) at RT was added dropwise the product of Example 18 (0.2 g) in DMF (4 mL). After 20 min, 1-(3-chloro-propyl)-piperdine (0.139 g) was added dropwise and the mixture stirred for 12 h. The mixture was diluted with water and extracted several times with diethyl ether. The combined organic layers were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure, giving the title compound as a dark red oil (0.257 g). 1H NMR (400 MHz, C6D6): 7.35 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.72 (t, J=2.5 Hz, 1H), 6.44 (d, J=2.5 Hz), 3.82 (m, 4H), 2.37–2.16 (m, 8H), 2.06 (br s, 4H), 1.96 (t, J=6.6 Hz, 2H), 1.87–1.81 (m, 2H), 1.59–1.22 (m, 16H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1)([CH3:7])[CH3:6])C.[BH4-].[Na+]>C(O)C>[N:8]1([C:5]([CH3:7])([CH3:6])[CH2:4][OH:3])[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9]1
Reactant: CCOC(=O)C(C)(C)n1cnc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CO)n1cnc2ncccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 2-imidazo[4,5-b]pyridin-1-yl-2-methyl-propionic acid ethyl ester (1 eq) in ethanol was added sodium borohydride (4 eq) at room temperature. The reaction mixture was left stirring at room temperature overnight and then quenched by addition of H2O. Once the reaction solvent was removed in vacuo, the residue was dissolved in dichloromethane, washed with NaCl (sat.), dried over sodium sulfate, filtered, and concentrated to give compound 2-imidazo[4,5-b]pyridin-1-yl-2-methyl-propan-1-ol (92%) MH+(192)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:22][CH:21]=3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH:34]=O)[CH3:33]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:29])[N:27]=[CH:31][N:32]([CH3:34])[CH3:33])=[CH:22][CH:21]=3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CON(C)C(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1c(-c2ccc(S(=O)(=O)N=CN(C)C)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.19 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-N-methoxy-N, 1,4-trimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxamide (compound 49, 0.650 g, 1.45 mmol) in ethyl acetate (12 ml) was added DMF (0.65 ml) and DMF acetal (0.207 g, 0.233 ml, 1.74 mmol) sequentially at room temperature. The reaction mixture was then stirred at room temperature for 15 hr under a nitrogen atmosphere. The progress of the reaction was monitored by TLC. The precipitated out product was filtered and washed with ether (10 ml) to obtain the title compound (0.600 g, 82.19%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.O1CCCC1.[C:16]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(=O)C>[OH:23][C:16]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1
Reactant: COc1ccc(Br)cc1
Reactant: CCOC(=O)N1CCC(C(=O)c2ccccc2)CC1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(OC)cc2)CC1
Reaction time: 2 h

Procedure:
To a stirred and refluxing Grignard-complex, previously prepared starting from 15 parts of magnesium, 112.2 parts of 1-bromo-4-methoxybenzene and 540 parts of tetrahydrofuran, was added dropwise a solution of 80 parts of ethyl 4-benzoyl-1-piperidinecarboxylate in 360 parts of tetrahydrofuran at reflux temperature. Upon completion, stirring was continued for 2 hours at reflux. After cooling overnight, the reaction mixture was poured onto a mixture of 300 parts of crushed ice and 40 parts of acetic acid at 10° C. After stirring for 15 minutes, the layers were separated. The organic layer was dried, filtered and evaporated. The residue was taken up in methylbenzene and the latter was evaporated. The residue was suspended three times in 70 parts of 2,2'-oxybispropane and the latter was decanted each time. The residue was evaporated to dry, yielding 106 parts of ethyl 4-[hydroxy(4-methoxyphenyl)phenylmethyl]-1-piperidinecarboxylate as a residue (intermediate 31).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:37]([NH2:43])[C:38]1[O:42][CH:41]=[CH:40][CH:39]=1>>[O:42]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:37][NH:43][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1
Reactant: NCc1ccco1
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: O=C(NCc1ccco1)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 96.9 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30 mmol, 0.6M in DMF) were combined to give 56 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 578 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[C:7]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:8]=[C:9]3[C:13]=2[N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH2:3][CH2:2]1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1>[CH:1]1([N:4]([S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)(=[O:39])=[O:38])[C:5]2[CH:6]=[C:7]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:8]=[C:9]3[C:13]=2[N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:10]3)[CH2:2][CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CCOC(=O)C1Cc2cc(OCCOC)cc(NC3CC3)c2N1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: CCOC(=O)C1Cc2cc(OCCOC)cc(N(C3CC3)S(=O)(=O)c3ccccn3)c2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a mixture of 1-tert-butyl 2-ethyl 7-(cyclopropylamino)-5-(2-methoxyethoxy)indoline-1,2-dicarboxylate (1.9 g) and pyridine (3 mL) was added a mixture of 2-pyridylsulfonyl chloride (1.2 g) and pyridine (2 mL) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water. The organic layer was washed with aqueous 10% aqueous citric acid solution, aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give the title compound (1.70 g, yield 67%) as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 562 (MH+).
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[K+].[CH2:24](Br)[CH:25]=[CH2:26]>C(O)(C)C>[CH2:26]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:11]=1)[CH:25]=[CH2:24]
Reactant: NS(=O)(=O)c1cc(C(=O)NNc2ccccc2)ccc1Cl
Reactant: C=CCBr
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: C=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Reaction time: 0.5 h

Procedure:
In a three necked 12 liter round bottom reaction flask equipped with a mechanical stirrer and reflux condenser was placed isopropanol 6.1 liters and 1-phenyl-2-(3-sulfamoyl-4-chlorobenzoyl)-hydrazine 1.3 kg (4.1 mol), potassium iodide 68.0 g (0.41 mol) and allyl bromide 768 g (8 mol). This mixture was stirred at gentle reflux for about 20 hours then suction filtered while still hot. The cake was washed with isopropanol 300 ml and the combined filtrate and wash were diluted with warm water 2.7 liters. Crystallization occured in about 0.5 hours. The crystals were filtered and washed with isopropanol-water (70% v/v) to provide the compound (m.p. 99°-101° C.).
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)(=[O:36])[CH2:34][CH3:35]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A165) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:35])=O>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:35])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Phosphorus oxychloride (300 mL) was added to 7-benzyloxy-6-methoxyquinolin-4-ol (40 g, 140 mmol) and the mixture heated to reflux for 2 h. The mixture was carefully poured into a mixture of ice and sodium carbonate. The solution was adjusted to pH 8 with the addition of solid sodium bicarbonate and stirred at room temperature overnight. The solid was filtered and washed with water and dried to give 7-benzyloxy-4-chloro-6-methoxyquinoline as a pale brown solid (40.2 g, 95%). 1H NMR (400 MHz, d6-DMSO): δ 8.61 (s, 1H), 7.57-7.37 (m, 8H), 5.32 (s, 2H), 3.98 (s, 3H); 13C NMR (100 MHz, d6-DMSO): δ 152.4, 151.5, 148.5, 146.2, 139.6, 137.0, 129.2, 128.8, 121.7, 120.4, 110.1, 101.9, 70.8, 56.5; IR (cm−1): 2359, 2341, 1506, 1456, 1435, 1252, 1227, 1146, 999, 845, 752, 698, 667; LC/MS (M+H=300).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:16]([N:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]1=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=c1cc(OCc2ccccc2)ccn1Cc1ccccc1
Temperature: 25 °C

Procedure:
In following a method similar to that described in Katigiri, N; Sato, M.; Yoneda, N.; Saikawa, S.; Sakamoto, T.; Muto, M.; Kaneko, C. J. Chem. Soc. Perkin Trans. 1, 1289-1296, 1986, a solution of 4-benzyloxy-2-pyridone 1 (1.00 g, 5.00 mmol), benzylbromide (4.28 g, 2.97 mL, 25.0 mmol), finely powdered sodium hydroxide (1.00 g, 25.0 mmol), and tetrabutylammonium hydrogen sulfate (0.679 g, 2.00 mmol) in benzene (180 mL) was heated at reflux for 2 h and then cooled to room temperature. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown solid. This solid was recrystallized from ethyl acetate to afford 1-benzyl-4-benzyloxy-2-pyridone 2 as a tan solid. MS (MH+) 292.2; Calculated 291 for C19H17NO2.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][CH2:12][C:13]1[N:14]2[CH:21]=[N:20][CH:19]=[C:15]2[S:16][C:17]=1[CH3:18].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:1]([NH:11][CH2:12][C:13]1[N:14]2[CH:21]=[N:20][CH:19]=[C:15]2[S:16][C:17]=1[CH3:18])=[O:3]
Reactant: Cc1sc2cncn2c1CN
Reactant: O=CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: Cc1sc2cncn2c1CNC=O
Reaction time: 1 h

Procedure:
A mixture of 0.94 ml of formic acid and 0.47 ml of acetic anhydride which had been beforehand reacted with each other at 50° C. for 30 minutes was added at room temperature to 5 ml of a dry dichloromethane solution containing 167 mg of 3-aminomethyl-2-methylimidazo[5,1-b]thiazole, and the mixture was then stirred at the same temperature for 1 hour. Then, an aqueous potassium carbonate solution was added to the reaction solution to alkalify the same. The organic layer was separated, and the aqueous layer was further extracted five times with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to obtain 117 mg of the title compound.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:15][C:10]=2[N:9]=[CH:8]1)(=O)C.Cl>[OH-].[Na+]>[NH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: CC(=O)NCCn1cnc2cc(-c3ccc(=O)[nH]n3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCn1cnc2cc(-c3ccc(=O)[nH]n3)ccc21
Yield: 99 %

Procedure:
8.0 g (26.0 mmol) of 6-[1-(2-acetylaminoethyl)benzimidazol-5-yl]-3(2H)-pyridazinone are refluxed for 4 hours in 80 ml of 5N sodium hydroxide solution. After cooling the mixture is adjusted to pH 8-9 with concentrated hydrochloric acid, the product precipitated is suction filtered and dried in a vacuum drying cupboard. The crude product obtained is used again without any further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:9][CH2:10]1
Reactant: Cc1ccccc1N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccccc1N1CCN(Cc2ccccc2-c2ccccc2)CC1

Procedure:
140.7 mg of the target compound (0.41 mmol, 74.7%) was obtained using 1-(2-methylphenyl)piperazine (193.8 mg, 1.1 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: C1(C(C2CCCCC2)C(O)=O)CCCCC1.C(Cl)(=O)C(Cl)=O.[CH:23]1([CH:29]([N:36]=C=O)[CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[N-]=C=O>ClCCl.CN(C)C=O.Cl>[CH:23]1([CH:29]([NH2:36])[CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C=NC(C1CCCCC1)C1CCCCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)C(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(C1CCCCC1)C1CCCCC1
Reaction time: 2 h

Procedure:
A solution of dicyclohexylacetic acid (4.5 g) in dichloromethane (50 mL) was treated with oxalyl chloride (2.5 mL). Addition of a catalytic amount of N,N-dimethylformamide (1 drop) caused immediate gas evolution to take place. The reaction mixture was stirred for 2 hr, then concentrated to dryness. The residue, consisting of crude dicyclohexylacetyl chloride, was dissolved in acetone (45 mL) and treated at 0° C. with a solution of sodium azide (2.6 g) in water (45 mL). After stirring for 1 hr at 0° C., toluene (100 mL) was added. The organic layer (mainly containing dicyclohexylacetyl azide as shown by IR absorption band at 2128 cm−1) was separated, washed twice with brine, dried (Na2SO4), then heated at reflux for 2 hr. Following evaporation of the solvent, a waxy solid was obtained which mainly consisted of dicyclohexylmethyl isocyanate (IR absorption band at 2275 cm−1). This crude isocyanate was suspended in 20% hydrochloric acid (100 mL) and heated at reflux for 8 h. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The solid residue was taken up in diethyl ether/1N aqueous NaOH and the aqeous layer was re-extracted with ethyl ether. The organic phases were joined and washed with brine, then dried (Na2SO4) and rotoevaporated. The title product was thus obtained as a colourless oil (1.8 g). H1-NMR (200 MHz, DMSO-d6) 0.8-1.8 (m, 22 H); 2.01 (t, 1 H, J=5.4 Hz) ppm.