Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].N1C=CC=CC=1.[CH3:16][Si:17]([CH3:20])([CH3:19])Cl>C(Cl)(Cl)(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][O:9][Si:17]([CH3:20])([CH3:19])[CH3:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: C[Si](C)(C)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCO[Si](C)(C)C
Yield: 91.4 %

Procedure:
In a three-neck flask having a capacity of 500 ml, 26 g (0.2 moles) of 2-hydroxyethyl methacrylate (abbreviated to HEMA) and 16 g of pyridine were dissolved in 200 ml of carbon tetrachloride. At room temperature, 107.5 g (0.2 moles) of trimethylchlorosilane was slowly dropped into the solution in the flask to complete the addition of the entire amount in 30 min. During this process precipitation of hydrochloric acid salt of pyridine took place. After filtration, carbon tetrachloride in the reaction liquid was distilled out by using an evaporater, and the remaining liquid was distilled under reduced pressure to obtain 37 g of 2-trimethylsiloxyethyl methacrylate (abbreviated to HEMA-Si).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:12][C:11]([OH:22])=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31].O>CN(C)C=O.C(OCC)(=O)C.O1CCCC1>[CH2:30]([O:22][C:11]1[N:12]=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[CH3:31]
Reactant: CCI
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOc1nc(-c2ccc(OC)cc2)n(-c2ccc(OC)cc2)n1
Reaction time: 72 h
Yield: 43.5 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazol-3-ol (0.3 g, 1.01 mmol), potassium carbonate (418 mg, 3.01 mmol), and iodoethane (0.406 mL, 5.05 mmol) in dimethylformamide (3 mL) was stirred for 3 days. Water and ethyl acetate-tetrahydrofuran (9:1) were poured into the mixture and the organic layer was separated, washed with brine-water (1:1) and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography to give 3-ethoxy-1,5-bis(4-methoxyphenyl)-1H-1,2,4-triazole (143 mg, 43.6% yield).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>CC(O)=O>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=4)[CH2:24][CH2:25]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1cccc2[nH]ccc12
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 1H-indole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 376.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>COCCOC.O.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>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[CH:3]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccn(-c2ccccn2)c1
Reactant: COc1cccc(B(O)O)c1
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: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2ccn(-c3ccccn3)c2)c1
Temperature: 84 °C

Procedure:
2-(3-Bromo-1H-pyrrol-1-yl)pyridine (1.34 g, 2 mmol), 3-methoxyphenylboronic acid (0.61 g, 4 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol) and potassium carbonate (560 mg, 4 mmol) were dissolved in a mixture of DME (18 mL) and H2O (2 mL) and degassed for 15 min with Ar (g). The reaction mixture was then heated at 84° C. for 18 h. At this time, a further 0.25 eq. of 3-methoxyphenylboronic acid (0.15 g, 1 mmol) was added and heating was continued. After a total of 42 h, the reaction mixture was cooled to rt, H2O (40 mL) and EtOAc (40 mL) were added and the reaction mixture shaken, the EtOAc layer was separated and the aqueous layer shaken with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4 and concentrated to a yellow oil. This was purified by liquid chromatography on silica gel eluting with EtOAc:hexane (3:7) to afford a white solid that was further purified by preparative HPLC to afford 2-[3-(3-methoxyphenyl)-1H-pyrrol-1-yl]pyridine as a white solid. 1H NMR (CD3Cl, 300 MHz) δ 8.52-8.54 (1H, m), 7.55 (1H, ddd), 7.38-7.39 (1H, m), 7.15-7.21 (2H, m), 6.76-6.85 (4H, m), 6.46-6.48 (1H, m), 6.41 (1H, dd). MS (ESI) 251 (M+H)+.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH:49]1[O:54][NH2:55]>CN(C=O)C.C(N(CC)CC)C.O>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH:55][O:54][CH:49]3[CH2:50][CH2:51][CH2:52][CH2:53][O:48]3)=[O:19])=[CH:11]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1)NOC1CCCCO1

Procedure:
Starting materials: (E)-3-[1-(biphenyl-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid (compound B2) (0.300 g), HOBt.H2O (0.130 g), triethylamine (668 μl), DMF (20 ml), EDC.HCl (0.508 g), O-(tetrahydro-2H-pyranyl)hydroxylamine (0.089 g). Reaction conditions: room temperature, 1 hour; room temperature, 18 hours.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(Br)C=3O2)(=O)=O)=CC=1.COC1C=CC=CC=1B(O)O.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:51][CH:52]2[CH2:56][C:55]3[CH:57]=[CH:58][CH:59]=[C:60]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[O:67][CH3:68])[C:54]=3[O:53]2)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[N-:80]=[N+:81]=[N-:82].[Na+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[N:80]([CH2:51][CH:52]1[CH2:56][C:55]2[CH:57]=[CH:58][CH:59]=[C:60]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[O:67][CH3:68])[C:54]=2[O:53]1)=[N+:81]=[N-:82]
Reactant: COc1ccccc1-c1cccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: COc1ccccc1B(O)O
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Product: COc1ccccc1-c1cccc2c1OC(CN=[N+]=[N-])C2

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2-methoxyphenylboronic acid (2.57 g, 16.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.532 g, 0.677 mmol), and potassium carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided (±)-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.76 g, 11.69 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.072 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.453 g (12%) of (±)-1-[7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C16H17NO2HCl: C, 65.86; H, 6.22; N, 4.8. Found: C, 65.72; H, 6.15; N, 4.86.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH2:8][CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=O>C1COCC1>[C:17]1([CH:9]([CH2:10][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][OH:7])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(C(CO)c1ccccc1)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(CN1CCCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of LAH (10 mmol) in THF (50 mL) is added 3-hydroxy-2-phenyl-1-pyrrolidin-1-yl propan-1-one (5 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 1.5 h. After cooled down to 0° C., the reaction is quenched by the addition of Na2SO4-10H2O. The resulting mixture is filtered through celite, and the filtrate is concentrated in vacuo to give 2-phenyl-3-pyrrolidin-1-yl propan-1-ol, which is directly used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH2:19]([O:31][CH2:32][CH:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>N1C=CC=CC=1.CCOCC>[CH2:19]([O:31][CH2:32][CH:33]1[NH:34][CH2:35][CH2:36][N:37]([C:10]2[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:14])[CH2:38]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: CCCCCCCCCCCCOCC1CNCCN1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOCC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)CCN1

Procedure:
A 710 mg portion of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was suspended in 5 ml of pyridine and 2 g of 2-[(dodecyloxy)methyl]piperazine added. This mixture was heated at 80°-85° C. for 4 hours, then cooled and diluted with ether. The solid was collected, washed with ether and dried, giving 1.3 g of the desired product, mp 125°-127° C.
Reaction SMILES: [Cl-].[Cl:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH3:25][N:26]1[C:32](=[O:33])[C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[N:29]2[CH:38]=[N:39][C:40]([CH:41]=O)=[C:28]2[CH2:27]1>O1CCCC1>[Cl:2]/[CH:3]=[CH:41]\[C:40]1[N:39]=[CH:38][N:29]2[C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[C:32](=[O:33])[N:26]([CH3:25])[CH2:27][C:28]=12
Reactant: CN1Cc2c(C=O)ncn2-c2ccccc2C1=O
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1Cc2c(/C=C\Cl)ncn2-c2ccccc2C1=O
Temperature: 25 °C

Procedure:
13.50 g of an equimolar mixture of chloromethyltriphenylphosphonium chloride and sodium amide were stirred for 15 minutes with 50 ml of tetrahydrofuran, whereby the temperature rose to 42°. 6.2 g (25.7 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde were then added portionwise thereto, the mixture was stirred at room temperature for a further hour, filtered and the filtrate was evaporated. After chromatography of the residue on silica gel while eluting with cyclohexane/ether/isopropanol (3:3:1) there was obtained 3-[(Z)-2-chlorovinyl]-4,5-dihydro-5-methyl-6H-imidazo-[1,5-a][1,4]benzodiazepin-6-one of melting point 197°-199°.
Reaction SMILES: [NH2:1][C:2](=[N:16][OH:17])[C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C(#N)C.[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22].C1CCN2C(=NCCC2)CC1>O.Cl>[S:22]=[C:21]1[O:17][N:16]=[C:2]([C@@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])[NH:1]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(N)=NO
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1c1noc(=S)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a mixture of tert-butyl {(1S,2R)-2-[amino(hydroxyimino)methyl]cyclopentyl}carbamate (320 mg) and acetonitrile (8.0 ml) were added 1,1′-carbonothioyl bis(1H-imidazole) (391 mg) and DBU (787 μl) in this order, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with water (15 ml), and 1 M hydrochloric acid was added thereto to adjust the pH to about 4, followed by extraction with ethyl acetate (40 ml). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was then removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (3% methanol-chloroform) and then washed with cooled ethyl acetate (2 ml) to obtain tert-butyl [(1S,2R)-2-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopentyl]carbamate (160 mg) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:8]2[C@@H:9]([OH:16])[C@H:10]([Br:15])[C:11]([CH3:14])([CH3:13])[O:12][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].C(Cl)CCl.[C:26]([S:29][CH2:30][C@H:31]([CH3:35])[C:32](Cl)=[O:33])(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:8]2[C@@H:9]([O:16][C:32](=[O:33])[C@H:31]([CH3:35])[CH2:30][S:29][C:26](=[O:28])[CH3:27])[C@H:10]([Br:15])[C:11]([CH3:14])([CH3:13])[O:12][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H](C)C(=O)Cl
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])[C@@H](O)[C@H](Br)C(C)(C)O2
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])[C@@H](OC(=O)[C@H](C)CSC(C)=O)[C@H](Br)C(C)(C)O2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (±)-trans-7-acetylamino-3-bromo-4-hydroxy-3,4-dihydro-6-nitro-2,2-dimethyl-2H-1-benzopyran, ethylene chloride and pyridine was added (S)-(-)-3-acetylthio-2-methylpropionyl chloride under ice-cooling over 5 minutes and stirred for 1.5 hours under room temperature. The reaction mixture was washed with diluted hydrochloric acid once and 10% aqueous sodium chloride solution twice. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give (±)-trans-7-acetylamino-3-bromo-3,4-dihydro-6-nitro-2,2-dimethyl-4-[(S)-(-)-3-acetylthio-2-methylpropionyloxy]-2H-1-benzopyran.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=1>O>[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14]([CH3:15])=[O:2])[N:9]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1nccc(N)n1
Agent: [Na+]
Solvent: O
Product: CS(=O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
Sodium metaperiodate (1.3 g.) in water (5 ml.) was added to a solution of 4-amino-2-methylthiopyrimidine (0.7 g.) in water (10 ml.) at 90°, and the solution kept at 90° for 1 hour. A further 1.3 g. of sodium metaperiodate was added and the solution heated a further 0.5 hours and then cooled to room temperature. The mixture was filtered and the filtrate evaporated to dryness. The residue was triturated with MeOH and the suspension filtered and then the filtrate was evaporated to dryness. The residue was triturated with acetonitrile and the insoluble solid collected to give 4-amino-2-methylsulphinylpyrimidine (0.7 g.) which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:41]>C(Cl)Cl.O1CCOCC1>[ClH:41].[ClH:41].[NH:8]1[CH2:9][CH:10]=[C:11]([CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:28][CH:29]=3)[CH:23]=2)=[O:17])[CH2:12][CH2:13]1
Reactant: CCCCc1nnc(C(=O)NCC2=CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(C(=O)NCC2=CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (70 mg) in DCM (2 mL) was added 4 N HCl in dioxane (1.0 mL) at 0° C., and the reaction was stirred for 1 h at room temperature. The volatiles were removed under reduced pressure, and the residue was triturated with anhydrous ethyl ether and dried under high vacuum to provide 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (1,2,3,6-tetrahydro-pyridin-4-ylmethyl)-amide dihydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:11]1[C:2]([CH3:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][N:7]=[CH:6][CH:5]=2
Reactant: Cc1nc2ccncc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cnccc4nc3C)c2cc1OC
Temperature: 140 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
2-Methyl-[1,6]naphthyridin-3-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline (84 mg), and 4-dimethylaminopyridine (46 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 3 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (23 mg, yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]1[C:15]2[C:10](=[C:11]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]([CH3:17])=[CH:13][C:14]=2[CH3:16])[NH:9][CH2:8]1)=[O:4].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].CCOC(C)=O>CN(C=O)C>[CH2:26]([N:9]1[C:10]2[C:15](=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=2[NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH2:8]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCI
Reactant: COC(=O)CCC1CNc2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCN1CC(CCC(=O)OC)c2c(C)cc(C)c(NC(=O)C(C)(C)C)c21
Temperature: 40 °C
Reaction time: 10 h
Yield: 82.2 %

Procedure:
N-[3-(2-Methoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (1.0 g) was dissolved in DMF (10 ml) and 1-iodooctane (1.44 g) and K2 CO3 (830 g) were added, which was followed by stirring at 40° C. for 10 hr. AcOEt (100 ml) was added, and after washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=20/1−5/1) to give 1.1 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([N:15]=[C:16]([CH3:18])[CH3:17])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([NH:15][CH:16]([CH3:17])[CH3:18])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1N=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1NC(C)C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
A solution of N-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylideneamine (18.4 g, 53.3 mmol) in 100 mL of methanol was placed under an atmosphere of nitrogen and cooled in an ice water bath. The solution was treated with sodium borohydride (2.32 g, 61.3 mmol) over 30 min. The reaction mixture was allowed to slowly come to ambient temperature. After 1.5 h, the reaction was quenched by the addition of 25 mL of saturated NH4Cl solution. The reaction mixture was concentrated under reduced pressure to remove the methanol. The residue was partitioned between chloroform (150 mL) and 10% Na2CO3 solution (35 mL), and the phases were separated. The organic portion was washed with another portion of 10% Na2CO3 solution (35 mL), water (35 mL) and brine (35 mL). The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to yield a brown foam. The foam was purified by chromatography (SiO2, 97:3 CHCl3:MeOH gradient to 9:1) to give 16.3 g of N-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine as a dark tan solid.
Reaction SMILES: C([O:3][C:4]1[CH:15]=[CH:14][C:7]2[N:8]3[CH2:13][CH2:12][N:11]=[C:9]3[S:10][C:6]=2[CH:5]=1)C.[BrH:16]>C(O)(=O)C>[BrH:16].[N:11]1[CH2:12][CH2:13][N:8]2[C:7]3[CH:14]=[CH:15][C:4]([OH:3])=[CH:5][C:6]=3[S:10][C:9]=12
Reactant: CCOc1ccc2c(c1)SC1=NCCN12
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)SC1=NCCN12

Procedure:
A mixture of 10 parts of 7-ethoxy-2,3-dihydroimidazo[2,1-b]benzothiazole and 150 parts of hydrobromic acid solution 48% in glacial acetic acid is stirred and refluxed overnight. The reaction mixture is evaporated. The solid residue is washed with ethanol and crystallized from ethanol 80%. The product is filtered off and dried, yielding 8 parts of 2,3-dihydroimidazo[2,1-b]benzothiazol-7-ol monohydrobromide; mp. 259.9° C.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1COC1C=C(C=CC=1)C=O.BrCC(OCC)=O.[OH:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)[CH:37]=1)[CH2:30][C:31](OCC)=[O:32].[H-].[Al+3].[Li+].[H-].[H-].[H-]>[Zn]>[CH:45]1[C:46]2[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:52]=[CH:53][C:44]=1[CH2:43][O:42][C:38]1[CH:37]=[C:36]([CH:29]([OH:28])[CH2:30][CH2:31][OH:32])[CH:41]=[CH:40][CH:39]=1
Reactant: CCOC(=O)CC(O)c1cccc(OCc2ccc3ccccc3c2)c1
Agent: CCOC(=O)CBr
Agent: O=Cc1cccc(OCc2ccc3ccccc3c2)c1
Agent: [Al+3]
Product: OCCC(O)c1cccc(OCc2ccc3ccccc3c2)c1

Procedure:
A mixture of 3-(naphth-2-ylmethoxy)benzaldehyde, ethyl bromoacetate and zinc was reacted using the procedure described in Example 2. There was thus obtained ethyl 3-hydroxy-3-[3-(naphth-2-ylmethoxy)phenyl)propionate which was reduced with lithium aluminium hydride using the conditions described in note d above to give 3-[3-(naphth-2-ylmethoxy)phenyl]propane-1,3-diol as a colourless oil.