Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11][CH3:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.O.[CH3:20]O>>[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11][CH3:12])[C:5]([O:7][CH3:20])=[O:6]
Reactant: CSc1ccc(C(=O)O)c(C)c1N
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(SC)c(N)c1C
Temperature: 60 °C

Procedure:
2 g of 3-amino-2-methyl-4-methylsulfanylbenzoic acid (0.01 mol) were dissolved in 20 ml of methanol and admixed with 2.0 g of conc. sulfuric acid, and the mixture was heated at 60° C. for 2 h. After cooling, the reaction mixture was poured into water, neutralized and extracted with ethyl acetate. After washing and drying, the solvent was removed.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH2:10][NH2:11]>C(O)C>[C:4]1([CH2:1][CH:2]=[N+:10]=[N-:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Product: [N-]=[N+]=CCc1ccccc1
Reaction time: 2 h
Yield: 68.8 %

Procedure:
Acetopheneone hydrazone: acetophenone (2.0 g, 16 mmol) is diluted in 16 ml of absolute ethanol and then hydrazine (2.3 ml, 48 mmol) is added. The mixture is heated to reflux temperature. After 2 h, the solvent is evaporated and the residue is taken up in ether (150 ml). The medium is washed with water (100 ml). After drying over Na2SO4, the ether is evaporated off. A pale yellow oil (1.5 g, 11 mmol, 69%) is obtained.
Reaction SMILES: BrC1C=C2C(=C(CBr)C=1)N(COCC[Si](C)(C)C)N=C2.[Br:21][C:22]1[CH:30]=[C:29]([CH2:31]Br)[C:28]2[C:24](=[CH:25][N:26]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:27]=2)[CH:23]=1>>[Br:21][C:22]1[CH:30]=[C:29]([CH3:31])[C:28]2[C:24](=[CH:25][N:26]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])[N:27]=2)[CH:23]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(Br)cc(CBr)c2n1
Agent: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(CBr)c21
Product: Cc1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12

Procedure:
5-Bromo-7-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole and 5-Bromo-7-(bromomethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole. A flask was charged with 5-bromo-7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (2.0 g, 5.86 mmol), N-bromosuccinimide (1.04 g, 5.86 mmol), benzoic peroxyanhydride (0.043 g, 0.18 mmol), and carbon tetrachloride (12 mL). The reaction was heated at reflux overnight. The reaction was concentrated. The resulting residue was suspended in diethyl ether (10 mL). To this was added pentane (20 mL). After stirring for 5 min, the solid was removed by filtration and the mother liquor concentrated. The residue was purified by column chromatography (3%→8% EtOAc/Hex) to give 3 fractions. The fastest eluting fraction was concentrated to give 5-bromo-7-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.95 g, 39%). The slowest eluting fraction was concentrated to give 5-bromo-7-(bromomethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (420 mg, 17%). 5-Bromo-7-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole: 1H-NMR (CDCl3, 500 MHz) δ 7.95 (s, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), 5.98 (s, 2H), 4.93 (s, 2H), 3.50 (t, J=8.2 Hz, 2H), 0.85 (t, J=8.2 Hz, 2H), <0.10 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 136.2, 133.5, 132.0, 128.4, 124.6, 123.1, 114.1, 80.4, 66.4, 29.8, 17.9, −1.4. 5-Bromo-7-(bromomethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole: 1H-NMR (CDCl3, 500 MHz) δ 8.07 (s, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.41 (d, J=1.5 Hz, 1H), 5.72 (s, 2H), 4.84 (s, 2H), 3.64 (t, J=8.2 Hz, 2H), 0.93 (t, J=8.2 Hz, 2H), 0.00 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 145.6, 130.2, 129.3, 123.8, 123.4, 122.8, 115.2, 82.1, 67.9, 28.2, 18.0, −1.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][S:7](=[O:15])(=[O:14])[C:8]3[C:9]=2[C:10]=1[CH:11]=[CH:12][CH:13]=3.[H-].[Na+].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)[S:7](=[O:15])(=[O:14])[C:8]3[C:9]=2[C:10]=1[CH:11]=[CH:12][CH:13]=3
Reactant: ClCCCN1CC=C(c2ccccc2)CC1
Reactant: O=S1(=O)Nc2ccc(Cl)c3cccc1c23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3c(Cl)ccc(c23)N1CCCN1CC=C(c2ccccc2)CC1
Temperature: 70 °C
Yield: 45.5 %

Procedure:
The experiment is carried out as in Example 18, starting with 5-chloronaphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 g), sodium hydride (0.15 in an 80% dispersion in vaseline oil, 1-(3-chloropropyl)-4-phenyl 1,2,3,6-tetrahydropyridine (1.4 g), obtained as in Example 18, and dimethylformamide (30 cc). The reaction mixture is heated for one hour at 70° C., cooled to a temperature of about 20° C. then concentrated to dryness at 20° C. under reduced pressure (0.5 mm Hg; 0.07 kPa). The residue is redissolved in dichloromethane (100 cc) and the solution is washed with distilled water (50 cc), dried over magnesium sulphate and concentrated to dryness at 20.C under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by chromatography on a silica column with a mixture of dichloromethane and ethyl acetate (90-10 vol) as eluant, and recrystallized from boiling acetonitrile (30 cc). 5-Chloro-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (1 g) is obtained, m.p. 135° C.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: BrCc1ccccc1
Product: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Yield: 38 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.623 g) was reacted with benzyl bromide as in General Procedure 1 to give the title compound as a light yellow solid (38% yield). M.p. 225° C., LCMS: m/z=366.03 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.14 (s, 2H), 5.10 (s, 2H), 7.13 (s, 1H), 7.7.22-7.29 (m, 4H), 7.31-7.38 (m, 2H), 7.78 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]4)[C@H:6]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][CH3:32])=O)[CH2:5][C:4]=2[CH:3]=1.B.Cl>O1CCCC1>[CH3:32][NH:31][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:6]1[CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:19]=[CH:18][C:17]=2[C@@H:16]2[C@@H:7]1[C@H:8]1[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C@@H:11]([OH:20])[CH2:10][CH2:9]1
Reactant: CNC(=O)CCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12

Procedure:
A mixture of 9-(3,17β-dihydroxyoestra-1,3,5(10)-trien-7α-yl)-N-methylnonanamide (Example 27; 0.047 g.) and a molar solution of borane in tetrahydrofuran (5 ml.) was heated under reflux for 2 hours, cooled and concentrated aqueous hydrochloric acid (2 ml.) was added. The tetrahydrofuran was removed by evaporation and the residue was basified with aqueous 5N-sodium hydroxide solution and extracted three times with ethyl acetate (10 ml. each time). The combined extracts were washed with water (2 ml.), dried and evaporated to dryness. There was thus obtained as an oil 7α-(9-methylaminononyl)oestra-1,3,5(10)-triene-3,17β-diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](=[O:7])[CH:6]=1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:25](=O)[CH3:26])[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]>CN(C)C=O.CCOCC>[CH3:26][C:25]1[NH:1][C:2]2[N:3]([NH:4][C:5](=[O:7])[CH:6]=2)[CH:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=2)[C:18]=1[C:19]([O:21][CH:22]([CH3:23])[CH3:24])=[O:20]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)C
Reactant: NC1=CC(=O)N=N1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)n2[nH]c(=O)cc2N1
Temperature: 70 °C

Procedure:
A mixture of 3-amino-5-pyrazolone (3.57 g; 36.1 mmole) and 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, 1-methylethyl ester (10.0 g; 36.1 mmole) in dry dimethylformamide (30 ml) was heated at 70° C. under argon for 24 hours. The reaction mixture was allowed to cool to room temperature and then diluted with ether. The resultant precipitate was filtered off and recrystallized from isopropanol to provide the title compound in crystalline form (4.23 g; melting point 254°-256° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:4][CH:3]1[C:5](O)=[O:6].C([O:11][C:12](=[O:32])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1)C.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>CN(C=O)C.CN(C1C=CN=CC=1)C.C(O)=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]([OH:32])=[O:11])=[C:16]([CH:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][N:23]2[C:5]([CH:3]2[CH2:4][C:2]2([CH3:8])[CH3:1])=[O:6])[CH:17]=1
Reactant: CC1(C)CC1C(=O)O
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=CO
Solvent: CN(C)C=O
Product: CC1(C)CC1C(=O)N1CCc2ccccc2C1c1cc(Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 62 h

Procedure:
To a solution of (±)-2,2-dimethyl-cyclopropanecarboxylic acid (26 mg, 0.20 mmol, 1.0 eq.) and (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester (73 mg, 0.20 mmol, 1.0 eq.) in DMF (2.4 mL), DMAP (37 mg, 0.30 mmol, 1.5 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol, 1.5 eq.) were added. The resulting solution was stirred at r.t. for 62 hours. 1M aq. NaOH soln. (1.2 mL) was added and the solution was stirred at r.t. for 3.5 hours. Formic acid (0.2 mL) was added. The crude mixture was purified by prep. HPLC (column: Waters XBridge, 19×50 mm, 5 um, UV/MS, acidic conditions). The two racemic diastereoisomers were separated (LC-MS 3: tR (±)-dial=0.91 and tR (±)-dia2=0.93). The title compound showed: tR=0.93.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:15][CH2:16][CH3:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][OH:14].Cl[C:19]1[C:20](=[O:25])[C:21](=[O:24])[C:22]=1[CH3:23].CCN(CC)CC.[K+].[Br-]>CN(C=O)C.O>[CH2:16]([S:15][C:3]1[C:2]([NH:1][C:19]2[C:20](=[O:25])[C:21](=[O:24])[C:22]=2[CH3:23])=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:6][NH:7]2)[CH3:17]
Reactant: Cc1c(Cl)c(=O)c1=O
Reactant: CCSc1c(N)ccc2[nH]cc(CCCO)c12
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCSc1c(Nc2c(C)c(=O)c2=O)ccc2[nH]cc(CCCO)c12
Temperature: 23 °C
Reaction time: 50 h

Procedure:
A mixture of 3-(5-amino-4-ethylthio-3-indolyl)-1-propanol (0.93 g, 3.7 mmol), 3-chloro-4-methyl-1,2-dioxocyclobut-3-ene (0.58 g, 4.4 mmol) and Et3N (0.62 ml, 4.4 mmol) in DMF (50 ml) was stirred at 23° C. for 50 h before adding water (200 ml). The aqueous solution was extracted with EtOAc (3×75 ml). The organic extracts were washed with water (50 ml), dried (MgSO4) and concentrated in vacuo. The crude material was purified on silica gel dry column using first a mixture of CH2Cl2 :EtOAc (1:4) and then EtOAc:Et3N (49:1). Appropriate fractions were concentrated in vacuo leaving yellow crystals, 0.815 g, m.p. 119° C., 64%. 1H NMR (DMSO-d6) δ (ppm): 11.17, 11.11, 10.80 and 10.51 (4 br s, 2H indolic NH, and 5-NH), 7.4 (br s, 1H), 7.26 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 4.40 (t, J=5.2 Hz, 1H, OH), 3.46 (t, J=3.5 Hz, 2H after D2O exchange), 2.95-3.10 (m, 2H, CH2CH2CH2O), 2.66 (br s, 2H, CH3CH 2 S), 2.26 (br s, 1H, CH3 on dioxocyclobutene), 1.7-1.9 (m, 2H, CH2CH2CH2O), 1.59 (br s, 2H, CH3 on dioxocyclobutene), 0.9-1.1 (m, 3H, CH3CH2S). IR (KBr) n:3420, 3300-3000, 1775, 1728, 1620, 1580 and 1400 cm-1. Anal. calcd. for: C18H20N2O3S: C 62.77; H 5.85; N 8.13; S 9.31. Found: C 62.75; H 5.85; N 8.20; S 9.25.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].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.C([O-])([O-])=O.[Cs+].[Cs+].[NH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CN(C=O)C.C(Cl)Cl.O.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]>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([NH:65][C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1ncc2cc(Br)ccc2c1O
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncc2cc(Nc3ccccc3)ccc2c1O
Temperature: 135 °C
Reaction time: 16 h

Procedure:
A mixture of 7-bromo-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (141.0 mg, 0.50 mmol), xantphos (28.9 mg, 0.05 mmol, Strem), Pd2(dba)3 (22.9 mg, 0.03 mmol, Sigma-Aldrich), Cs2CO3 (488.7 mg, 1.5 mmol) and aniline (0.1 mL, 1 mmol) in DMF (5 mL) was stirred at 135° C. for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with CH2Cl2 (50 mL) and H2O (50 mL). The layers were separated and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 62.4 mg. MS: (−) m/z 293.04 (M−1).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])C=1.C(I)C.[Li+].CC([N-]C(C)C)C>CCCCCC.C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[C:7]=1[CH2:5][CH3:6]
Reactant: Brc1cccc(Br)c1
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1c(Br)cccc1Br
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a three litre neck round flask charged with 19.30 g of diisopropylamine and 110 mL of THF was added 76 mL of n-BuLi in hexane (2.5 M) in dropwise at −70° C. After addition was finished, the resulting mixture was stirred at the same temp. for 10 min. In another 500 mL three neck round flask, 25 g of 1,3-dibromobenzene and 49.6 g of ethyl iodide was mixed well and cooled to −70° C. The freshly prepared LDA was introduced dropwise to above mixture below −65° C. After the addition was finished, the resulting mixture was stirred for 4 h at the same temp. GCMS showed that the desired product was formed. The reaction was warmed to 0° C. in 30 mins. To the reaction mixture was added 100 mL of sat. ammonium chloride solution to quench the reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[C:15]([F:21])=[C:14]([F:22])[C:12]=2[N:13]=1.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[NH2:33].CCN(C(C)C)C(C)C>C1COCC1>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[NH:33][C:18]([C:16]1[C:15]([F:21])=[C:14]([F:22])[C:12]2[N:13]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[NH:10][C:11]=2[CH:17]=1)=[O:19]
Reactant: Nc1ccc2ccccc2n1
Reactant: O=C(Cl)c1cc2[nH]c(-c3c(Cl)cccc3Cl)nc2c(F)c1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2ccccc2n1)c1cc2[nH]c(-c3c(Cl)cccc3Cl)nc2c(F)c1F
Temperature: 60 °C

Procedure:
To a stirred suspension of 2-(2,6-dichlorophenyl)-6,7-difluoro-3H-benzoimidazole-5-carbonyl chloride (150 mg, 0.38 mmol) and quinolin-2-ylamine (55 mg, 0.38 mmol) in THF (10 mL) was added DIPEA (0.2 ml, 1.14 mmol) and the solution was heated at 60° C. for 4 days. The reaction was quenched with water and aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using a gradient of heptane/EtOAc (4:1 to 100% EtOAc) to give 2-(2,6-dichlorophenyl)-6,7-difluoro-3H-benzoimidazole-5-carboxylic acid quinolin-2-ylamide as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 13.67 (s, 1H), 11.26 (s, 1H), 8.47 (d, 1H), 8.41 (d, 1H), 7.98 (d, 1H), 7.87 (d, 1H), 7.81 (d, 1H), 7.77 (m, 4H), 7.56 (m, 1H). MS (m/z) 469.1 (M+1); Retention time: 1.51 min (Method 10).
Reaction SMILES: [CH:1]1([CH:7]([C:14]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15]2)[NH:8][C:9](=O)[CH2:10][O:11][CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCCC1>[CH:1]1([CH:7]([C:14]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][CH2:16][CH2:17]2)[NH:8][CH2:9][CH2:10][O:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCC(=O)NC(C1CCCCC1)C1(c2ccccc2)CCC1
Solvent: C1CCOC1
Product: COCCNC(C1CCCCC1)C1(c2ccccc2)CCC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Borane-methyl sulphide complex (2.48 ml) was added dropwise to a refluxing solution of the acetamide (2.6 g) prepared above in tetrahydrofuran (6 ml). The mixture was heated under reflux for 2 hours left at room temperature for 16 hours and heated under reflux for 2 hours, cooled in ice, and hydrolysed by the slow dropwise addition of ice-water. The mixture was acidified, basified, and extracted with ether. The washed and dried extracts were evaporated to leave an oil which was purified by high pressure liquid chromatography to give N-[(cyclohexyl)(1-phenylcyclobutyl)methyl]-2-methoxyethylamine as a pale yellow oil the physical characteristics of which were not determined.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@H:12]2OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:31][CH3:32])[CH:4]=[CH:5]2.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C=O)C>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@H:12]2[N:37]2[C:33](=[O:43])[C:34]3=[CH:42][CH:41]=[CH:40][CH:39]=[C:35]3[C:36]2=[O:38])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:31][CH3:32])[CH:4]=[CH:5]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc2c3c1O[C@H]1[C@H](OS(=O)(=O)c4ccc(C)cc4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c3c1O[C@H]1[C@H](N4C(=O)c5ccccc5C4=O)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 80 °C
Reaction time: 15 h
Yield: 38.5 %

Procedure:
In 15 mL of DMF, 321 mg (0.70 mmol) of toluene-4-sulfonic acid-(4,5α-epoxy-3-methoxy-17-methyl-morphinan-6β-yl)-ester was dissolved, and 196 mg of potassium phthalimide was added thereto, followed by stirring the mixture at 80° C. for 15 hours and then at 140° C. for 20 hours. After allowing the reaction solution to cool to room temperature, water was added to the reaction mixture and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The thus obtained crude product was purified by silica gel column chromatography to obtain 116 mg (yield: 38%) of the captioned compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][CH:20]([OH:22])[CH3:21])[CH:12]=1.[OH-].[Na+]>ClCCl.O.C(N(CC)CC)C>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH:12]=1
Reactant: CC(O)CCCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)CCCc1cccnc1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
(according to J. W. Tilley, P. Levitan, J. Lind, A. F. Welton, H. J. Crowley, L. D. Tobias, M. O'Donnell J. Med. Chem. 1987, 30, 185-93; Swern oxidation of the alcohol) 59.5 ml of oxalyl chloride in 1.4 l of absolute dichloromethane are cooled to −60° C. and 96 ml of absolute DMSO (dissolved in 280 ml of absolute dichloromethane) are slowly added dropwise. After 15 minutes' stirring at −60° C., 93 g of 5-(3-pyridyl)-2-pentanol in 470 ml of the same solvent are added dropwise at ˜60° C. After 20 minutes' stirring, 396 ml of triethylamine are slowly added, the mixture stirred for a further 20 minutes at −60° C. and allowed to rise to room temperature. The reaction solution is finally poured into 700 ml of iced water, which has previously been combined with NaOH pellets. Once the phases have separated, the aqueous, alkaline phase is extracted 3 times with 300 ml portions of dichloromethane, the combined organic phases are washed 4 times with 500 ml portions of water, dried over potassium carbonate and evaporated. After distillation, 5a of b.p. 98-104° C., 3·101 Pa (0.2 Torr) is obtained in good yield.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([O:35][C:36](=[O:41])[CH2:37][C:38]([O-])=[O:39])[CH3:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:27]=[C:26]([CH3:28])[C:20]([O:21][CH2:22][CH2:23][CH2:24][NH:25][C:38](=[O:39])[CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:41])=[C:19]([CH2:29][CH3:30])[CH:18]=4)[N:13]=3)[CH:9]=[C:8]([O:31][CH3:32])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)NCCCOc1c(C)cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc1CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 118.2 %

Procedure:
To a solution of 3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)propan-1-amine (200 mg, 0.458 mmol), monoethylmalonate (91 mg, 0.687 mmol) and DIPEA (178 mg, 1.37 mmol) in DMF (5 mL) is added TBTU (191 mg, 0.596 mmol). The mixture is stirred at rt for 18 h. The solution is diluted with EA (50 mL) and washed twice with sat aq. NaHCO3 solution (50 mL) followed by brine (50 mL). The org. extract is dried over Na2SO4, filtered and concentrated to give crude ethyl 3-((3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy) propyl)amino)-3-oxopropanoate (298 mg) as a yellow oil; LC-MS: tR=1.19 min, [M+H]+=551.38. This material is dissolved in methanol (2 mL), THF (2 mL) and 2 N aq. LiOH (1 mL). The solution is stirred at rt for 2 h before it is concentrated, diluted with DCM (20 mL) and washed with 2 N aq. HCl (10 mL). The aq. phase is extracted three times with DCM (3×20 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC to give the title compound (105 mg) as a white solid; LC-MS: tR=1.14 min, [M+H]+=523.21; 1H NMR (CD3OD): δ 7.82 (s, 1H), 7.79 (s, 1H), 7.49 (s, 1H), 7.23 (s, 1H), 3.99 (s, 3H), 3.92 (t, J=6.2 Hz, 2H), 3.52 (t, J=6.9 Hz, 2H), 3.31 (s, 2H), 3.22-3.31 (m, 1H), 2.75 (q, J=7.5 Hz, 2H), 2.36 (s, 3H), 2.04-2.15 (m, 4H), 1.85-1.95 (m, 4H), 1.73-1.82 (m, 2H), 1.29 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[S:18][C:16]=2[N:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Product: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.