Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13](Cl)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1
Reactant: Clc1cc(Cl)c2nccn2n1
Reactant: Nc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(Nc2ccccn2)c2nccn2n1
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
A solution of 2-aminopyridine (0.388 g, 4.12 mmol) in 8 mL of N,N-dimethylformamide was treated with 60% sodium hydride/mineral oil (0.167 g, 4.18 mmol) and the lightly bubbling, pale yellow solution was stirred for 30 min., in which time it became a dark yellow cloudy solution. The solution was added via Pasteur pipette to a flask containing 6,8-dichloro-imidazo[1,2-b]pyridazine (0.310 g, 1.65 mmol), and the cloudy orange solution was stirred for 16 h then partitioned between 80 mL of a saturated aq. NH4Cl solution and 80 mL of ether. The organic layer was sequentially washed with two 40 mL portions of water and 40 mL of a saturated aq. NaCl solution; dried over MgSO4, filtered and concentrated to a pale yellow solid. Column chromatography (0->33% EtOAc/hexanes) afforded 0.141 g (35%) of (6-chloro-imidazo[1,2-b]pyridazin-8-yl)-pyridin-2-yl-amine as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Yield: 80.4 %

Procedure:
A mixture of 4.7 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate in 45 ml of ethyl acetate was hydrogenated in the presence of 500 mg of 10% palladium hydroxide on barium sulfate and 6.5 ml of quinoline and the mixture was filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral, dried and evaporated to dryness. The 5.1 g of oil residue were chromatographed over silica gel and eluted with a 70-30-1 mixture of hexane-ethyl acetate-acetic acid to obtain 3.8 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[(Z)3-hydroxy-3-oxo-1-propenyl]-cyclopropane-carboxylate
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:23](Cl)=[O:24])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1.N1C=CC=CC=1>ClCCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:22][O:21][CH2:20]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:23]([O:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[O:24])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: Oc1cccnc1
Reactant: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)Cl)C[C@@H]1C
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)Oc2cccnc2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
A solution of (S)-4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carbonyl chloride (0.050 g, 0.13 mmol) in 1,2-dichloroethane (1 mL) was added dropwise to a 50° C. solution of pyridine-3-ol (0.053 g, 0.26 mmol) and pyridine (1 mL) in 1,2-dichloroethane (20 mL). The resulting solution was stirred for 6 h at 50° C. and then concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1-20% methanol-dichloromethane) and then by preparative-HPLC (conditions: Column, SunFire™Prep C18OBD™, 19×150 nm; Mobile phase, A: 0.05% ammonium carbonate, B: acetonitrile; Detector, 220 and 254 nm) to afford (S)-pyridin-3-yl 4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.026 mg, 46%) as a white solid. 1H NMR (300 MHz, CD3OD) 1.17 (d, J=6.60 Hz, 3H), 2.27 (s, 3H), 3.50-3.79 (m, 1H), 4.35-4.45 (m, 1H), 5.02-5.25 (m, 5H), 5.55-5.65 (m, 1H), 7.39-7.49 (m, 2H), 7.51-7.57 (m, 1H), 7.78-7.83 (m, 1H), 7.97 (s, 1H), 8.10-8.19 (m, 2H), 8.47-8.50 (m, 1H), 8.52-8.56 (m, 1H). MS (ESI, pos. ion) m/z 434 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[Br:13]Br.OS([O-])=O.[Na+]>C(O)(=O)C>[Br:13][C:9]1[CH:10]=[C:5]([NH:1][C:2]([CH3:4])=[O:3])[CH:6]=[CH:7][C:8]=1[O:11][CH3:12]
Reactant: BrBr
Reactant: COc1ccc(NC(C)=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(NC(C)=O)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 10.0 g (60.5 mmol) of 4-acetaminoanisole (5) in 80 mL of acetic acid, was added dropwise 11.6 g (72.7 mmol) of bromine and maintaining internal temperature of the reaction below 50° C. After stirring for 1 h, the reaction mixture was poured into 400 mL of ice-water containing 1.2 g of NaHSO3. The mixture was stirred until yellow-red color disappeared and left at room temperature for overnight. The solid (product) was filtered, dried under vacuum at 70° C., and crystallized from ethanol to give 10.19 g (69% yield). 1H NMR (CDCl3) δ 7.67 (d, J=2.5 Hz, 1 H), 7.44 (dd, J=9, 2.5 Hz, 1 H), 7.1 (bs, 1 H, NH), 6.85 (d, J=9 Hz, 1 H), 3.87 (s, 3 H, OMe), 2.16 (s, 3 H, CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][S:8][C:9](=[N:25][CH3:26])[C:10]2([N:17]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[N:19]=[CH:18]3)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[OH:16])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:31]([O:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C:10]1([C:9]([S:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=1)=[N:25][CH3:26])[N:17]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[N:19]=[CH:18]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN=C(SCc1ccc(OC)cc1)C1(n2cnc([N+](=O)[O-])c2)CCCCC1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN=C(SCc1ccc(OC)cc1)C1(n2cnc([N+](=O)[O-])c2)CCCCC1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 11.7 %

Procedure:
A solution of 42.76 g (106 mmol) of the 2-((4-methoxybenzylthio)(methylimino)methyl) -2-(4-nitroimidazol-1-yl)cyclohexanol prepared in the Preparative Example 13 in 300 ml of tetrahydrofuran was dropped into a suspension of 5.13 g (60% dispersion in mineral oil, 128 mmol) of sodium hydride in 60 ml of tetrahydrofuran in a nitrogen atmosphere at room temperature in 20 minutes. The obtained mixture was further stirred at 50° C. for 10 minutes, followed by the addition of 13.2 ml (111 mmol) of benzyl bromide at 50° C. The obtained mixture was stirred at 50° C. for one hour and then under reflux by heating for 20 hours. The obtained brown suspension was cooled by allowing to stand, and poured onto ice-water. The obtained mixture was extracted with ethyl acetate. The obtained organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue (55.8 g) was purified by silica gel column chromatography [solvent: benzene/acetone (25:1 to 5:1)] to give 6.15 g of the title compound as a brown oil (yield: 12%).
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][C:12]2[S:16][C:15]([CH2:17][C:18](Cl)=[N:19][OH:20])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.[C:24]([C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1)#[CH:25].C(N(CC)CC)C>O>[CH3:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][C:12]2[S:16][C:15]([CH2:17][C:18]3[CH:25]=[C:24]([C:26]4[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=4)[O:20][N:19]=3)=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(Cc2ccc(CC(Cl)=NO)s2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(Cc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)s2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 35.2 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (5-(4-methyl-benzyl)-thiophen-2-yl)acetohydroximoyl chloride (250 mg, 0.894 mmol) described in Manufacturing Example 92-1-5 and 3-ethynyl-pyridin-2,6-diamine (50.0 mg, 0.376 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (157 μL, 1.13 mmol) at room temperature, which was stirred for 30 minutes at 60° C. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: heptane=2:1→3:1) to obtain the title compound (49.8 mg, 35.2%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>S(=O)(=O)(O)O.CO>[CH2:11]([NH:15][C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCCCN
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCCNC(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
Phenylacetic acid (16 g, 117.6 mmol) and methanol (60 ml) were added to a 250 ml three-necked flask, followed by addition of 5 drops of concentrated sulphuric acid. The resulting solution was heated to reflux for 6 hours. Then, the mixture was cooled to room temperature, followed by adding n-butylamine (12 ml, 121.4 mmol), and heated to reflux for another 3 hours. After the reaction was completed, it was cooled to room temperature. Most of the solvent was removed by rotary vacuum evaporation, 30 ml of water was added thereinto, and the mixture was extracted with ethyl acetate (3×80 ml). The combined organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure to yield 15.9 g of N-n-butylphenylacetamide (white solid, yield: 70.4%).
Reaction SMILES: CN(C)/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C@H:22]([CH3:25])[CH2:23][OH:24]>C1COCC1>[OH:24][CH2:23][C@H:22]([N:21]1[C:12]2[C:11](=[CH:16][C:15]([I:17])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1)[CH3:25]
Reactant: C[C@@H](N)CO
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Solvent: C1CCOC1
Product: CCOC(=O)c1cn([C@H](C)CO)c2ccc(I)cc2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a solution of ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (Intermediate 24, 1 g, 2.56 mmol) dissolved in THF (10 mL) was added (R)-2-aminopropan -1-ol (300 mg, 2.56 mmol). The reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was suspended in DMF (10 mL). Potassium carbonate was added (1.06 g, 7.67 mmol, 3 equiv.), and the reaction mixture was stirred at 70° C. for 18 h. The reaction mixture was cooled down to room temperature and quenched with 1 N HCl. The precipitate that formed was collected by filtration, washed with water and hexanes to provide (R)-ethyl 1-(1-hydroxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (446 mg, 39%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([O:32][CH3:33])[CH:24]=3)[CH2:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)(=O)C.CCOC(C)=O.[BrH:44]>>[BrH:44].[CH3:33][O:32][C:25]1[CH:24]=[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][CH:17]([N:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)[CH2:18]2)[CH:28]=[CH:27][C:26]=1[N+:29]([O-:31])=[O:30]
Reactant: COc1cc(N2CCCC(N3CCN(C(=O)OCc4ccccc4)CC3)C2)ccc1[N+](=O)[O-]
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCCC(N3CCNCC3)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-[1-(3-methoxy-4-nitro-phenyl)-piperidin-3-yl]-piperazine-1-carboxylic acid benzyl ester (300 mg, 0.66 mmol) in 4 M of hydrogen bromide in acetic acid (6 mL, 20 mmol) was heated at 40-45° C. for 45 min, then allowed to cool to room temperature while being stirred overnight. The orange homogenous solution was added dropwise to a vigorously stirred flask of EtOAc (50 mL) and the resulting precipitate was filtered, washed with EtOAc and dried in-vacuo to give 294 mg of an orange solid, used without further purification. MS=322 (M-HBr+1).
Reaction SMILES: S(=O)(=O)(O)O.O[CH:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[O:9][CH2:8]1.O>C1C=CC=CC=1>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]2[CH:7]=[CH:8][O:9][C:10]=2[CH:15]=1
Reactant: Cc1ccc2c(c1)OCC2O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc2ccoc2c1
Reaction time: 3 h

Procedure:
Sulfuric acid (0.2 ml) and 10.0 g of 3-hydroxy6-methyl-2,3-dihydrobenzofuran were dissolved in 200 ml of benzene and heated at reflux with the azeotropic removal of water. After 3 hours, the reaction mixture was added to water (500 ml) and extracted with ether. The combined ether extracts were washed with water and saturated aqueous sodium bicarbonate, dried with sodium sulfate and the solvent evaporated to give 6-methylbenzofuran.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[CH3:19][C:20]([OH:26])([CH2:23][CH2:24][CH3:25])[C:21]#[CH:22]>>[F:14][C:13]([F:16])([F:15])[C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:18])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:22]#[C:21][C:20]([OH:26])([CH3:19])[CH2:23][CH2:24][CH3:25])[CH:3]=1)=[O:17]
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(C)(O)CCC
Product: CCCC(C)(O)C#Cc1cccc(C(O)CCNC(=O)C(F)(F)F)c1

Procedure:
Sonogashira reaction of 25 with 3-methylhex-1-yn-3-ol yielded 2,2,2-trifluoro-N-(3-hydroxy-3-(3-(3-hydroxy-3-methylhex-1-ynyl)phenyl) propyl)acetamide as dark brown oil. Yield (0.611 g, 55%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.24-7.37 (m, 3H), 4.86 (m, 1H), 3.67-3.72 (m, 1H), 3.38-3.44 (m, 1H), 2.32 (bs, 1H), 1.94-2.01 (m, 3H), 1.71-1.76 (m, 2H), 1.59-1.62 (m, 1H), 1.53 (s, 3H), 0.99 (t, J=7.2, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([NH:5][C:6](OCC)=[O:7])=[S:4].[OH-].[Na+].Cl[O-].[Na+].[OH-].[NH4+:18]>O>[OH:7][C:6]1[N:5]=[C:3]([N:2]([CH3:11])[CH3:1])[S:4][N:18]=1
Reactant: [NH4+]
Reactant: CCOC(=O)NC(=S)N(C)C
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: CN(C)c1nc(O)ns1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 43 g of N,N-dimethyl-N'-ethoxycarbonyl-thiourea, 25 ml of sodium hydroxide and 250 ml of water and a solution of 1M sodium hypochlorite were simultaneously added at 0° to 5° C to 450 ml of concentrated ammonium hydroxide and the reaction mixture was stirred for 2 hours at 0° to 5° C and 3 hours at room temperature. The mixture was evaporated until it congealed into a mass and the mass was adjusted to a pH of 4 with concentrated hydrochloric acid. The mixture was extracted with chloroform and the extracts were dried over magnesium sulfate and were evaporated to dryness. The crystalline residue was washed with petroleum ether (B.p. = 40°-75° C) to obtain 11 g of 3-hydroxy-5-dimethylamino-1,2,4-thiadiazole melting at 142° C and having a Rf = 0.2 (acetone -CHCl3 - 1-1).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](OS(C)(=O)=O)([CH2:18][CH2:19][CH3:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:26]>C(O)C>[NH2:26][C:16]1([CH2:18][CH2:19][CH3:20])[CH2:17][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15]1
Reactant: N
Reactant: CCCC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCO
Product: CCCC1(N)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 16 h

Procedure:
7.5 g of 1-benzhydryl-3-methanesulphonyloxy-3-propyl-azetidine are added to a solution at approximately 5° C. of 100 cm3 of a solution of ammonia in ethanol (prepared from 15 g of ammonia in 100 cm3 of ethanol at 5° C., the temperature is allowed to rise to approximately 20° C. and the mixture is stirred for 16 hours at the same temperature. After concentration to dryness under reduced pressure (20 kPa) at approximately 40° C., the residue is taken up with 25 cm3 of water and 2.22 g of methanesulphonic acid. The aqueous phase is washed with twice 25 cm3 of ethyl ether, treated with 10 cm3 of 40% aqueous sodium hydroxide and extracted with 3 times 50 cm3 of dichloromethane; the combined organic extracts are washed with 10 cm3 of water saturated with sodium chloride, dried over magnesium sulphate and concentrated to dryness under the above conditions. 5.2 g of 3-amino-1-benzhydryl-3-propylazetidine are obtained in the form of an oily product, which is used without further purification for the subsequent steps.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])[CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].C(N(CC)CC)C.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([S:14]([F:19])([F:15])([F:16])([F:17])[F:18])[CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CON(C)C(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cc(NC(C)=O)cc(S(F)(F)(F)(F)F)c1

Procedure:
3-Amino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide (1.2 g) was dissolved in methylene chloride (15 ml), and triethylamine (0.7 ml) followed by acetic anhydride (1.75 ml) were added while stirring with exclusion of moisture. After stirring at RT for 3 h, water and saturated sodium hydrogencarbonate solution were added, the phases were separated and the methylene chloride phase was washed three times more with water, dried over magnesium sulfate, filtered and concentrated. The resulting product (1.3 g) was used in the next stage without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[OH-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(O)(=O)C>O>[CH2:18]([O:17][C:15]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C(=O)O)ccc1NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A mixture of 4-amino-3-methylbenzoic acid (35.1 g, 232 mmol) in water (400 mL) was treated with 2.5N NaOH (200 mL, 500 mmol) and benzyl chloroformate (37.0 mL, 259 mmol). After 1 h, 150 mL water was added, the resulting mixture was treated with glacial acetic acid (15 mL) and the solids collected by filtration. The filter cake was rinsed with water and the resulting solid taken up in ethyl acetate/2-methyl tetrahydrofuran. The organic was washed with brine, dried over MgSO4, filtered and concentrated. The resulting solid was dried under vacuum to give 45.1 g of the title compound. LCMS m/z=307.9 MH+, Rt=2.508 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7]Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30]N.[CH2:32]([N:34](CC)CC)C.O>CS(C)=O>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][CH2:32][NH:34][CH2:7][CH:6]([O:5][C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=1[O:2][CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1ccccc1OC(CCl)c1ccccc1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1OC(CNCCCc1c[nH]c2ccc(F)cc12)c1ccccc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 13.3 %

Procedure:
A solution of 2-(2-methoxy-phenoxy)-2-phenyl-ethylchloride (0.71 g, 2.7 mmol), 2-(5-fluoro-1H-indol-3-yl)-ethylamine (1.04 g, 5.4 mmol) and triethylamine (0.75 ml, 5.4 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 12 hours at 90° C. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×100 ml), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (7% methanol-methylene choride plus ammonium hydroxide) afforded 0.15 g (13%)of product of product as a yellow oil. The citrate salt was prepared in ethyl ether: mp 64.5-67° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16]S(C(C)(C)C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[NH2:16][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[CH2:26][CH2:27]2
Reactant: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6′-bromo-1′-(1,1-dimethylethylsulfinamido)-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-carboxylate (6) (62.8 mg, 0.129 mmol) in MeOH (5 mL) was added a 4 M HCl solution in dioxane (2 mL). The resulting mixture was stirred for 30 min. Solvent was removed under reduced pressure, and the residue 7 was used for next step without further purification. MS ESI+ve m/z 382 (M+H)+.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:33])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[S:29][CH:30]=[CH:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.B(Br)(Br)Br.ClCCl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>ClCCl>[CH3:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]2[CH:11]=[C:6]([CH:7]=[C:8]([C:23]3[NH:27][C:26]([C:28]4[S:29][CH:30]=[CH:31][N:32]=4)=[CH:25][CH:24]=3)[CH:9]=2)[O:5][C@@H:4]([CH3:33])[CH2:3][OH:2])=[CH:18][CH:17]=1)(=[O:21])=[O:20]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3nccs3)[nH]2)c1
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
Under nitrogen atmosphere, 2-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole (88.8 mg, 0.183 mmol) synthesized in Example (1i) was dissolved in dichloromethane (5 mL), and a boron tribromide/dichloromethane solution (1.0M, 220 μL, 0.22 mmol) was added at −78° C. Subsequently, the temperature was brought back to room temperature, followed by stirring for 30 minutes. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-50%) to afford the desired compound (52.2 mg, yield 61%) as a pale yellow solid.