Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)=[O:10]>CCOCC.ClCCl>[Br:17][C:13]1[CH:12]=[C:11]([C:9](=[O:10])[CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1cccc(Br)c1
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CN1CCOCC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
To a solution of morpholine (4.72 mL, 54.0 mmol) in ether (40 mL) cooled at 0° C., was added dropwise 2-bromo-1-(3-bromophenyl)ethanone (7.53 g, 27.0 mmol) in a mixture of ether (100 mL) and dichloromethane (100 mL). The reaction mixture was then warmed to room temperature, stirred at room temperature for 1 h, and concentrated under reduced pressure to give white solid. The white solid was dissolved in dichloromethane (200 mL) and washed with 5% NaHCO3 (200 mL) and brine (200 mL). The organic layer was dried (MgSO4) and concentrated to yield 1-(3-bromophenyl)-2-(4-morpholinyl)ethanone 7.8 g (100%) as a white solid, which was used without purification. MS (ESI): 284.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.Cl>C(O)(C)C>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][N:18]=[C:17]2[NH:1][C:2]1[CH:3]=[C:4]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9]
Reactant: CNS(=O)(=O)c1ccc(N(C)C)c(N)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccc(N(C)C)c(Nc2ncnc3cc(OC)c(OC)cc23)c1
Yield: 38.7 %

Procedure:
To a mixture of 3-amino-4-(dimethylamino)-N-methylbenzenesulfonamide (0.100 g, 0.434 mmol) and 4-chloro-6,7-bis(methyloxy)quinazoline (0.075 g, 0.334 mmol) in isopropanol (2 mL) was added HCl (0.334 mL, 0.334 mmol). The resulting mixture was then subjected to microwave irradiation (150° C., 6 bar) for 15 minutes. The mixture was then concentrated and purified via column chromatography (5-10% MeOH/CH2Cl2) to give an orange solid that was triturated with EtOAc and dried to afford 3-{[6,7-bis(methyloxy)-4-quinazolinyl]amino}-4-(dimethylamino)-N-methylbenzenesulfonamide (54 mg, 35% yield) as orange crystals.
Reaction SMILES: [Br:1]Br.[CH:3]1([C@H:6]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=3)[C:20](=[O:28])[N:19]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C:18]=2[CH3:35])=[O:16])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH2:5][CH2:4]1>ClCCCl>[CH:3]1([C@H:6]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=3)[C:20](=[O:28])[N:19]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[C:18]=2[CH2:35][Br:1])=[O:16])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH2:5][CH2:4]1
Reactant: BrBr
Reactant: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CC2)c2cccc(F)c2c(=O)n1-c1cccnc1
Solvent: ClCCCl
Product: O=C(N[C@H](c1cccc(F)c1)C1CC1)c1c(CBr)n(-c2cccnc2)c(=O)c2c(F)cccc12
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Bromine (220 mg, 1.3 mmol) in 0.5 ml 1,2-dichloroethane was added to 8-fluoro-3-methyl-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (200 mg, 0.450 mmol) in 1,2-dichloroethane (5 mL) at 60° C. The reaction mixture was stirred for 15 minutes at 60° C. The reaction mixture was concentrated in vacuo to give crude 3-bromomethyl-8-fluoro-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide, which was used in the next step without purification.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:16]2[C:10]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[N:9]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.C(Cl)Cl.CCOCC>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][OH:2])[N:9]=[C:10]3[C:16]=2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[CH:19][CH:20]=1
Reactant: COC(=O)CCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Product: OCCCCCn1nc2c(c1-c1ccc(Cl)cc1)CCNCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 12 %

Procedure:
5-[3-(4-Chloro-phenyl)-5,6,7,8-tetrahydro-4H-1,2,6-triaza-azulen-2-yl]-pentanoic acid methyl ester (Example 82, 0.009 g) was dissolved in 9:1 Et2O/CH2Cl2 (3 mL) and the solution was added slowly to a stirred suspension of lithium aluminum hydride (2 mg) in 5 mL of anhydrous Et2O. After stirring at RT for 6 h, the reaction was quenched with 2 mL of water. The mixture was treated with 2 mL of 1 N NaOH, followed by another 2 mL of water. The mixture was then filtered through diatomaceous earth. The organic layer was separated, dried over MgSO4, and concentrated. After further drying via vacuum line, the resulting oil was dissolved in 2 mL of 9:1 CH2Cl2/MeOH and treated with 3 mL of 1 N HCl in Et2O. After 4 h, the volatiles were removed in vacuo. The crude oil was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.001 g of the title compound as a colorless oil. MS (ESI): exact mass calculated for C18H24ClN3O, 333.16. found, m/z 334.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.52 (m, 2H), 7.32-7.30 (m, 2H), 3.95 (t, J=7.1 Hz, 2H), 3.44 (t, J=6.6 Hz, 2H), 3.13-3.09 (m, 2H), 3.03-3.00 (m, 2H), 2.98-2.95 (m, 2H), 2.61-2.58 (m, 2H), 1.70-1.64 (m, 2H), 1.40-1.35 (m, 2H), 1.20-1.16 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1I)=[O:5])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[C:20]1[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(CC)c(C#N)c1I
Reactant: OB(O)c1ccc(Br)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(Br)cc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
Add 4-cyano-5-ethyl-3-iodo-thiophene-2-carboxylic acid ethyl ester (268.1 g, 0.8 mol) and 4-bromophenyl boronic acid (173.5 g, 0.86 mol), to a solution of bis(tri-o-tolylphosphine)palladium (II) diacetate (7.00 g, 0.008 mole) in acetonitrile(1.9 L) within a 5000 mL, 3-neck round-bottom flask equipped with an overhead stirrer, internal temperature probe, heating mantle, and a glycol-cooled condenser fitted with a nitrogen inlet. Add a solution of sodium carbonate (169.6 g, 1.6 mol) in water (1.3 L) and stir the reactor contents at room temperature while sweeping the headspace with nitrogen for 10 min. the reaction apparatus was then set for a nitrogen by-pass and the reaction mixture was heated to 73° C. Observe that HPLC analysis indicates substantial (>98%) consumption of 4-bromophenyl boronic acid and 4-cyano-5-ethyl-3-iodo-thiophene-2-carboxylic acid ethyl ester (flow rate: 1.5 mL/min; detection: 210 nm; mobile phase: isocratic 65/35 (v/v) acetonitrile/0.1% trifluoroacetic acid in water; column: Zorbax® SB-Phenyl; 4.6 mm×25 cm; 5 microns at 35 C). Cool the mixture to 23° C. and separate the phases. Extract the aqueous phase twice with methyl t-butyl ether (300 mL). Combine the organic phases and concentrate under reduced pressure to an oil. Dissolve the oil in a mixture of heptane (500 mL) and methyl t-butyl ether (500 mL). This results in separation of an immiscible water phase which is separated, extracted with methyl t-butyl ether (100 mL) and discarded. The organic phases are combined and concentrated under reduced pressure to an oil. The oil is dissolved in a mixture of heptane (500 mL) and methyl t-butyl ether (300 mL) and the solution is transferred to a flask set for atmospheric distillation at 83° C. The distillation is continued until distillation at 83° C. and atmospheric pressure stops. The resulting solution is cooled to 30° C. and is seeded with 3-(4-Bromo-phenyl)-4-cyano-5-ethyl-thiophene-2-carboxylic acid ethyl ester, then the mixture is further cooled to 18° C. Filter the resulting suspension and wash the filter cake with heptane (3×100 mL). The resulting cake is air-dried and then transferred to a vacuum oven (40° C.) to afford the title compound (263 g, 90.4% yield). The title compound may be additionally purified as follows if desired.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.C(NCC)(C)C.[CH3:33][O:34][CH2:35]Cl>C(Cl)Cl>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][CH:9]([O:12][CH2:33][O:34][CH3:35])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COCCl
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(O)CCC3(C)C)cc1
Agent: CCNC(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(OCOC)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (+/−) ethyl 4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate (Compound D5, 49.7 mg, 0.141 mmol) in 4 ml of dry CH2Cl2 at 0° C. was added isopropyl ethyl amine (0.152 ml, 0.847 mmol) followed by chloromethyl methyl ether (0.0323 ml, 0.423 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed with NaHCO3 (sat.), and brine. The organic layer was dried (MgSO4). The solvent was removed under reduced pressure, the residue was purified by flash chromatography (silica, ethyl acetate:hexane, 1:3) to afford the title compound as a red oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.Cl[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-])=O)=[CH:13][N:12]=1>>[CH3:17][C:16]1[CH:15]=[C:14]([NH2:18])[CH:13]=[N:12][C:11]=1[N:5]1[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]1
Reactant: FC(F)(F)c1cn[nH]c1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Product: Cc1cc(N)cnc1-n1cc(C(F)(F)F)cn1

Procedure:
The title compound was prepared by a method analogous to that described for Intermediate (6) using 4-trifluoromethyl-1H-pyrazole and 2-chloro-3-methyl-5-nitropyridine. 1H NMR (400 MHz, CDCl3, δ): 8.21 (s, 1H), 7.85 (s, 1H), 7.75 (d, J=2.4 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 3.85 (s, 2H), 2.32 (s, 3H).
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[CH:7]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH2:20][C:21](OCC)=[O:22])[N:15]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:14]2=[O:30])([CH3:9])[CH3:8]>C(O)C>[CH2:26]([N:15]1[C:14](=[O:30])[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH:7]([CH3:8])[CH3:9])[CH:12]=2)[CH:16]1[CH2:20][C:21]([NH:5][C:4]([NH2:6])=[NH:3])=[O:22])[CH:27]([CH3:29])[CH3:28]
Reactant: CCOC(=O)CC1c2ccc(OC(C)C)cc2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: CC(C)CN1C(=O)c2cc(OC(C)C)ccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
N-[2-(2-Isobutyl-5-isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 9, starting with 20 cm3 of absolute ethanol, 0.086 g of sodium, 0.36 g of guanidinium chloride and 0.42 g of ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 18 hours and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is then taken up in 50 cm3 of ethyl acetate and the organic phase is washed twice with 30 cm3 of aqueous 1 N sodium hydroxide solution and then twice with 50 cm3 of aqueous 1N hydrochloric acid solution. The acidic aqueous phase is treated with aqueous 30% sodium hydroxide solution to pH 14, and then extracted with 3 times 30 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of saturated brine, dried over magnesium sulfate and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is triturated with diethyl ether and then filtered and dried in a desiccator under reduced pressure (2 Pa) at a temperature in the region of 40° C. for 2 hours. 0.0175 g of N-[2-(2-Isobutyl-5-isopropoxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is thus obtained in the form of a white powder melting at 208° C. 1H NMR (300 MHz, d6-(CD3)2SO, δ in ppm): 0.75 (d, J=6.5 Hz: 3H); 0.90 (d, J=6.5 Hz: 3H); 1.30 (mt: 6H); 2.01 (mt: 1H); 2.40 (dd, J=15 and 6.5 Hz: 1H); 2.65 (dd, J=15 and 6.5 Hz: 1H); 3.00 (dd, J=13.5 and 5.5 Hz: 1H); 3.53 (dd, J=13.5 and 10 Hz: 1H) 4.68 (mt: 1H); 4.96 (broad t, J=6.5 Hz: 1H); from 6.40 to 7.10 (broad multiplet: 2H); 6.98 (dd, J=8.5 and 2 Hz: 1H); 7.09 (d, J=2 Hz: 1H); 7.54 (d, J=8.5 Hz: 1H); from 7.60 to 8.20 (broad multiplet: 2H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Na+].[Cl-].[CH2:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][C:10](=[O:19])[N:9]3[CH2:8]1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1.Cl>C(O)C.O>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([C:15]2[CH:14]=[C:13]3[C:18]4=[C:17]([CH2:7][CH2:8][N:9]4[C:10](=[O:19])[CH2:11][CH2:12]3)[CH:16]=2)=[O:28])[CH:23]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C1CCc2cccc3c2N1CC3
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: O=C(c1cccnc1)c1cc2c3c(c1)CCN3C(=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 22.4 %

Procedure:
To a molten mixture of AlCl3 (8.0 g, 60.0 mmol) and NaCl (2.34 g, 40.0 mmol) at 150° C. was added 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-one (1.79 g, 10.0 mmol) and thereafter nicotinoylchloride hydrochloride salt (1.96 g, 11.0 mmol) portionwise. After stirring for 15 min and cooling to room temperature, excess aluminum chloride was decomposed by the addition of a chilled mixture of 10 ml concentrated hydrochloric acid and 200 ml water. Neutralization with NaHCO3 solution and subsequent extraction with ethyl acetate (3×100 ml), followed by drying over MgSO4 and removal of the solvent gave the crude product. Purification by crystallization from ethanol gave the acylation product (624 mg, 2.24 mmol, 22%) as a yellow solid, mp (ethanol) 147° C. 1H-NMR (500 MHz, CDCl3): δ=2.72 (t, 3J=7.9 Hz, 2H), 3.02 (t, 3J=7.9 Hz, 2H), 3.23 (t, 3J=8.6 Hz, 2H), 4.14 (t, 3J=8.6 Hz, 2H), 7.44 (ddd, 3J=7.9 Hz, 3J=4.7 Hz, 5J=1.0 Hz, 1H), 7.53 (s, 1H), 7.58 (s, 1H), 8.06 (m, 1H), 8.78 (dd, 3J=5.0 Hz, 4J=1.9 Hz, 1H), 8.92 (dd, 4J=1.9 Hz, 5J=0.8 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ=24.2, 27.3, 31.4, 45.8, 199.9, 123.4, 126.1, 128.9, 129.4, 132.3, 134.0, 137.0, 146.1, 150.4, 152.4, 167.8, 193.6. MS m/z 278.79 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH:13]=[CH:14][S:15][C:3]=12.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[S:15][CH:14]=[CH:13][C:4]3=[N:5][CH:6]=2)=[O:10])=[CH:19][CH:18]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccsc2c1O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccsc2c1O
Temperature: 190 °C

Procedure:
A mixture of ethyl 7-hydroxythieno[3,2-b]pyridine-6-carboxylate (223 mg) prepared as described in the literature (Elliott, R. L.; O'Hanlon, P. J.; Rogers, N. H. Tetrahedron 1987, 43, 3295-3302) and 4-chlorobenzylamine (1.2 mL) was heated to 190° C. for 1 h. The crude product was purified by column chromatography (CH2Cl2/methanol, 100/1; 50/1; 33/1) and the resulting solid was recrystallized from glacial acetic acid/water to afford 84 mg of the title compound as a tan solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:25][C@@:23]3([CH3:24])[C@@H:19]([CH2:20][C@@H:21]([CH3:31])[C@@H:22]3[C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C@H:18]3[C:9]2=[C:10]2[C:15]([CH2:16][CH2:17]3)=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:28]1([C:26]([C@H:22]2[C@H:21]([CH3:31])[CH2:20][C@H:19]3[C@H:18]4[C:9]([C@@H:8]([C:5]5[CH:4]=[CH:3][C:2]([C:36]6[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=6)=[CH:7][CH:6]=5)[CH2:25][C@:23]23[CH3:24])=[C:10]2[C:15](=[CH:14][C:13](=[O:32])[CH2:12][CH2:11]2)[CH2:16][CH2:17]4)=[O:27])[CH2:29][CH2:30]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Reactant: OB(O)c1ccncc1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4ccncc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Yield: 44 %

Procedure:
(11β,16α,17β)-11-(4-Bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one and 4-pyridinylboronic acid were applied as described in example 1 step h. Purification by HPLC followed by crystallisation (acetonitrile/water) gave the product (44% yield). 1H NMR (400 MHz, CDCl3): δ 0.33 (s, 3H), 0.84-2.85 (m, 24H), 4.46 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.26-7.30 (m, 2H), 7.48-7.50 (m, 2H), 7.55-7.59 (m, 2H), 8.63-8.65 (m, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[Na].[CH3:22][SH:23].CN(C=O)C>O>[CH3:22][S:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 50 °C
Yield: 68.2 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g of methyl mercaptan sodium salt and 2 ml of DMF was stirred while heating at 50° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to give 0.21 g of 2-[3-(methylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 40”).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O.C(N(CC)CC)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nccs1)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Procedure-A: To a mixture of 2-(4-cyclopropanesulfonylphenyl)-2-(2,4-difluorophenoxy)acetic acid (obtained in step III), 2-aminothiazole, HOBt, and EDCI, in methylene chloride, was added triethyl amine. The resulting mixture was stirred at room temperature overnight followed by dilution with methylene chloride. The reaction mixture was poured into water; organic layer was washed with water, brine, dried over sodium sulfate, and the organic solvent evaporated to get a residue which was purified by preparative TLC or column chromatoghaphy to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)=O>C1(O)C=CC=CC=1>[F:1][C:2]([F:18])([F:17])[C:3]1[N:8]2[C:9]3[C:14]([CH:15]=[CH:16][C:7]2=[N:6][N:5]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=C(NNc1ccc2ccccc2n1)C(F)(F)F
Solvent: Oc1ccccc1
Product: FC(F)(F)c1nnc2ccc3ccccc3n12

Procedure:
2-Hydrazinoquinoline (25.0 grams), 50 milliliters of trifluoroacetic acid, and 250 milliliters of xylene were combined in a 500-milliliter three-necked flask equipped with a condenser. The reaction mixture was refluxed overnight. In the morning it was allowed to cool and the solvent was stripped off, yielding 10 grams of a compound determined to be 2-(2-(trifluoroacetyl)hydrazino)quinoline. It was placed in 40 milliliters of phenol and refluxed for 20 hours. The reaction mixture was then steam distilled to remove the phenol, yielding the desired 1-trifluoromethyl-s-triazolo(4,3-a)quinoline product. It was recrystallized from ethanol, m.p., 133.5°-4.5°C.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][C:15]1[NH:16][CH:17]=[N:18][CH:19]=1)[C:4]1[C:5]([F:13])=[C:6]([C:9]([F:12])=[CH:10][CH:11]=1)[CH:7]=[O:8])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([N:3]([CH2:14][C:15]1[NH:16][CH:17]=[N:18][CH:19]=1)[C:4]1[C:5]([F:13])=[C:6]([CH2:7][OH:8])[C:9]([F:12])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCN(Cc1cnc[nH]1)c1ccc(F)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN(Cc1cnc[nH]1)c1ccc(F)c(CO)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 579.4 %

Procedure:
To a stirred solution of 3-[ethyl-(3H-imidazol-4-ylmethyl)-amino]-2,6-difluoro-benzaldehyde (0.10 g, 0.39 mmol) in methanol (3 ml) was added sodium borohydride (0.06 g, 1.56 mmol) and the mixture was stirred at room temperature for 5 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: methanol/dichloromethane gradient) to yield a colourless gum (604 mg, 76%); MS (ISP): 268.3 ((M+H)+.).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([C:20](Cl)=[O:21])[N:14]=[N:13]2)=[CH:8][CH:7]=1>CC(C)=O.C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH:17]([CH3:19])[CH3:18])=[C:15]([C:20]([N:1]=[N+:2]=[N-:3])=[O:21])[N:14]=[N:13]2)=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1c(C(=O)Cl)nnn1-c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C)c1c(C(=O)N=[N+]=[N-])nnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium azide (610 mg in 2.5 mL of H2O, 9.39 mmol) was added to a cooled (0° C.) solution of 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carbonyl chloride in acetone (7.5 mL). The resulting mixture was stirred at room temperature for 30 min, diluted with CH2Cl2 (100 mL), washed with water (50 mL) and brine (50 mL), dried (MgSO4), and concentrated in vacuo to give the crude 1-(4-chlorophenyl)-5-isopropyl-triazole-4-carbonyl azide (777 mg) which was used in the next step without further purification.