Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)CCN(C)C.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].C(N(CC)CC)C.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)(Cl)Cl.ClCCl.[Ti](Cl)(Cl)(Cl)Cl.O>[O:12]=[C:11]([CH:13]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:10][C:9]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(=O)C=Cc1ccccc1

Procedure:
A solution of 0.020 moles of titanium tetrachloride in 5 ml of carbon tetrachloride was added dropwise at room temperature to 50 ml of dichloromethane. The mixture was cooled to 0° and a solution of 0.020 moles of N,N,N',N'-tetramethylethylenediamine in 5 ml of dichloromethane was added dropwise over 15 minutes. After the mixture was stirred an additional hour, a solution of 0.015 moles of ethyl acetoacetate in 10 ml of dichloromethane was added dropwise over 15 minutes. After the mixture was stirred an additional hour, a solution of 0.030 moles of triethylamine in 15 ml of dichloromethane was added over 10 minutes. After thirty minutes, a solution of 0.015 moles of benzaldehyde in 10 ml of dichloromethane was added over 10 minutes. The reaction mixture was stirred for 20 hours. Water (25 ml) was added and the resultant two-phase mixture was stirred for two hours. After the layers were separated, the aqueous layer was extracted with 50 ml of ethyl acetate. The ethyl acetate extract was combined with the initially separated organic layer, dried over sodium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel gave the title compound as a solid. The material prepared by this procedure was identical to that prepared by the method of Example 1, as indicated by the reverse phase chromatographic method described in Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][NH:5][CH:6]([CH3:8])[CH3:7].[S:13](N)(N)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:7][CH:6]([N:5]1[CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[NH:1][S:13]1(=[O:15])=[O:14])[CH3:8]
Reactant: CC(C)NCc1ccccc1N
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Product: CC(C)N1Cc2ccccc2NS1(=O)=O

Procedure:
To a 500 ml 3-necked round bottom flask equipped with reflux condenser, thermometer, magnetic stirrer bar and nitrogen bubbler was charged 2-amino-N-(1-methylethyl)-benzylamine (148.0 g, 0.907 mol), sulfamide (87.9 g, 0.907 mol) and pyridine (975 ml) and the stirred solution heated at reflux for 5 hours under nitrogen (reaction followed by GC and HPLC). The reaction mixture allowed to cool, then pyridine removed under reduced pressure. The residue was dissolved in 5N hydrochloric acid (1000 ml) and ethyl acetate (1000 ml) and the acidic layer was extracted with further ethyl acetate (5×1000 ml). The combined organic layer was washed with 5N hydrochloric acid (250 ml), then extracted with 2N sodium hydroxide (3×1000 ml), the combined aqueous layer washed with diethyl ether (2×500 ml). Ice was then added to the aqueous layer, followed by addition of 5N hydrochloric acid with cooling and stirring of the suspension to pH 1. The oily suspension was stirred at room temperature overnight, the solid filtered and dried at room temperature under vacuum to leave an off-white solid, 3,4-dihydro-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-2,2-dioxide.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([O:10][CH3:11])[CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][C:5]=1[CH2:6][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1cc(O)ccc1C=O
Reactant: C1CCNCC1
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCl
Product: COc1cc(O)ccc1CN1CCCCC1
Yield: 30.8 %

Procedure:
To a pre-stirred solution of 4-hydroxy-2-methoxybenzaldehyde (1.02 g, 6.7 mmol), titanium isopropoxide (2.14 mL, 7.0 mmol) and piperidine (0.70 mL, 7.0 mmol) in DCM (20 mL) was added sodium triacetoxyborohydride (2.84 g, 13.4 mmol) in portions. After 3 h the reaction mixture was quenched by the addition of methanol (1.0 mL) and then the solvents were removed under reduced pressure to afford a residue. The resultant residue was then loaded onto an SCX-2 cartridge (10 g) and eluted with 2N ammonia in methanol to afford the title compound (456 mg, 30%). 1H NMR (CD3OD, 300 MHz): 7.17 (d, J=8.3 Hz, 1H), 6.51 (d, J=2.3 Hz, 1H), 6.43 (dd, J=8.2, 2.2 Hz, 1H), 4.07 (s, 2H), 3.84 (s, 3H), 3.16-2.99 (m, 4H), 1.84-1.73 (m, 4H), 1.67-1.56 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:20])([F:19])[C:12]3[N:17]=[N:16][C:15]([NH2:18])=[CH:14][CH:13]=3)=[N:9][N:10]=2)[CH:7]=1.P([O-])([O-])(O)=O.[Na+].[Na+].Br[CH2:29][C:30]([NH:32][C:33]([CH:35]1[CH2:37][CH2:36]1)=[O:34])=O.[I-].[K+]>CN(C)C(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:20])([F:19])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:29]=[C:30]([NH:32][C:33]([CH:35]5[CH2:37][CH2:36]5)=[O:34])[N:18]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: O=C(CBr)NC(=O)C1CC1
Reactant: Nc1ccc(C(F)(F)c2nnc3ccc(Br)cn23)nn1
Agent: O=P([O-])([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1)C1CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 48.5 %

Procedure:
To a mixture of 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)pyridazin-3-amine (21.8 g, 63.9 mmol) and sodium hydrogenphosphate (27.2 g, 192 mmol) in N,N-Dimethylacetamide (250 ml) were added N-(2-bromoacetyl)cyclopropanecarboxamide (19.75 g, 96 mmol) and potassium iodide (10.61 g, 63.9 mmol) at room temperature. The reaction mixture was stirred for 5 h at 100° C. Reaction mixture cooled to room temperature, diluted with EtOAc (1000 ml) and washed with brine solution (5×), dried over Na2SO4, volatiles evaporated and the residue was purified by combiflash (2 to 30% MeOH in dichloromethane over 120 min). Product containing fractions were combined and concentrated to get N-(6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (13.9 g, 31.0 mmol, 48.5% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.92 (s, 1H), 8.18-8.35 (m, 2H), 7.92-8.06 (m, 1H), 7.61-7.80 (m, 2H), 1.91-2.02 (m, 1H), 0.78-0.89 (m, 4H). ESI-MS:m/z 450.0 (M+2H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1)#[N:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:29].[Ca+2].[OH-:31]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8](=[O:31])(=[O:29])[C:7]=2[CH:17]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1C=C2
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1C=C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.4 G. 3-cyanodibenzo[b,f]thiepin (0.023 mole) are dissolved in 300 cc. methylene chloride and 15.87 g. m-chlorperbenzoic acid (0.092 mole) are added in portions. The resulting solution is stirred at room temperature for one hour, then excess calcium hydroxide is added. The mixture is filtered through celite and the filtrate is stripped to dryness. The yellow solid is triturated in benzene and filtered. One obtains 5.46 g. (89%) of the sulfone, m.p. 229° C.-231° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH3:30])([CH3:29])[C:13]([NH:15][CH:16]1[CH:23]2[CH2:24][C:19]3([C:26](O)=[O:27])[CH2:20][CH:21]([CH2:25][CH:17]1[CH2:18]3)[CH2:22]2)=[O:14])(=[O:10])=[O:9].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:53]([NH:55][CH2:56][CH3:57])[CH3:54]>O.C(Cl)Cl>[CH2:53]([N:55]([CH2:56][CH3:57])[C:26]([C:19]12[CH2:18][CH:17]3[CH2:25][CH:21]([CH2:22][CH:23]([CH:16]3[NH:15][C:13](=[O:14])[C:12]([NH:11][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:9])=[O:10])([CH3:29])[CH3:30])[CH2:24]1)[CH2:20]2)=[O:27])[CH3:54]
Reactant: CCNCC
Reactant: CC(C)(NS(=O)(=O)c1ccccc1Cl)C(=O)NC1C2CC3CC1CC(C(=O)O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)C12CC3CC(C1)C(NC(=O)C(C)(C)NS(=O)(=O)c1ccccc1Cl)C(C3)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
In a 25-mL flask, 4-[2-(2-chloro-benzenesulfonylamino)-2-methyl-propionylamino]-adamantane-1-carboxylic acid (100 mg, 0.22 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (85 mg, 0.44 mmol), 1-hydroxybenzotriazol (60 mg, 0.44 mmol), and methylenechloride (10 mL) were charged, and stirred for 15 minutes at room temperature. Then, diethylamine (48 mg, 0.66 mmol) was added thereto, followed by stirring for 12 hours at room temperature. Purified water (5 mL) was added thereto, followed by stirring for 5 minutes. Then, the organic layer was separated, and added with magnesium sulfate (50 mg) so as to remove remaining moisture. The filtrate was concentrated and obtained as a residue. The mixture was purified with column chromatography (MC/MeOH=20:1) to obtain 4-[2-(2-chloro-benzenesulfonylamino)-2-methyl-propionylamino]-adamantane-1-carboxylic acid diethylamide (46 mg, 41.0%).
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.[C:6]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14]C=1)([CH3:9])([CH3:8])[CH3:7].S(Cl)(Cl)(=O)=O>O>[C:6]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][C:1]=1[Cl:5])([CH3:9])([CH3:8])[CH3:7]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cccc(O)c1
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1cc(O)ccc1Cl
Temperature: 70 °C
Reaction time: 48 h

Procedure:
Into 30 ml of carbon tetrachloride were dissolved 9 g of 3-tert-butylphenol and the mixture was heated up to 70° C. With stirring at this temperature, 10.5 g of sulfuryl chloride were added dropwise to the mixture. After completion of this dropwise addition, the reaction mixture was subjected to stirring over a period of 48 hours at 70° C. After cooling the reaction mixture down to room temperature, the reaction mixture was poured into cold water and the resultant product was extracted with carbon tetrachloride. After drying over anhydrous calcium chloride, carbon tetrachloride of the extraction solution was distilled off under reduced pressure, and the residue was purified through a column chromatography (employing silica gel as carrier and benzene as developing solvent) to give 1.3 g of 3-tert-butyl-4-chlorophenol, having the following properties.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:16]=[C:15]2[CH:28]=O.[BH3-]C#N.[Na+]>CO>[NH2:10][C:8]([C:7]1[NH:6][CH:5]=[N:4][C:3]=1[NH:2][CH2:28][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([F:11])[CH:13]=2)[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:16]=1)=[O:9]
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2cc(F)ccc21
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)n1cc(CNc2nc[nH]c2C(N)=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
A reaction mixture of 4-amino-5-imidazolecarboxamide hydrochloride (0.20 g, 1.23 mmol), tert-butyl 5-fluoro-3-formyl-1H-indole-1-carboxylate (0.39 g, 1.48 mmol, obtained from Example 6(a)), and NaCNBH3 (0.078 g, 1.23 mmol) in methanol (3 mL) was stirred at r.t. for 1 h. Additional 5-fluoro-3-formyl-indole-1-carbonylic acid tert-butyl ester (0.31 equiv.) was added and after stirring at r.t. for 1 h the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (heptane/ethyl acetate (1:0 to 0:1) then CH2Cl2), obtaining 0.32 g (70%) of the title compound. MS (ESI) m/z 374 (M+1).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O)([O-:3])=[O:2].[NH3:11]>CO>[N+:1]([CH2:4][CH2:5][CH2:6][C:7]([NH2:11])=[O:9])([O-:3])=[O:2]
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: N
Solvent: CO
Product: NC(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
To a solution of methyl 4-nitrobutyrate (8.83 g, 60 mmol) in methanol (20 mL) at 0° C. was added a solution of ammonia in methanol (7N, 30 mL). The solution was then warmed to room temperature and stirred at for 72 h. The solvent was evaporated and the residue was re-crystallized from ethyl acetate to give the title product (6.2 g, 78%). 1H NMR (acetone-d6): 6.86 (bs, NH, 1H), 6.28 (bs, NH, 1H), 4.59 (t, J=6.9 Hz, 2H), 2.36-2.30 (m, 2H), 2.28-2.20 (m, 2H).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(O[Na])(C)(C)C>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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(N3CCOCC3)cc2)C(=O)O1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
A flask was charged with (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (400 mg, 0.96 mmol), morpholine (100 mg, 1.15 mmol) and t-BuONa (129 mg, 1.34 mmol) and Pd2(dba)3 (9 mg, 0.01 mmol) and BINAP (6 mg, 0.01 mmol) and toluene. The flask was heated to 80° C. and stirred overnight. The reaction mixture was concentrated to leave a residue, which was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-morpholinophenyl)ethyl)-1,3-oxazinan-2-one (162 mg, 0.4 mmol). LC-MS Method 3 tR=1.29, min, m/z=425; 1H NMR (CD3OD): 1.50 (m, 3H), 2.20 (m, 2H), 2.40 (m, 1H), 2.60 (m, 2H), 3.00 (m, 5H), 3.85 (m, 4H), 5.00 (m, 2H), 5.45 (m, 1H), 5.65 (m, 1H), 6.70 (m, 2H), 6.90 (m, 2H), 7.05 (m, 2H), 7.30 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH:12]=[CH2:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.Br[C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([F:43])[CH:36]=1>C1COCC1.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:39]([C:38]1[CH:41]=[CH:42][C:35]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:10])=[CH:36][C:37]=1[F:43])#[N:40]
Reactant: C=CNC(=O)OCc1ccccc1
Reactant: N#Cc1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CCNC(=O)OCc2ccccc2)cc1F
Temperature: -10 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
Into a 100 mL single neck flask was placed (phenylmethoxy)-N-vinylcarboxamide (5.54 g, 31.25 mmol) in THF (15 mL). The mixture was cooled down to −10° C. while treated dropwise with a solution of 9-BBN dimer (3.81 g, 15.62 mmol) in THF (20 mL). The reaction mixture was warmed up to RT while stirring for additional 2 hours. The reaction mixture was quenched with 3N NaOH (2mL) and the mixture was stirred for 10 minutes before its addition to a solution of 4-bromo-2-fluorobenzonitrile (5 g, 25 mmol) and [1,1′bis(diphenylphosphino)-ferrocene] dichloropalladium (II), PdCl2(dppf), (0.4 g, 0.5 mmol) in THF (10 mL). The mixture was stirred at RT for 12 hour and then was quenched with a 2:1 mixture of pH=7 buffer hydrogen peroxide (10 mL). The product was extracted with EtOAc and the organic layer was separated and washed twice with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced vacuum. The resulting semi-solid was further purified via flash chromatography (Silica gel, isocratic) and eluting with a solvent of Hexanes/EtOAc 50% to provide the intermediate title compound, N-[2-(4-cyano-3-fluorophenyl)ethyl](phenylmethoxy)carboxamide, (6.4 g, 86%) as a white solid. Electron spray M.S. 299 (M*+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[Cl:12][C:13]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]=[N+:16]([CH3:18])[CH3:17].ClC1C(Cl)=CC=CC=1C=O.CNC>>[Cl:12][C:13]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:14]=1[CH:15]([N:16]([CH3:18])[CH3:17])[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1ccc2ccccc21
Reactant: C[N+](C)=Cc1cccc(Cl)c1Cl
Agent: CNC
Agent: O=Cc1cccc(Cl)c1Cl
Agent: [Cl-]
Product: CN(C)C(c1cccc(Cl)c1Cl)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methylindole and (2,3-dichloro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2,3-dichloro-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]([C@@:3]1([OH:25])[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1)#[CH:2].[Br:26]Br>CO.Br.C(Cl)Cl>[Br:26][CH2:14][C:13](=[O:15])[C@@H:12]1[C@:16]2([CH3:24])[C@H:9]([C@H:8]3[C@H:19]([CH2:18][CH2:17]2)[C@:20]2([CH3:23])[C@H:5]([CH2:4][C@:3]([C:1]#[CH:2])([OH:25])[CH2:22][CH2:21]2)[CH2:6][CH2:7]3)[CH2:10][CH2:11]1
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Reactant: BrBr
Agent: Br
Solvent: ClCCl
Solvent: CO
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of 3β-ethynyl-3α-hydroxy-5α-pregnan-20-one (2.3 g, 6.72 mmol) in MeOH (80 mL) was treated with two drops of HBr (48%), followed by bromine (0.4 mL, 7.73 mmol). The mixture was stirred at room temperature for 1 hr and was poured into ice-water. The separated solid was collected by filtration, washed with water, and dried (2.5 g). This semi-dried solid was then dissolved in EtOAc and dried over anhyd. MgSO4. Filtration and removal of the solvent gave the crude bromo derivative. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with hexane:EtOAc mixture (85:15) gave 21-Bromo-3β-ethynyl-3α-hydroxy-5α-pregnan-20-one (2.1 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24](O)=[O:25])=[CH:22][N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1.Cl.C([N:49]=C=NCCCN(C)C)C.CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([NH2:49])=[O:25])=[CH:22][N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(COc2nn(Cc3ccc(Oc4ccccc4)cc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(Cc3ccc(Oc4ccccc4)cc3)cc2C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A mixture of 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (0.80 g), 1H-1,2,3-benzotriazol-1-ol ammonia complex (0.22 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.28 g), and N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carbamide (0.75 g, yield 94%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from acetone-hexane. Melting point: 105–106° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].B(F)(F)F.CCOCC.C([SiH](CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[C:5]([O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)([CH3:22])[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc(OC)cc1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
3-(4-Benzyloxyphenyl)-2-(4-methoxyphenoxy)-3-hydroxy-2-methylpropionic acid ethyl ester (2.15 g, 4.9 mmol) in anhydrous CH2Cl2 (30 mL) was cooled to 0° C. and treated with BF3-Et2O (0.91 mL, 7.4 mmol, d=1.154) and triethylsilane (1.18 mL, 7.4 mmol, d=0.728). The mixture was stirred for 2 h, gradually warming to ambient temperature. Saturated aqueous Na2CO3 (15 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 3-(4-benzyloxy-phenyl)-2-(4-methoxyphenoxy)-2-methylpropionic acid ethyl ester as a colorless oil (428 mg, 21%). Rf=0.36 in 4:1 hexanes:ethyl acetate 1H NMR (300 MHz, CDCl3): δ 7.45 (t, 2H, J=7.1), 7.35 (d, 2H, J=7.1), 7.34 (t, 1H, J=7.0), 7.18 (d, 2H, 8.6), 6.91 (d, 2H, J=6.6), 6.79 (d, 2H, 8.6), 6.74 (d, 2H, J=6.6), 5.05 (s, 2H), 4.21 (q, 1H, J=7.1), 3.75 (s, 3H), 3.23 (d, 1H, J=13.7), 3.10 (d, 1H, J=13.7), 1.31 (s, 3H), 1.25 (t, 3H, J=7.1). MS [EI+] 438 (M+NH4)+, [EI−] 419 (M−H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH:15]([CH3:17])[CH3:16])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)c(O)cc2n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc2cc(F)c(OC(C)C)cc2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 39 %

Procedure:
To 6-fluoro-2-methylquinolin-7-ol (800 mg, 3.16 mmol) in acetone (5 mL) were added 2-iodopropane (1075 mg, 6.32 mmol) and potassium carbonate (1310 mg, 9.48 mmol). The reaction was stirred at 70° C. in a sealed tube for 18 hours then cooled and diluted with water. The aqueous phase was extracted with DCM, dried over MgSO4, filtered and concentrated under reduced pressure to yield 6-fluoro-7-isopropoxy-2-methylquinoline (270 mg, 39.0% yield) as an oil.