Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:11]([S:16][CH3:17])=[N:12][CH:13]=[N:14][CH:15]=1)O.S(Cl)([Cl:20])=O>ClCCl>[Cl:20][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:10]1[C:11]([S:16][CH3:17])=[N:12][CH:13]=[N:14][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ncncc1C(O)c1ccccc1F
Solvent: ClCCl
Product: CSc1ncncc1C(Cl)c1ccccc1F
Reaction time: 1 h

Procedure:
To a slurry of 9.5 g (38 mmol) of (2-fluorophenyl) (4-methylthio-5-pyrimidinyl)methanol in 50 mL of dichloromethane was added slowly with stirring 10 g (84 mmol) of thionyl chloride. The resulting solution was stirred 1 hr. and then was concentrated by evaporation under reduced pressure. The resulting amber oil was diluted with 5 mL of dichloromethane and then 100 mL of hexane. The light tan solid that formed was collected by filtration and dried under reduced pressure to obtain 10.1 g (99 percent of theory) of the title compound in crude form melting at 144°-145° C.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.[O:16]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17]1>>[O:16]1[CH:20]=[CH:19][C:18]2[CH:21]=[C:2]3[C:1](=[O:13])[O:14][C:5](=[O:7])[C:4]4=[CH:9][CH:10]=[CH:11][C:12]([C:17]1=2)=[C:3]34
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Reactant: O=Cc1ccoc1
Product: O=C1OC(=O)c2cc3ccoc3c3cccc1c23

Procedure:
As described in example 14, the following compounds were prepared from dimethyl homophthalate and 3-furaldehyde:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].Cl.[Cl:6]([O-:10])(=[O:9])(=[O:8])=[O:7].[Na+]>>[Cl:6]([OH:10])(=[O:9])(=[O:8])=[O:7].[NH2:1][C:2]([NH2:4])=[O:3]
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Product: [O-][Cl+3]([O-])([O-])O
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
606 Grams of urea were added to 1040 g of 35% hydrochloric acid and dissolved therein under agitation. Then, 1405 g of sodium perchlorate were added to the solution and the mixture was stirred vigorously for 10 minutes at 40°C and cooled to 20°C. The precipitated crystals were separated by filtration. These crystals were sodium chloride. The filtrate contained about 65% of urea perchlorate but still contained a small amount of sodium chloride dissolved therein. Thus, the filtrate was concentrated under reduced pressure at a temperature below 80°C and filtered while hot, thereby removing the majority of the sodium chloride. By repeating this procedure comprising concentration and cooling for the aqueous solution of urea perchlorate thus obtained, crystals of urea perchlorate could be produced in a high yield.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@@H:6]([CH2:15][CH3:16])[N:5]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:4]=2[N:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34].Cl.C([O-])(O)=O.[Na+]>C(O)C.O>[CH:17]1([N:5]2[C:4]3[N:3]=[C:2]([NH:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([NH:29][CH3:30])=[O:28])=[CH:25][C:24]=4[O:33][CH3:34])[N:11]=[CH:10][C:9]=3[N:8]3[CH:12]=[N:13][N:14]=[C:7]3[C@H:6]2[CH2:15][CH3:16])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Reactant: CC[C@@H]1c2nncn2-c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC[C@@H]1c2nncn2-c2cnc(Nc3ccc(C(=O)NC)cc3OC)nc2N1C1CCCC1
Temperature: 90 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a solution of (R)-7-chloro-5-cyclopentyl-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine (80 mg, 0.263 mmol) in a mixture ethanol/water (1/4, 5 mL) were added 4-amino-3-methoxy-N-methylbenzamide (72 mg, 0.394 mmol) followed by a catalytic amount of concentrated HCl (0.04 mL). The reaction mixture was stirred at 90° C. for 24 hours, then cooled to room temperature and basified with saturated aqueous solution of NaHCO3. The mixture was extracted with ethyl acetate, the organic layer was dried (MgSO4) and the residue purified by flash chromatography to give the title compound as a colourless solid (92 mg, 78% yield).
Reaction SMILES: [C:1]1([S:7]([CH:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH2:29][CH:30]=[CH:31][CH2:32][CH:33]=[CH:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=[O:45]>>[C:1]1([S:7]([CH:10]([CH2:23][CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:45])=[O:22])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=O
Reactant: CCCCCC=CCC=CCC=CCC=CCCCCC(CCCCCCCCCCCO)S(=O)(=O)c1ccccc1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC(CCCCCCCCCCC(=O)O)S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Jone's reagent was added dropwise to a stirred solution of 17Z,20Z,23Z,26Z)-12-(phenylsulfonyl)dotriaconta-17,20,23,26-tetraen-1-ol (1 M solution in THF, 0.764 mL, 0.764 mmol) dissolved in acetone (5 mL) till the completion of reaction (TLC monitoring). The reaction was quenched with methanol (2 mL) and stirred for 30 min. The solvent was then removed and the crude was purified by silica gel column chromatography using 30% ethyl acetate/hexane to furnish the title compound as a clear oil (0.0643, 84%). 1H NMR (CDCl3): δ7.88 (d, 2H, J=7.2 Hz), 7.60 (m, 3H), 5.36 (m, 8H), 2.79 (m, 7H), 2.27 (t, 2H, J=6.8 Hz), 2.07 (m, 4H), 1.68 (m, 2H), 1.37-1.20 (m, 28H), 1.04 (t, 3H, J=6.8 Hz). m/z (APCI) 613.45 (M++1).
Reaction SMILES: [C:1]([O:4][CH:5]1[O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:6]1[NH2:7])(=[O:3])[CH3:2].[I:25][C:26]1[C:31]([CH2:32][CH3:33])=[C:30]([I:34])[C:29]([CH2:35][CH3:36])=[C:28]([I:37])[C:27]=1[C:38]1[CH:43]=[CH:42][C:41]([C:44](Cl)=[O:45])=[C:40]([N+:47]([O-:49])=[O:48])[CH:39]=1>>[N+:47]([C:40]1[CH:39]=[C:38]([C:27]2[C:28]([I:37])=[C:29]([CH2:35][CH3:36])[C:30]([I:34])=[C:31]([CH2:32][CH3:33])[C:26]=2[I:25])[CH:43]=[CH:42][C:41]=1[C:44]([C:5]1([O:19][C@H:18]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:6]1[NH2:7])[O:4][C:1](=[O:3])[CH3:2])=[O:45])([O-:49])=[O:48]
Reactant: CCc1c(I)c(CC)c(I)c(-c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)c1I
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCc1c(I)c(CC)c(I)c(-c2ccc(C(=O)C3(OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3N)c([N+](=O)[O-])c2)c1I

Procedure:
1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′,4′,6′-triiodo-3′,5′-bis(ethyl-3-nitrobiphenyl-4-carbonyl chloride (19) to yield 2-nitro-4-[3′,5′-bis(ethyl)-2′,4′,6′-triiodophenyl]benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (20).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:20](=[O:30])[N:21]([CH2:27][CH2:28][CH3:29])[C:22](=[O:26])[NH:23][C:24]=1[NH2:25].CCN=C=NCCCN(C)C>CO>[NH2:25][C:24]1[NH:23][C:22](=[O:26])[N:21]([CH2:27][CH2:28][CH3:29])[C:20](=[O:30])[C:19]=1[NH:18][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CCCn1c(=O)[nH]c(N)c(N)c1=O
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CCCn1c(=O)[nH]c(N)c(NC(=O)c2ccc(OCc3ccccc3)cc2)c1=O
Temperature: 22.5 °C
Reaction time: 20 h
Yield: 37.6 %

Procedure:
A mixture of 4-benzyloxy-benzoic acid (7.44 g, 0.033 mol), 5,6-diamino-3-propyl-1H-pyrimidine-2,4-dione (5.0 g, 0.027 mol), methanol (60 ml), EDCI (10.0 g, 0.052 mol), were taken and stirred for 20 hours at 20-25° C. The reaction mixture was concentrated and water (50 ml) was added to obtain solid precipitate. The compound was purified by column chromatography to obtain N-(6-Amino-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-4-benzyloxy-benzamide as light yellow solid (4.0 g, 38%).
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:11]([O:13]C)=O)[C:7]([O:9]C)=O.C[O-].[Na+].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[NH:31])[NH2:30])[N:24]=1>CO>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[C:7]([OH:9])=[N:30][C:29]([C:25]2[N:24]=[N:23][CH:28]=[CH:27][CH:26]=2)=[N:31][C:11]=1[OH:13]
Reactant: N=C(N)c1cccnn1
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(-c2cccnn2)nc1O
Reaction time: 0.17 h

Procedure:
Dimethyl 2-(2-methoxyphenoxy)malonate (3.05 g, 12.6 mmol) (Ref. Canadian Patent Application No. CA2071193A, 1992) in methanol (15 ml) was added over 5 minutes to a stirred, 25% w/v solution of sodium methoxide in methanol (8.58 ml, 37.8 mmol of sodium methoxide) at room temperature. The resulting mixture was stirred for 10 minutes and then a solution of 3-pyridazinecarboximidamide hydrochloride (2.0 g, 12.6 mmol) in methanol (15 ml) was added dropwise over 5 minutes and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and then diluted with water (100 ml). The aqueous solution was acidified to pH 4 with sulfuric acid (20%), resulting in the formation of the title compound as a purple solid, which was isolated by filtration (1.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=4)[O:22][CH2:23][C:24]#[N:25])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:5][CH:4]=1.C[Si]([N:39]=[N+:40]=[N-:41])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C:19]4[CH:28]=[CH:27][CH:26]=[C:21]([O:22][CH2:23][C:24]5[NH:41][N:40]=[N:39][N:25]=5)[CH:20]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCC#N)c4)c23)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Nc4cccc(OCc5nnn[nH]5)c4)c23)cc1

Procedure:
Stir a mixture of 100 mg (0.223 mmol) of (3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]-pyrimidin-4-yl]amino}phenoxy)acetonitrile, 383 mg (3.345 mmol) of trimethylsilyl azide and 83.32 mg (0.334 mmol) of di-n-butyltin oxide in 5 ml of toluene at 80° C. overnight. After cooling, filter off the precipitated solid with suction, wash with toluene and dry at 50° C. under high vacuum overnight. 80.1 mg (73.1% of theory) of the target compound are obtained as a whitish solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Reactant: C1COCCN1
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1N1CCOCC1

Procedure:
Using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2, 1-c][1,4]benzodiazepin-10(11H) -ylcarbonyl)-phenyl]-2-chloropyridine-3-carboxamide and 5 ml of morpholine gives 800 mg of the desired product: M+ =493.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1.NN.[OH-].[K+]>C(O)CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:12]=3[C:13]=2[CH3:14])=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)c2oc3cccc(O)c3c2C)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc(Cc2oc3cccc(O)c3c2C)cc1
Temperature: 195 °C
Yield: 37270.7 %

Procedure:
A mixture of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxybenzofuran (2.0 gm; 7.0 mmoles), 99% hydrazine (50 mL) and potassium hydroxide (2.7 gm; 49 mmoles) in ethylene glycol (50 mL) was heated at 140° C. for a period of 2.5 hours and at 195° C. for one hour. The reaction mixture was cooled, poured in water, and extracted with ethylacetate. The organic phase was washed with 20% citric acid, with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 700 gm (37%) of 2-(p-methoxybenzyl)-3-methyl-4-hydroxybenzofuran, mp.130°-133° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[CH2:41]2)=[O:37])=[O:30])[CH2:3]1.C[Br:48].[C:49](#N)C>>[Br-:48].[OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][N+:42]([CH3:49])([CH3:46])[CH2:41]2)=[O:37])=[O:30])[CH2:3]1
Reactant: CBr
Reactant: CC#N
Reactant: CN1CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Product: C[N+]1(C)CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Product: [Br-]
Reaction time: 12 h

Procedure:
To 15 mg of (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-{((3S)-1-methyl-3-piperidyl)methyl}pyrrolidine-2-carboxamide, 0.5 ml of 10% methyl bromide-acetonitrile was added at room temperature, followed by 12 hours' stirring. The solvent in the reaction liquid was distilled off under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography (aluminium oxide 60F254, Art. 5713 (Merck), choroform/methanol=18/1) to provide 15 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:20][C:21]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.CC([O-])=O.[Na+]>CC(O)=O>[OH:20][C:21]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=[CH:1][C:2]1[N:11]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(C=O)c1O
Reactant: Cc1cccc(-n2c(C)nc3ccccc3c2=O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(C=Cc2nc3ccccc3c(=O)n2-c2cccc(C)c2)c1O
Yield: 96.4 %

Procedure:
In a 50 mL round-bottom flask a mixture of 50 (0.5 g, 002 mol), 2-hydroxy-3 methoxybenzaldehyde (0.4 g, 0.0025 mol) and NaOAc (0.233 g, 0.002 mol) in AcOH was heated under reflux for 10 hours. After cooling the precipitate formed was filtered off, washed with water, dried and recrystallized from acetic acid to yield 51 (0.74 g, 85%). M. Wt. 384. LCMS [M+H]+=385.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:48][C:49]1([F:54])[CH2:53][CH2:52][NH:51][CH2:50]1.CCN(C(C)C)C(C)C>ClCCl.CO>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:51]3[CH2:52][CH2:53][C:49]([F:54])([F:48])[CH2:50]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:24])[F:23])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: FC1(F)CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCC(F)(F)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 9.2 %

Procedure:
In a 100 mL, 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (1 g, 1.0 eq.) was charged in dichloromethane (20 mL, 20 V). The reaction mixture was cooled to 0° C. HOBT (0.461 g, 1.2 eq.), EDC.HCl (0.819 g, 1.5 eq.), 3,3-Difluoropyrrolidine hydrochloride (0.490 g, 1.2) and DIPEA (0.731 mL, 1.5 eq.) was added to the reaction mixture. The clear reaction mixture was stirred at 0° C. for 1.5 h. The progress of the reaction was followed by TLC using 5% methanol in dichloromethane as mobile phase and visualization with UV. Reaction mixture was quenched in water (50 mL). Organic layer was separated and aqueous layer was extracted with dichloromethane (20×2). The combined organic layer was washed with brine solution, dried over Na2SO4 and concentrated by rotary evaporation (25° C., 20 mm Hg) to afford 0.67 g of crude compound. The crude compound was purified by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner starting with fraction collection (25 mL fractions). The compound started eluting from 0.9% to 1.0% methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.115 g Yield (9.2%).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:36]2([CH3:37])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:35]2[CH2:34][CH2:33][C@@:32]2([CH3:38])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:25][C:26]([CH2:30][CH3:31])([OH:29])[CH2:27][CH3:28])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:39][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:27]([C:26]([OH:29])([CH2:30][CH3:31])[CH2:25][O:24][C:21]([CH3:23])([C:20]1[C@:32]2([CH3:38])[C@H:17]([C:16]3[C@H:35]([CH2:34][CH2:33]2)[C@:36]2([CH3:37])[C:13]([CH2:12][C@@H:11]([OH:39])[CH2:10][C@@H:9]2[OH:8])=[CH:14][CH:15]=3)[CH2:18][CH:19]=1)[CH3:22])[CH3:28]
Reactant: CCC(O)(CC)COC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)COC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 93.7 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-(2-ethyl-2-hydroxybutoxy)-20-methylpregna-5,7,16-triene (32.0 mg, 0.0475 mmol), a 1M tetra-n-butylammonium fluoride tetrahydrofuran solution (0.3 ml, 0.3 mmol) and tetrahydrofuran (0.5 ml) were subjected to reaction using a procedure similar to that of Example 5(2) (reflux under heating for 16 hours), worked up and the thus obtained residue was purified by preparative thin layer chromatography (1 sheet (0.5 mm thickness), hexane:ethyl acetate:ethanol=10:5:1, developed twice) to give the titled compound (19.8 mg, 94%) as a colorless oil.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[Cl-].[C:12]([C:14]1[CH:39]=[CH:38][C:17]([CH2:18][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:16][CH:15]=1)#[N:13].[K].CC(C)([O-])C>C1(C)C(C)=CC=CC=1>[O:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[CH2:18][C:17]1[CH:38]=[CH:39][C:14]([C:12]#[N:13])=[CH:15][CH:16]=1
Reactant: O=C1Cc2ccccc2O1
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K]
Solvent: Cc1ccccc1C
Product: N#Cc1ccc(Cc2cc3ccccc3o2)cc1

Procedure:
10.4 g (77.3 mmol) of 2-coumaranone are dissolved in 200 ml xylene and after the addition of 32 g (77.3 mmol) of 4-cyanobenzyl-triphenylphosphonium chloride and 8.7 g (77.3 mmol) of potassium-tert.butoxide the mixture is refluxed for 3 hours under a nitrogen atmosphere. The solvent is distilled off, the residue is taken up in ethyl acetate, combined with silica gel and concentrated by evaporation. Then it is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (8:2). The desired fractions are combined and concentrated by evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.B(F)(F)F.CCOCC>ClC1C=CC=CC=1>[OH:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:18](=[O:19])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1
Reactant: COc1cccc(O)c1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: FB(F)F
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: COc1ccc(C(=O)Cc2ccc(O)cc2)c(O)c1
Temperature: 7.5 °C
Reaction time: 4.5 h

Procedure:
A suspension of 3-methoxyphenol (44.69 kg, 360 mol) and 4-hydroxyphenylacetic acid (68.5 kg, 450 mol) in 144 L of chlorobenzene was purged with nitrogen gas. Boron trifluoride diethyl etherate (177 L, 1440 mol) was added at 20 to 25° C. The resultant suspension was heated to 80° C., stirred for 4 to 5 h, cooled to 5 to 10° C. and stirred overnight.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:15][N:14]([CH3:16])[CH2:13]1)[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22].[CH2:23]([NH:26][C:27](=[O:47])[NH:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[C:31]([C:38]2[S:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:42]=2)[CH:30]=1)[CH2:24][CH3:25].C(=O)(O)[O-].[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][N:14]1[CH2:15][CH:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:32]4[CH:33]=[N:34][C:29]([NH:28][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[O:47])=[CH:30][C:31]=4[C:38]4[S:39][CH:40]=[C:41]([C:43]([F:46])([F:44])[F:45])[N:42]=4)=[CH:11][CH:10]=3)[C:5](=[O:22])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2)[CH2:13]1
Reactant: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Reactant: CCOC(=O)c1cn(C2CN(C)C2)c2ccc(I)cc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C2CN(C)C2)cn1
Temperature: 30 °C

Procedure:
A suspension of ethyl 6-iodo-1-(1-methylazetidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 31, 500 mg, 1.21 mmol) in dimethoxyethane (9.7 mL) in a vial was stirred with heating to obtain solution. The solution was cooled to 30° C. and trans dichlorobis(triphenylphosphine)palladium (II) (111 mg, 0.16 mmol) was added. The mixture was stirred for ˜10 min at room temperature, then 6-(3-propylureido)-4-(4-trifluoromethylthiazol-2-yl)pyridin-3-ylboronic acid (Intermediate 47, 1.3 eq) was added to the mixture followed by an aqueous solution of sodium bicarbonate (252 mg in 2.4 mL of water) and the vial was sealed. The mixture was stirred at 75° C. for 1 h and then cooled to 0° C. The solid that formed was isolated by filtration, washed with a small amount of dimethoxyethane, then methyl tert-butyl ether to give 735 mg of yellow solid, which was used without further purification.