Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[OH-].[Na+].Cl.CC#N.O>O1CCCC1>[F:24][C:22]1[CH:21]=[CH:20][C:19]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5cccc(OC)c5)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(Cc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{(S)-6-[(R)-7-Fluoro-4-(3-methoxybenzyl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}-acetic acid methyl ester (30 mg) is dissolved in tetrahydrofuran (4 mL) and 1 N aqueous sodium hydroxide solution (0.4 mL) is added. The mixture is stirred at room temperature overnight and then acidified with 1 N aqueous hydrochloric acid (0.4 mL). The solution is submitted to HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=0.71 min; Mass spectrum (ESI−): m/z=447 [M−H]−.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][NH2:13])[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].C(OC1C=C(CCN)C=CC=1)CCC.C(N(CC)CC)C.[Cl:35][C:36]1[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=1[CH:38]=[CH:39][C:40](Cl)=[O:41]>C(#N)C.O>[Cl:35][C:36]1[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=1[CH:38]=[CH:39][C:40]([NH:13][CH2:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=1)=[O:41]
Reactant: O=C(Cl)C=Cc1ccccc1Cl
Reactant: CCCOc1cccc(CCN)c1
Agent: CCCCOc1cccc(CCN)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCCOc1cccc(CCNC(=O)C=Cc2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(3-propyloxyphenyl)ethylamine prepared in a manner analogous to that described in Example 1E (2.69 g) in acetonitrile (40 cm3) was added triethylamine (3 cm3). A solution of 2-chlorocinnamoyl chloride (3.6 g) in acetonitrile (20 cm3) was added slowly, the reaction mixture being cooled in an ice bath. When addition was complete, the mixture was stirred at room temperature for 40 minutes, treated with water (60 cm3) and SVM (2 cm3) and stirred well. The resulting precipitate was filtered off, washed and air-dried (5.49 g) m.p. 96°-99° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:19][C:20]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23].COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:22]([C:21]2[C:20]([CH3:19])=[N:28][C:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[4-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[4-(2-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])[CH:3]=[O:4].[H][H]>[Pd].C(O)C>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:13])[CH3:14])[CH:3]=[O:4]
Reactant: [H][H]
Reactant: CC(C=O)=CCC1CC=C(C)C1(C)C
Agent: [Pd]
Solvent: CCO
Product: CC1=CCC(CCC(C)C=O)C1(C)C

Procedure:
A mixture of 111 g (0.58 mole) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)but-2-enal, 2.7 g of 5% palladium on carbon and 80 ml of ethanol was hydrogenated at 30°-40° C and 40-55 psi until hydrogen uptake ceases. The mixture was filtered to remove the catalyst and the solvent removed by distillation. The residual oil was fractionally distilled to yield 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butanal. Yield 110.7 g (98.4% theory); bp 60°-61° (1.4 mm); mol wt. 194 (ms); ir, 3040, 2700, 1728 (s), 800 cm-1 ; nmr, 0.5δ, 0.8, 0.9 and 1.0 (6H, 4 s, geminal dimethyl groups of various diastereomers in the mixture), 1.1 (3H, d, J~7 Hz), 1.3-2.6 (7H, broad complex), 1.6 (3H broad s, olefinic methyl), 5.2 (1 H, broad multiplet, olefinic H), 9.7 (1H, d, J~1.5 Hz, aldehyde H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11]Br.[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccc(Br)cc1
Yield: 55.4 %

Procedure:
To a suspension of 4-bromophenol (2.00 g, 11.6 mmol) in water (20 mL) was added 1,2-dibromoethane (5.40 g, 28.8 mmol) and sodium hydroxide (0.700 g, 17.5 mmol). Then, the mixture was heated at reflux for 12 hours. Water was added, and the mixture was extracted with ethyl acetate (4×30 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (0-10% ethyl acetate/petroleum ether) to afford the title compound (1.8 g, 56%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]1[C:11]1[CH:16]=[C:15]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH:20]=[C:19]([CH2:31][O:32]C(=O)C)[C:18]=2[CH2:36][O:37]C(=O)C)[CH:14]=[CH:13][N:12]=1.C[O-].[Na+].C(O)(=O)C>CO>[O:1]=[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]1[C:11]1[CH:16]=[C:15]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH:20]=[C:19]([CH2:31][OH:32])[C:18]=2[CH2:36][OH:37])[CH:14]=[CH:13][N:12]=1
Reactant: COc1cc2cc(COC(C)=O)c(COC(C)=O)c(-c3ccnc(-n4cc([N+](=O)[O-])ccc4=O)c3)c2cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4cc([N+](=O)[O-])ccc4=O)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of 1-{2-[2-oxo-1,2-dihydro-5-nitropyridin-1-yl]-4-pyridyl}-2,3-bis(acetoxymethyl)-6,7-dimethoxynaphthalene (1.83 g) in methanol (50 ml) is added sodium methoxide (0.72 g) under ice-cooling. The mixture is stirred at room temperature for one hour. To the mixture is added acetic acid (0.8 ml) under ice-cooling, and the mixture is concentrated under reduced pressure to remove the solvent. To the residue are added chloroform and an aqueous sodium hydrogen carbonate solution, and the chloroform layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:acetone=3:1), and crystallized from ethyl acetate to give 1-{2-[2-oxo-1,2-dihydro-5-nitropyridin-1-yl]-4-pyridyl}-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (0.81 g,) which is listed in Table 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:20])[C:11]([NH:14][CH2:15][C:16]([O:18]C)=[O:17])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>O1CCCC1.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:20])[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CNc1ncc(-c2cccc(Cl)c2)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)CNc1ncc(-c2cccc(Cl)c2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a 50 mL flask is charged methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}-acetate, 4, (0.45 g, 1.4 mmol), tetrahydrofuran (4.5 mL) and 1 M NaOH (4.5 mL, 4.5 mmol). The mixture was stirred for 2 hours at room temperature after which it was determined by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components that the reaction was complete. The reaction solution was adjusted to pH 1 with concentrated HCl and the solution was heated at 35° C. under vacuum until all of the tetrahydrofuran had been removed. A slurry forms as the solution is concentrated. With efficient stirring the pH is adjusted to ˜2 with the slow addition of 1 M NaOH. The solid which forms was collected by filtration, washed with water, followed by hexane, then dried under vacuum to afford 0.38 g (88% yield) of the desired product as a white solid. 1H NMR (DMSO-d6) δ 12.84 (s, 1H), 12.39 (s, 1H), 9.39 (t, 1H), 8.56 (d, 1H), 7.94 (s, 1H), 7.81 (m, 2H), 7.55 (q, 2H), and 4.02 (d, 2H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]3[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[C:22]1([CH:15]2[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:11]3([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:14]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCC3(CC2)OC(c2ccccc2)C2CCCCN23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(C2OC3(CCNCC3)N3CCCCC23)cc1

Procedure:
A solution of 11 g of hexahydro-1'-benzyl-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine] in 95 ml of methanol and 5 ml of acetic acid is mixed with 1 g of 20% palladium on carbon and subjected to hydrogen pressure of about 50 p.s.i. After the theoretical amount of hydrogen is consumed, the reaction is stopped and the filtered solution is evaporated to dryness in vacuo. The residue is dissolved in methylene dichloride and stirred with excess dilute ammonium hydroxide solution to convert the acetate salt of hexahydro-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine] to the free base. The organic layer containing the aforementioned free base is separated, washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is recrystallized from ethyl acetate or methanol-water to obtain the pure free base of hexahydro-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine]; mp 169°-171° C.; yield 7 g.
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH:12](=[O:15])[CH2:13]C.[OH-].[Na+].[CH:18](O)(C)C>O>[N:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:13][CH:12]=[O:15])=[C:6]([CH3:18])[CH:5]=1)=[N+:2]=[N-:3]
Reactant: CCC=O
Reactant: [N-]=[N+]=Nc1ccc(C=O)cc1
Reactant: CC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N=[N+]=[N-])ccc1C=CC=O
Reaction time: 2 h
Yield: 61.8 %

Procedure:
4-Azidobenzaldehyde (29.42 g, 0.2 mol) and propionaldehyde (12.22 g, 0.2 mol) were dissolved in a solvent mixture of isopropyl alcohol (100 g) and pure water (50 g). Under cooling in an ice bath, sodium hydroxide (2 g) dissolved in pure water (20 g) was added to the solution, and the mixture was stirred for two hours. Propionaldehyde (12.22 g, 0.2 mol) was added again to the mixture, and the resultant mixture was stirred for a further three hours. The formed precipitates were collected through filtration and dried, to thereby yield 23.14 g of p-azido-2-methylcinnamaldehyde as yellow crystals (yield: 62%). The compound thus obtained was identified on the basis of the 1H-NMR measurements shown in Table 1.
Reaction SMILES: [N:1]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([N:11]2[CH2:12][CH2:13][CH:8]([N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]3)[CH2:9][CH2:10]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CCCN(C2CCNCC2)C1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCC(O)C3)CC2)cc1

Procedure:
The compound was prepared from [1,4′]bipiperidinyl-3-ol (ChemBridge) and 4-fluoro-nitrobenzene (Aldrich) following the procedure used in Example 1. MS (m+H)+: 306.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]1([C:22](Cl)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>C(N(CC)CC)C>[CH:13]1([C:22]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1
Reactant: C1CCC(CN2CCCC2)NC1
Reactant: O=C(Cl)C1C=Cc2ccccc21
Solvent: CCN(CC)CC
Product: O=C(C1C=Cc2ccccc21)N1CCCCC1CN1CCCC1
Yield: 32.2 %

Procedure:
From 2.36 g of 2-(pyrrolidin-1-ylmethyl)piperidine. 2.5 g of indene-1-carbonyl chloride and 4.88 ml of triethylamine. 1.4 g of 1-(indene-1-carbonyl)-2-(pyrrolidin-1-ylmethyl)piperidine was obtained using a procedure similar to that in Example 2. In a mixed solvent to methanol, water and ethanol (2:1:1), this compound was catalytically reduced with 10% palladium on carbon. After completion of the reduction, the catalyst was filtered off. After evaporation of the solvent, the residue was treated with a 4N 1,4-dioxane solution of hydrogen chloride to obtain 1.05 g of the title compound, melting at 218°-221° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)[CH2:29][O:28]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)[CH:13]=[N:12]2)[C:8]([NH:38][C:35]2[CH:36]=[CH:37][N:33]([CH2:32][C@@H:30]3[CH2:29][O:28][C:27]([CH3:39])([CH3:26])[O:31]3)[N:34]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: Cc1cccc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)n1
Product: Cc1cccc(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)c(=O)c2)n1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[4-(6-methyl-pyridin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 77) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[4-(6-methyl-pyridin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as a light tan foam as a mixture of diastereomers (0.95 g, 62%).
Reaction SMILES: CO[C:3]1[C:8]([C:9]([C:11](=[C:17](SC)SC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:7][N:6]=[C:5]([S:22][CH3:23])[N:4]=1.[NH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28].[H-].[Na+]>C(Cl)Cl.O>[CH2:15]([O:14][C:12]([C:11]1[C:9](=[O:10])[C:8]2[CH:7]=[N:6][C:5]([S:22][CH3:23])=[N:4][C:3]=2[N:24]2[C:17]=1[NH:29][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]2=1)=[O:13])[CH3:16]
Reactant: NC(=O)c1ccccc1N
Reactant: CCOC(=O)C(C(=O)c1cnc(SC)nc1OC)=C(SC)SC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(=O)c2cnc(SC)nc2n2c1[nH]c(=O)c1ccccc12
Temperature: 140 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
A solution of ethyl 2-(4-methoxy-2-(methylthio)pyrimidine-5-carbonyl)-3,3-bis(methylthio)acrylate (250 mg, 0.668 mmol) and 2-aminobenzamide (118 mg, 0.867 mmol) in DCM (5 mL) was heated over stream of nitrogen allowing DCM to evaporate and continued heating as neat at 140° C. for over night. The residue was dissolved in DMF (7 mL) after cooling to rt and treated with NaH (60 mg, 1.500 mmol). The reaction was stirred at rt for 1 h and diluted with DCM (20 mL) and H2O (20 mL). The layers were separated and DCM was removed under reduced pressure. Trituration of the crude in Et2O (10 mL) afforded the desired product as a yellow solid (50 mg, 20%). MS (m/z): 383 (MH+). 1H NMR (CDCl3) δ: 13.58 (br s, 1H), 9.43 (s, 1H), 8.60 (d, 1H), 8.33 (dd, 1H), 7.79 (m, 1H), 7.59 (m, 1H), 4.48 (q, 2H), 2.62 (s, 3H), 1.46 (t, 3H).
Reaction SMILES: COC1C=CC(CC(Cl)=O)=CC=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[C:22]=[C:23]([CH3:29])[C:24]([O:26]CC)=[O:25])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[C:22]=[C:23]([CH3:29])[C:24]([OH:26])=[O:25])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(C)=C=Cc1ccc(OC)cc1
Agent: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(C=C=C(C)C(=O)O)cc1

Procedure:
Repeating the procedure of Example 1 but replacing the p-thiomethylphenyl acetyl chloride with an equivalent amount of p-methoxyphenyl acetyl chloride, there is similarly obtained ethyl 4-(p-methoxyphenyl)-2-methyl-buta-2,3-dienoate, which when treated according to the procedure of Example 2, yields 4-(p-methoxyphenyl)-2-methyl-buta-2,3-dienoic acid (m.p. 105° - 108° from ether/pentane).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][O:15][CH3:14])=[CH:26][CH:25]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1ccc(CBr)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COCCOc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
In 30 ml of 95% ethanol were dissolved 1.5 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 1.85 g of 4-(2-methoxyethoxy)benzyl bromide, and then 0.48 g of anhydrous sodium carbonate was added thereto. The resulting mixture was stirred overnight at room temperature, poured into water, extracted with benzene, washed with water and dried over anhydrous sodium sulfate. Benzene was distilled off under reduced pressure and the resulting solid was recrystallized from n-hexane-benzene to obtain 1.64 g of the aimed compound, m.p. 105.6°~107.3° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([O:13]CC)=O)=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:9][C:10]([C:16](=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20])=[C:11]2[OH:13]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)CC(C)C
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.6 %

Procedure:
To Dowtherm at 250° C. was added a solution of ethyl 2-[(4-bromophenylamino)methylene]-5-methyl-3-oxohexanoate (700 mg, 6.75 mmol) in Dowtherm (5 mL) portionwise and the reaction mixture was stirred for 1.5 h. The reaction mixture was cooled to room temperature, diluted with hexanes and the resulting precipitate was filtered to afford the desired product (490 mg, 23%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.55 (d, J=6.4 Hz, 1H), 8.30 (d, J=2.3 Hz, 1H), 7.88 (dd, J=8.7, 2.3 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 2.99 (d, J=6.8 Hz, 2H), 2.21-2.04 (m, 1H), 0.91 (d, J=6.7 Hz, 6H).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:45][C:46]1[C:50]([CH3:51])=[N:49][O:48][N:47]=1>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:42])([F:43])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:45][C:46]3[C:50]([CH3:51])=[N:49][O:48][N:47]=3)[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nonc1CBr
Reactant: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: Cc1nonc1Cn1nc2nc(NC(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole. MS (m/e): 394.4 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](C=C)=[CH:4][CH:3]=1.[NH+]1([O-])[CH2:15][CH2:14][O:13]CC1.S([O-])([O-])(=[O:19])=S.[Na+].[Na+]>CC(C)=O.O.O=[Os](=O)(=O)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:14]([OH:13])[CH2:15][OH:19])=[CH:4][CH:3]=1
Reactant: [O-][NH+]1CCOCC1
Reactant: O=S([O-])([O-])=S
Reactant: C=Cc1ccc(Br)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: OCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-bromostyrene (Compound [LXI], 366 mg, 2 mmol, 1 eq.) in acetone (10 mL) was added morpholine N-oxide (953 mg of a 50% solution in H2O, 4.0 mmol, 2.0 eq.) and then OsO4 (1.3 g for a 4% OsO4 in H2O, 0.2 mmol, 0.1 eq). The mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was then added to an aqueous solution of sodium thiosulfate and then extracted three times with EtOAc. The combined organics were dried over Na2SO4, concentrated, and subjected to silica gel chromatography using EtOAc-heptane as the eluant to provide Compound [LXII]: 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.54-3.66 (m, 2H) 4.66 (dd, J=6.76, 5.10 Hz, 1H) 7.24-7.35 (m, 2H) 7.41-7.53 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.O.Cl(O)(=O)(=O)=O.NC[C@@H]1OC(=O)N(C2C=CC([N:50]3[CH2:55][CH2:54][O:53][CH2:52][C:51]3=[O:56])=CC=2)C1>C(#N)C>[ClH:1].[NH2:50][CH2:55][CH2:54][O:53][CH2:52][C:51]([N:9]([CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C:24]3=[O:29])=[CH:21][CH:22]=2)[CH2:12]1)[C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])=[O:56]
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: Cl
Product: NCCOCC(=O)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1

Procedure:
Agilent 1100 with DAD (G1315A), quat. pump (G1311A), autosampler CTC HTS PAL, degasser (G1322A) and column thermostat (G1316A); column. Zorbax Extend-C18 3.5μ; temperature: 40° C.; eluent A: water+5 ml of perchloric acid/litre, eluent B: acetonitrile; flow rate: 0.7 ml/min; gradient: 0-0.5 min 98% A, 2% B; ramp 0.5-4.5 min 10% A, 90% B; 4.5-6 min 10% A, 90% B; ramp 6.5-6.7 min 98% A, 2% B; 6.7-7.5 min 98% A, 2% B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:13](=[C:14]([CH2:19]O)[N:15]([CH3:18])[N:16]=2)[CH:12]=[CH:11][CH:10]=1.[NH3:21].CC(O)C.[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:17]2[C:13](=[C:14]([C:19]#[N:21])[N:15]([CH3:18])[N:16]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: N
Reactant: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1CO
Agent: O=[Mn]=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1C#N
Reaction time: 48 h
Yield: 39 %

Procedure:
To a solution of [7-(2,4-dichloro-phenyl)-2-methyl-2H-indazol-3-yl]-methanol from step 2 (0.153 g) in 2 mL of THF was added a 2 M ammonia in IPA solution (1.0 mL, 2.0 mmol), MgSO4 (0.910 g, 7.56 mmol), and 85% activated MnO2 (0.771 g, 7.54 mmol). The dark mixture was stirred for 2 d, then filtered thru CELITE® 521 (rinsing with dichloromethane) and concentrated to a yellow solid. Column chromatography (0→10% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole-3-carbonitrile (20: R3=2,4-dichlorophenyl; 0.058 g; 39%; m.p. 137-139) as a white solid: