Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]=[C:4]1[CH3:8])[CH3:2].[C:9](=[O:14])([O:12]C)[O:10][CH3:11]>CO>[CH3:11][O:10][C:9](=[O:12])[O-:14].[CH2:1]([NH+:3]1[CH2:7][CH2:6][N:5]([CH3:9])[CH:4]1[CH3:8])[CH3:2]
Reactant: COC(=O)OC
Reactant: CCN1CCN=C1C
Solvent: CO
Product: CC[NH+]1CCN(C)C1C
Product: COC(=O)[O-]
Yield: 100 %

Procedure:
11.2 9 (0.10 mol) of 1-ethyl-2-methylimidazoline, 18.0 g (0.20 mol) of dimethyl carbonate and 27.2 g of methanol were charged into a 100 ml autoclave to effect a reaction in a nitrogen gas atmosphere at 145° C. for 8 hours, obtaining 1-ethyl-2,3-dimethylimidazolinium methylcarbonate in 100% yield. Subsequently, the resultant reaction mixture was transferred to a flask made of Teflon® having a reflux condenser, and 3.70 g (0.10 mol) of ammonium fluoride was mixed into the mixture to effect a reaction at 50° C. for 5 hours, obtaining 1-ethyl-2,3-dimethylimidazolinium fluoride in 100% yield. After completion of the reaction, a white solid substance formed from ammonia and carbon dioxide was deposited onto the reflux condenser and part of the solid substance was mixed into the reaction mixture, and therefore it was removed by filtration and the resultant mixture was used in the subsequent step for reaction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O.CO>[C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccccc1C[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Adapting a literature known protocol (Dayal, et al., Steroids, 1990, 55(5), 233-237), a reaction mixture of methyl 2-[(2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butyl]benzoate (23a) (1.97 g, 5.0 mmol) and commercial lithium hydroxide monohydrate (LiOH.H2O) (420 mg, 10.0 mmol) in a mixture of water (10 mL) and methanol (MeOH) (3 mL) is stirred at room temperature. The reaction is monitored by TLC and/or LC/MS to completion. The solvent is partially removed under reduced pressure using a rotary evaporator. Acidic aqueous work-up and purification by silica gel column chromatography furnish the title compound 2-[(2R)-4-tert-butoxy-2-(tert-butoxycarbonylamino)-4-oxo-butyl]benzoic acid (23b) which may be used directly in the next step without further isolation and purification.
Reaction SMILES: [H-].[Na+].[S:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:5]=[CH:4]1.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH:18]1[CH:19]=[CH:20][C:13]([Cl:12])=[C:14]([CH2:15][N:8]2[CH2:7][C:6]3[CH:5]=[CH:4][S:3][C:11]=3[CH2:10][CH2:9]2)[CH:17]=1
Reactant: ClCc1ccccc1Cl
Reactant: c1cc2c(s1)CCNC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.42 g, 8.6 mmole) in THF (5.0 ml) is added a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.0 g, 7.2 mmole), prepared, for example, as described in Example 3B, in THF (10 ml). The mixture is stirred under a nitrogen atmosphere at room temperature for 30 minutes and o-chlorobenzyl chloride (1.74 g, 10.8 mmole) is added. After stirring at room temperature for 90 minutes, toluene (15 ml) is added and the mixture is heated to reflux for 15 to 20 hours. Disappearance of starting material is confirmed by TLC. The mixture is then cooled to room temperature and acidified with 40 ml 1N hydrochloric acid. The organic layer is separated. The aqueous layer is extracted with 50 ml of toluene. The aqueous layer is then separated and basified with dilute aqueous sodium hydroxide to pH 13-14. The product is extracted into methylene chloride (3×40 ml). The methylene chloride extracts are washed (1×50 ml water) and (1×50 ml salt solution) then dried over anhydrous magnesium sulfate and concentrated to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([CH3:22])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([Cl:1])[CH:3]=2)[C:16]2[CH:21]=[C:20]([CH3:22])[S:19][C:17]=2[N:18]=1
Reactant: Cc1cc2c(Cl)nc(Cl)nc2s1
Reactant: COc1ccc(CN)cc1Cl
Product: COc1ccc(CNc2nc(Cl)nc3sc(C)cc23)cc1Cl

Procedure:
Following the procedure of Example 1, the reaction of 3-chloro-4-methoxybenzylamine with 2,4-dichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:33][C:30]3[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: COc1ccc(-c2cc(Oc3ccc([N+](=O)[O-])cc3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0.495 mmol) and 4-nitrophenol were reacted as starting materials at 150° C. for 15 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (146.1 mg, 74.1%). Melting point: 197.7-201.1° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:35]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)Oc1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)(C)Oc1ccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butoxyphenyl)-1-(3-chlorophenyl)propan-1-ol (300 mg, 0.90 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (171 mg, 0.90 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (258 mg, 1.35 mmol) and 1-hydroxybenzotriazole hydrate (138 mg, 0.90 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (278 mg, 61%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([C:25](=O)[NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[N-:34]=[N+:35]=[N-].[Na+]>ClCCl.CS(C)=O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][N:26]=[N+:34]=[N-:35])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(C(N)=O)cc3c21)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@@H](Cn1ncc2ccc3oc(CN=[N+]=[N-])cc3c21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of the product from Example 3, Step B (2.80 g, 7.39 mmol) in dichloromethane (30 mL) was cooled (ice bath), thionyl chloride (0.81 mL, 11.1 mmol) was added and the mixture was stirred for 30 minutes. During the reaction the white suspension dissolved to a yellow solution and then became a white suspension. The reaction was evaporated. The residue was treated with a solution of sodium azide (5 eq, 37 mmol, 2.4 g) in DMSO (40 mL, heated at 70° C. to dissolve) with stirring and let cool to room temperature for 20 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with dichloromethane (200 mL). The organic layer was washed with brine (100 mL), dried (MgSO4) and evaporated to give a yellow oil, 2.84 g. This residue was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a colorless waxy residue, 2.45 g (82%) LC/MS m/z 405 [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[OH:10].S(=O)(=O)(O)O.[N+:16]([O-:19])(O)=[O:17].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([O:10][CH:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[C:6]([N+:16]([O-:19])=[O:17])[CH:5]=2)[CH2:1]1)(=[O:22])[CH3:21]
Reactant: OC1Cc2ccccc2C1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OC1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A slurry of 6.7 g (0.05 moles) of 2-indanol in 75 ml acetic anhydride was cooled to -15°C (ice-acetone bath) and treated with 0.2 ml of 98% sulfuric acid. In about 10 minutes the solid had completely dissolved. The stirred and cooled mixture was then treated over 15 min with a cold solution of 3.6 ml (5.0 g) of 70% nitric acid in 125 ml of acetic anhydride. The mixture was stored at -20°C overnight, then poured into 1 kg of crushed ice. The mixture was stirred until the ice had completely melted and most of the anhydride had reacted. The mixture was extracted with 500 ml of hexane. The organics were washed with saturated bicarbonate and evaporated to 3.0 g of an oil which solidified on standing. Trituration with hexane and recrystallization from the same solvent gave 1.1 g of 2-acetoxy-5-nitroindan, mp 84°-85°C. The aqueous from the hexane extraction yielded 5.3 g of an oil on extraction with benzene. All but 0.9 g of this oil went into hot hexane. Cooling to room temperature gave some oil. The mother liquor was decanted and cooled to 5°C overnight to give 2.0 g (35% total) of the 5-nitro compound, mp 82°-84°C. The filtrate was concentrated to 100 ml cooled again and filtered to give another 0.4 g crude 5-nitro, mp 60°-74°C. The mother liquors were concentrated but gave no solid on cooling. Evaporation afforded 2.0 g (22%) of oily 2-acetoxy-4-nitroindan, contaminated with some 4-nitroindene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([OH:20])=O)[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:24]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:36]([NH:39][C:18]([C:12]3[NH:13][C:14]4[C:10]([CH:11]=3)=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=[CH:16][CH:15]=4)=[O:20])[CH2:37][CH2:38]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3ccccc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-Benzyloxy-1H-indole-2-carboxylic acid and amine 5.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:21]([CH2:22]Br)=[CH:20][C:19]=4[C:30]([F:33])([F:32])[F:31])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:34]#[N:35].[Na+].C1(C)C=CC=CC=1>CN(C)C=O.O>[CH:1]1([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:21]([CH2:22][C:34]#[N:35])=[CH:20][C:19]=4[C:30]([F:33])([F:32])[F:31])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1Oc1ccc2[nH]cc(CC3CCCCC3)c2c1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cc(C(F)(F)F)c(Oc2ccc3[nH]cc(CC4CCCCC4)c3c2)c(C(F)(F)F)c1

Procedure:
Preparation is carried out in analogy to the procedure of Example VIII from 0.85 g (1.59 mmol) of benzyl bromide from Example XXII with 0.1 g (1.99 mmol) of sodium cyanide in 5 ml of dimethylformamide and 0.5 ml of water at 50° C. in 1.5 hours. The chromatography of the crude product is carried out on silica gel 60 by means of toluene.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:13]([F:14])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[Cl:15].[CH:16]1[CH:21]=[CH:20][C:19]([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Br-:1].[Cl:15][C:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=[C:13]([F:14])[C:3]=1[CH2:2][P+:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:19]1[CH:18]=[CH:17][CH:16]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc(F)c(CBr)c(Cl)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Product: [Br-]
Temperature: 90 °C
Yield: 87.2 %

Procedure:
To a solution of ethyl 4-(bromomethyl)-3-chloro-5-fluorobenzoate (531 mg, 1.797 mmol) in toluene (10 mL) was added PPh3 (471 mg, 1.797 mmol). The solution was refluxed at 90° C. overnight. Upon cooling a white precipitate formed. The mixture was diluted with hexanes, filtered and dried under vacuum to yield (2-chloro-4-(ethoxycarbonyl)-6-fluorobenzyl)triphenylphosphonium bromide (0.874 g, 86%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.05-7.87 (m, 3H), 7.85-7.58 (m, 13H), 7.20 (tt, J=15.1, 7.1 Hz, 1H), 5.21 (d, J=15.0 Hz, 2H), 4.34 (dq, J=14.2, 7.1 Hz, 2H), 1.33 (dt, J=14.2, 7.1 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.Cl.[Cl:12][C:13]1[CH:14]=[C:15]([NH:19]N)[CH:16]=[CH:17][CH:18]=1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(N(CC)CC)C>[F:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:19]2[C:15]3[CH:14]=[C:13]([Cl:12])[CH:18]=[CH:17][C:16]=3[C:24]3[CH2:23][N:22]([CH3:21])[CH2:27][CH2:26][C:25]2=3)=[CH:5][CH:6]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3ccc(Cl)cc3n2CCc2ccc(F)cc2)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-4-fluorobenzene, 3-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])[CH:3]=1.CC1(C)C(C)(C)OB(/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:8](=[O:9])[C:4]2[CH:3]=[C:2](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:7]=[CH:6][N:5]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CNC(=O)c2cc(Br)ccn2)cc1
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CNC(=O)c2cc(/C=C/c3ccccc3)ccn2)cc1
Temperature: 95 °C
Reaction time: 12 h
Yield: 77.7 %

Procedure:
To a flask containing 4-bromo-N-(4-methoxybenzyl)picolinamide (0.3 g) in 1,4-dioxane (1.1 mL) was added (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (0.22 g), Pd(dppf)—chloroform adduct (0.04 g) and 2M aqueous cesium carbonate (1.9 mL). The mixture was stirred at about 95° C. for about 12 h. The reaction was diluted with water and washed three times with CH2Cl2. The organic solution was filtered over Celite®, and concentrated under reduced pressure yielding (E)-N-(4-methoxybenzyl)-4-styrylpicolinamide as a deep yellow oil (0.25 g, 80%). LC/MS (Table-1, Method f) Rt=2.03 min; MS m/z 345 (M+H)+. This intermediate was then dissolved in 4.3 mL of 1,4-dioxane and treated with 0.87 mL of water and sodium periodate (0.75 g). After stirring for approximately 30 min at RT, osmium tetroxide (0.30 mL of a 0.1 M solution in t-butanol) was added to the reaction which was then stirred for about an additional 4 h at RT. The layers were separated and the organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The product was isolated by flash chromatography to give 4-formyl-N-(4-methoxybenzyl)picolinamide (0.25 g, 80%): LC/MS (Table 1, method-f) Rt=1.01 min; MS m/z 271 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@H:13]1[CH2:17][CH2:16][C@@:15]([CH3:21])([C:18]([OH:20])=O)[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH:30][CH3:31]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@H:13]1[CH2:17][CH2:16][C@@:15]([CH3:21])([C:18]([N:30]([CH3:31])[CH3:29])=[O:20])[C:14]1([CH3:22])[CH3:23])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@H]1CC[C@@](C)(C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@H]1CC[C@@](C)(C(=O)N(C)C)C1(C)C

Procedure:
The product from Example 181 and dimethylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.49 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.25 (s, 3H), 1.26 (s, 3H), 1.26-1.33 (m, 2H), 1.37-1.46 (m, 1H), 1.57 (s, 9H), 1.57-1.70 (m, 3H), 1.98-2.10 (m, 1H), 2.62-2.67 (m, 2H), 2.74-2.83 (m, 1H), 2.83 (s, 3H), 3.05 (s, 3H), 3.33-3.39 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 422 (M+H)+. Anal. calcd. for C23H39N3O2S: C, 65.52; H, 9.32; N, 9.97. Found: C, 65.19; H, 9.18; N, 9.88.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[F:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)ccc3F)cccc2c1N
Yield: 82.6 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 2-fluoro-5-methoxy-phenylboronic acid (170 mg, 1.000 mmol) were reacted to afford the title compound (142 mg, 83% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (br, 1H), 7.92 (m, 1H), 7.82-7.69 (m, 2H), 7.12 (m, 1H), 7.02-6.89 (m, 2H), 3.81 (s, 3H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 1.66 (apparent sextet, J=7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). MS APCI, m/z=355 (M+H). HPLC 1.78 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([NH2:7])=[CH2:6].N1C=CC=CC=1.C(Cl)(=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.O.C1C[O:33][CH2:32]C1>>[CH3:1][O:2][C:3](=[O:11])[CH:4]([CH:8]([CH3:9])[CH3:10])[C:5]([NH:7][C:32](=[O:33])[C:21]1[CH:20]=[CH:19][CH:24]=[CH:23][C:22]=1[O:25][CH3:26])=[CH2:6]
Reactant: C1CCOC1
Reactant: C=C(N)C(C(=O)OC)C(C)C
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: C=C(NC(=O)c1ccccc1OC)C(C(=O)OC)C(C)C
Yield: 33 %

Procedure:
The crude 3-amino-2-isopropyl-but-3-enoic acid methyl ester of step (a) above in this method (Method B of Example 13) (5 g, 0.0318 mol) was dissolved in anhydrous THF (100 mL) and anhydrous pyridine (5.2 mL, 0.0637 mol) was added. Anisoyl chloride (4.28 mL, 0.0318 mol) was added dropwise, and the mixture was refluxed for 2 hours. After cooling, water (100 mL) was added and the organic layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with 1N HCl (3×100 mL), water (100 mL), and brine (100 mL), dried over sodium sulfate and concentrated on a rotary evaporator. The product was purified by column chromatography over silica gel (200400 mesh) eluting with 10% EtOAc/hexanes to give 2-isopropyl-3-(2-methoxy-benzoylamino)but-3-enoic acid methyl ester (3 g, 33%) as a white powder.
Reaction SMILES: [C:1]([CH:4]([N:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH2:7]1)[CH3:5])([OH:3])=[O:2].[CH2:17](I)[CH3:18]>>[CH2:17]([N:14]1[N:15]=[N:16][C:12]([C:8]2[CH2:7][N:6]([CH:4]([C:1]([OH:3])=[O:2])[CH3:5])[CH2:11][CH2:10][CH:9]=2)=[N:13]1)[CH3:18]
Reactant: CCI
Reactant: CC(C(=O)O)N1CCC=C(c2nnn[nH]2)C1
Product: CCn1nnc(C2=CCCN(C(C)C(=O)O)C2)n1

Procedure:
The title compound was prepared by treating 5 (5.97 g, 0.027 mol) with ethyl iodide instead of methyl iodide as described in Example 5. Yield: 4.14 g (0.0164 mol, 61%) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Mg].[CH2:26]([CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH:31]=[CH:30]1)[CH:27]=[CH2:28]>O1CCCC1>[CH2:18]([O:17][C:3]1[CH:4]=[C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:6]=[CH:7][C:2]=1[C@H:30]1[C@H:29]([CH2:26][CH:27]=[CH2:28])[CH2:34][CH2:33][C:32](=[O:35])[CH2:31]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CCC1C=CC(=O)CC1
Reactant: CCCCCCC(C)(C)c1ccc(Br)c(OCc2ccccc2)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC[C@@H]1CCC(=O)C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
A solution of 73.0 g. (0.188 mole) of 1-bromo-2-benzyloxy-4-(1,1-dimethylheptyl)benzene (BrZ') in 350 ml. of tetrahydrofuran was slowly added to 9.0 g. (0.375 mole) of 70-80 mesh magnesium metal. After a 5 minute initiation period the rate of addition was adjusted so as to just maintain reflux. The reaction was stirred 1.5 hours longer following completion of addition while cooling to 25° C. The reaction was cooled to -20° C. and 1.78 g. (9.38 mmoles) of cuprous iodide added. The resultant mixture was stirred 5 minutes and then a solution of 25.5 g. (0.188 mole) of 4-(2-propenyl)-2-cyclohexen-1-one (enone) in 30 ml. of tetrahydrofuran added dropwise while the reaction temperature was maintained at about -18° C. Additional 1.78 g. (9.38 mmoles) portions of cuprous iodide were added following addition of 1/3 and 2/3 of the enone reactant. The reaction was stirred 5 minutes longer at -20° C. and then added to 1000 ml. of ice cold saturated ammonium chloride. The quenched mixture was extracted with 1000 ml. of ether and the organic extract washed twice with 500 ml. of saturated ammonium chloride, once with 500 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated (aspirator) to an oil. The crude oil was purified via column chromatography on 1 kg. of silica gel eluted with 20% etherhexane to yield 58.3 g. (70%) of the title compound as an oil.