Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H:3]([S:7]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[O:30][CH:31]=[CH:32][C:33]=3[CH3:34])=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-:6])=O)C.[NH:41]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42]1>C1COCC1>[OH:46][CH:43]1[CH2:44][CH2:45][N:41]([C:4](=[O:6])[CH2:3][S:7](=[O:8])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[N:9][C:10](=[O:11])[C:12]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]4[O:30][CH:31]=[CH:32][C:33]=4[CH3:34])=[O:28])[CH:21]=3)[CH:15]=[N:14][CH:13]=2)[CH2:42]1
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Reactant: OC1CCNC1
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CC(=O)N3CCC(O)C3)c3ccccc3)c2)c1
Temperature: 65 °C

Procedure:
To the solution of (S)-ethyl(N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate (4.03 g, 7.26 mmol) in anhydrous THF (75 mL) was added dropwise 3-pyrrolidinol (6.0 mL) and the resulting reaction solution was heated at 65° C. for 5 hours. The reaction was then concentrated under reduced pressure and the yellow oily residue was partitioned between aqueous NH4Cl and EtOAc. The organic layer was separated and washed sequentially with brine (1×), saturated aqueous NaHCO3 (1×), brine (1×), and finally dried with anhydrous sodium sulfate overnight. The clear solution was decanted and concentrated. The oily residue was subject to multiple times of column chromatography (eg. from CH2Cl2 to MeOH—CH2Cl2 1:25 or from EtOAc-Hex 3:1 to MeOH-EtOAc 1:100) the title compound as white foam (2.35 g, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.Br.[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[Br-:1].[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][PH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:3]=1
Reactant: OCc1cncc(Br)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Brc1cncc(C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 90 °C
Yield: 183.8 %

Procedure:
To a solution of (5-bromopyridin-3-yl)methanol (1 g, 5.32 mmol) in acetic acid (Volume: 2 mL) was added hydrogen bromide (1.324 mL, 11.70 mmol) and triphenylphosphine (1.726 g, 6.38 mmol) then heat to 90° C. for four days, cooled to ambient temperature. The reaction mixture was wash with ether (20 mL×2) and EtOAc (20 mL×2) then was filtered and concentrated under high vacuum to remove solvent and provide a white solid of 3-bromo-5-((tri-phenylphosphino)methyl)pyridine bromide salt (3.05 g, 4.89 mmol, 92% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.24 (s, 1H), 7.94 (t, J=7.0 Hz, 3H), 7.83-7.70 (m, 12H), 7.46 (d, J=1.5 Hz, 1H), 5.32 (d, J=15.6 Hz, 2H), Mass spec.: 434.2 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:18]([S:21](Cl)(=[O:23])=[O:22])([CH3:20])[CH3:19]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][S:21]([CH:18]([CH3:20])[CH3:19])(=[O:23])=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.8 %

Procedure:
To a solution of 10.0 g (50 mmol) of 4-bromophenethylamine and 7.6 mL (55 mmol) of triethylamine in 150 mL of dichloromethane was added a solution of 6.2 mL (55 mmol) of isopropylsulfonyl chloride in 40 mL of dichloromethane dropwise. The mixture was stirred at room temperature for 18 hr. The mixture was washed with 100 mL of 1N aqueous hydrochloric acid, the organic layer was separated and the aqueous layer extracted one time with 100 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to afford 6.7 g (44%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=C(NC)C(N)=[N:6][CH:7]=1.[C:11]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)(N1C=CN=C1)=O.C1C[O:26]CC1>C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[C:22]2[N:18]([CH3:11])[C:19](=[O:26])[NH:20][C:21]2=[N:6][CH:7]=1
Reactant: CNc1cc(F)cnc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(=O)[nH]c2ncc(F)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
5-Fluoro-N3-methylpyridine-2,3-diamine (0.399 g, 2.83 mmol) and 1,1′-carbonyldiimidazole (0.917 g, 5.65 mmol) were mixed in THF (12 mL). The reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude brown solid was triturated with DCM and filtered to yield the title compound (0.304 g, 1.819 mmol, 64.3% yield) as a gray solid. M+1: 168.1.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:15]([F:24])[CH:14]=2)[C:8]([O:10]CC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:15]([F:24])[CH:14]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(c1ccccc1)c1ccc(NS(C)(=O)=O)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(C(C(=O)O)c2ccccc2)cc1F

Procedure:
Ethyl 2-phenyl-2-(3-fluoro-4-(methylsulfonamido)-phenyl)acetate (16.5 mmol, 5.8 g) was dissolved in a mixture of 32 mL of THF and 16 mL of water, 1.18 g of LiOH (49.5 mmol) were added, and the mixture was heated under reflux over a period of 15 h. To the reaction mixture there were added 15 mL of water and the phases were separated. The aqueous phase was acidified with aq. HCl and extracted with dichloromethane (3×50 mL). The combined organic phases were dried over MgSO4, concentrated, and the residue purified by means of column chromatography (silica gel: 100-200 mesh, eluent: 50% EA in cyclohexane). Yield 3.3 g (61.3%).
Reaction SMILES: [Na].[CH3:2][N:3]1[C:11]2[N:10]=[C:9]3[N:12]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:13](=[O:17])[CH:14]=[C:15]([OH:16])[N:8]3[C:7]=2[C:6](=[O:26])[N:5]([CH3:27])[CH2:4]1.Br[CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32]>C(O)C>[CH3:2][N:3]1[C:11]2[N:10]=[C:9]3[N:12]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:13](=[O:17])[C:14]([CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])=[C:15]([OH:16])[N:8]3[C:7]=2[C:6](=[O:26])[N:5]([CH3:27])[CH2:4]1
Reactant: CC(C)=CCBr
Reactant: CN1CN(C)c2nc3n(Cc4ccc(F)cc4)c(=O)cc(O)n3c2C1=O
Agent: [Na]
Solvent: CCO
Product: CC(C)=CCc1c(O)n2c3c(nc2n(Cc2ccc(F)cc2)c1=O)N(C)CN(C)C3=O
Temperature: 25 °C
Reaction time: 90 h

Procedure:
Dissolve 1.48 g (0.0644 mole) of sodium metal in 450 ml of ethanol (2B; anhydrous). Add 23.0 g (0.0644 mole) of 2,3-dihydro-1,3-dimethyl-9-(4-fluorobenzyl)-6-hydroxy-pyrimido[2,1-f]purine-4,8(1H,9H)-dione. Stir the resultant suspension under a nitrogen atmosphere for 0.5 hour, then add 9.60 g (0.0644 mole) of 1-bromo-3-methyl-2-butene. Stir the mixture at room temperature for 90 hours under a nitrogen atmosphere. Filter off the white solids, and remove solvent from the filtrate under reduced pressure. Dissolve the residue in 150 ml of chloroform, add 125 ml of 3N hydrochloric acid and shake the mixture. Separate the layers, and extract the aqueous phase with two 50-ml volumes of chloroform. Dry the combined extracts over anhydrous magnesium sulfate, filter off the drying agent, and remove solvent from the filtrate under reduced pressure. Chromatograph the residual glassy solid on silica gel, eluting with ethyl acetate(3)-hexanes(1). Triturate the product thus obtained with hexane (125 ml per gram) and filter to obtain the title compound as a solid (mp 188°-188.5° C.).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].[C:12]1([CH3:24])[CH:17]=[CH:16][C:15]([S:18]([O:21]CC)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[C:12]1([CH3:24])[CH:13]=[CH:14][C:15]([S:18]([O-:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[CH2:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N+:7]=1[CH2:12][CH3:13])[CH3:2]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCc1nc2ccccc2s1
Product: CCc1sc2ccccc2[n+]1CC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 160 °C
Yield: 157.3 %

Procedure:
2-Ethylbenzothiazole (16.3 g) and 22.0 g of ethyl p-toluenesulfonate were mixed and heated over an oil bath to 160° C. while stirring. The raw materials were once molten and after a while, a solid was precipitated. Five hours after that, heating was terminated. When the temperature was decreased to 100° C., acetone was added to disperse therein the solid. After cooling to room temperature, the solid was collected by filtration. The solid was then dried under vacuum for 2 days, whereby 31.4 g of the intended compound was obtained (yield: 86%).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH2:6][C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[C:14]([CH:17]1[CH2:22][CH2:21]O[C:18]1=[O:19])(=O)[CH3:15].N>O>[OH:13][C:12]1[C:7]2=[N:6][C:14]([CH3:15])=[C:17]([CH2:22][CH2:21][Cl:3])[C:18](=[O:19])[N:8]2[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)C1CCOC1=O
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ncccc1O
Agent: N
Solvent: O
Product: Cc1nc2c(O)cccn2c(=O)c1CCCl
Reaction time: 10 h

Procedure:
To a mixture comprising phosphorus oxychloride (2520 parts) and 2-amino-3-hydroxy pyridine (300 parts) was charged 2-acetyl butyrolactone (348 parts). The resulting mixture was heated to 60° to 65° C. and stirred for 10 hours at the same temperature. The reaction mass was cooled and poured into a mixture of ice and water to produce a quenched reaction mass. The pH was adjusted (pH meter) to 5.5 using aqueous ammonia. The resulting solid was filtered and washed with water followed by drying in vacuum oven to yield 235 parts of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one with a purity (HPLC) of 99%.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.O=[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH2:32])=[O:31].C(O)(=O)C.C([O-])(=O)C.[Na+]>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:25](/[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)\[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([NH2:32])=[O:31])=[CH:22][CH:23]=1
Reactant: NC(=O)CCCCC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCC(N)=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (600 mg), 6-oxo-6-phenylhexanamide (396 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and ethanol (20 ml) was heated to reflux for 18 hours, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain crystals from an ethyl acetate-hexane (3:1, v/v)-eluted fraction. The crystals were recrystallized from ethyl acetate-hexane to obtain E-6-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-6-phenylhexanamide (651 mg, yield 68%) as colorless crystals. m.p. 95-96° C.
Reaction SMILES: [CH:1](OC(Cl)(Cl)Cl)=[O:2].[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([NH:29][NH2:30])=[O:28])[N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.O>O1CCOCC1>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][C:24]3[CH:33]=[CH:32][CH:31]=[C:26]([C:27]4[O:28][C:1](=[O:2])[NH:30][N:29]=4)[CH:25]=3)[N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: NNC(=O)c1cccc(Cn2nc(-c3cc(F)cc(F)c3)ccc2=O)c1
Reactant: O=COC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]nc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)o1

Procedure:
7.2 A solution of 131 mg (0.65 mmol) of trichloromethyl formate in 3 ml of dioxane is added to a suspension of 178 mg (0.50 mmol) of 3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]benzohydrazide in 1 ml of dioxane, and the mixture is heated at the boil for 4 hours. The reaction mixture is allowed to cool, and water is added. The resultant precipitate is filtered off with suction, washed with water and dried. The residue is chromatographed on a silica gel column with dichloromethane/methanol, giving 6-(3,5-difluorophenyl)-2-[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzyl]-2H-pyridazin-3-one (“A15”) as colourless crystals; ESI 383;
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O:5][CH3:6])=[O:4].CC(C)([O-])C.[K+].[CH2:21](Br)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH3:1][O:2][P:3]([CH:7]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O:5][CH3:6])=[O:4]
Reactant: BrCCc1ccccc1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COP(=O)(OC)C(CCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 60.8 %

Procedure:
118 g of tert-butyl dimethylphosphonoacetate were dissolved, under a nitrogen atmosphere, in 875 ml of dry dimethylformamide. 58.9 g of potassium tert-butoxide were added to the solution while cooling with ice. The reaction mixture was subsequently heated at 60° C. for a short period and then allowed to cool down to room temperature. A solution of 104.9 g of phenethyl bromide in 110 ml of dimethylformamide was added dropwise to the reaction mixture. The reaction mixture was then heated at 60° C. for 2 hours. For the working-up, most of the dimethylformamide was evaporated under reduced pressure and the remaining residue was dissolved in methyl tert-butyl ether. The solution was acidified with aqueous potassium hydrogen sulfate solution. The organic phase was then separated, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography on 3 kg of silica gel using dichloromethane/methyl tert-butyl ether (4:1) as the eluent. 105.1 g of pure tert-butyl 2-(dimethylphosphono)-4-phenyl-n-butyrate were obtained as an oily product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[Cl:21][C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1.C(OCC)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([C:22]([Cl:21])=[O:24])[CH2:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(Cl)N1CC=C(c2ccc(Cl)cc2)CC1
Yield: 269.3 %

Procedure:
A mixture of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (1 g, 4.3 mmol), pyridine (680 mg, 8.6 mmol), and triphosgene (430 mg, 1.45 mmol) in toluene (20 ml) was heated under reflux for 3 hours. The reaction mixture was allowed to return to room temperature and diluted with diethyl ether. The mixture was washed with 10% hydrochloric acid, water and brine in this order, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-carbonylchloride (1 g, yield 90%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:15](=[O:20])[CH2:14][CH2:13]2.C(O)(=O)C>C1(C)C=CC=CC=1.O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:3]([O:6][CH3:7])=[O:8])=[C:15]([OH:20])[CH2:14][CH2:13]2
Reactant: O=C1CCc2cc(Cl)ccc2C1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C1=C(O)CCc2cc(Cl)ccc21
Temperature: 0 °C
Yield: 63.8 %

Procedure:
10.1 g (252 mmol) of 60% sodium hydride in oil, 621 ml of toluene and 14.18 ml (163 mmol) of dimethyl carbonate are introduced into a 2 l reactor. The reaction mixture is stirred at reflux for 1 h. A solution of 15.2 g (84 mmol) of 6-chloro-3,4-dihydro-1H-naphthalen-2-one in 268 ml of toluene is subsequently added. The reaction mixture is heated at reflux for 24 h. The reaction mixture is subsequently cooled to 0° C. and then acidified by addition of 92 ml of acetic acid. 114 ml of water are added and the separated organic phase is separated by settling and washed with three times 150 ml of water and then with 100 ml of a saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulphate and then concentrated under reduced pressure. The residue is purified by chromatography on a silica column (elution being carried out with a mixture of cyclohexane and of dichloromethane) to result in 12.8 g (53.6 mmol) of the expected product used as is in the following stage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][Al](C)C.C1(C)C=CC=CC=1.Cl>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH3:10])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(O)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Commercially available 3-bromobenzaldehyde (5.0 g, 27 mmol) was dissolved in anhydrous dichloromethane (200 mL) under a dry nitrogen atmosphere and cooled in a dry ice/acetone bath to −78° C. Trimethyl aluminum 2M solution in toluene (16.2 mL, 32 mmol) was added dropwise. After 0.5 h the reaction mixture was allowed to warm to room temperature during which time the cloudiness of the reaction resolved to a clear yellow solution which then proceeded to a colorless solution. After stirring for 1 h at room temperature the reaction mixture was cooled in an ice bath and 1N HCl (100 mL) was added dropwise. The reaction mixture was transferred to a separatory funnel and the organic layer was isolated, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by silica gel flash column chromatography eluting with 1:1 Ethyl acetate/hexane to provide 5.4 g (99%) of A4.1a as a colorless oil. LCMS (M+H−OH)+=183, 185
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([CH3:20])[NH:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:9][CH:8]=1.[I-].[K+].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C.C(N(CC)CC)C>[O:4]1[CH2:27][CH2:28][N:23]([CH2:24][C:25]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:14]([CH3:20])[NH:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:11][CH:12]=2)=[O:26])[CH2:2][CH2:3]1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: C1COCCN1
Reactant: O=C(Cl)CCl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1NC(=O)NN=C1c1ccc(NC(=O)CN2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
Chloroacetyl chloride (1.25 g) was added dropwise to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.04 g) and triethylamine (1.01 g) in DMF (10 ml) and then stirred for 30 minutes. To the stirred solution were added potassium iodide (0.53 g) and morpholine (4.53 g). The reaction mixture was stirred for 30 minutes and then evaporated in vacuo. To the residue was added water and the resultant solid was collected by filtration, washed with water and recrystallized from aqueous ethanol to give 6-[4-(2-morpholinoacetamido)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.13 g).
Reaction SMILES: [CH2:1]([CH:5]1[N:9]=[CH:8][C:7](Cl)([CH2:10][C:11]([O:13]C)=[O:12])[N:6]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH3:4].C(C1N=CC([Cl:39])(CC(O)=O)N1CC1C=CC([N+]([O-])=O)=CC=1)CCC>>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[C:8]([Cl:39])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1N=CC(Cl)(CC(=O)O)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCC1N=CC(Cl)(CC(=O)OC)N1Cc1ccc([N+](=O)[O-])cc1
Product: CCCCc1nc(Cl)c(CC(=O)O)n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
Methyl 2-butyl-5-chloro-1-(4-nitrobenzyl)-imidazole-5-acetate was also prepared by the procedure described in Example 2 Part B from 2-butyl-5-chloro-1-(4-nitrobenzyl)imidazole-5-acetic acid. NMR (200 MHz, CDCl3) δ8.23 (d, 2H, J=10 Hz); 7.20 (d, 2H, J=10 Hz); 5.21 (s, 2H); 3.75 (s, 3H); 3.67 (s, 2H); 2.58 (t of t, 2H, J=7 Hz); 1.32 (q of t, 2H, J=7 Hz); 0.86 (t, 3H, J=7 Hz). Mass Calcd. for C17H20ClN3O4 ; 365.1142. Found 365.1132.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH2:23]([NH:30][CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:23]([N:30]([CH3:31])[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CNCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)Cc3ccccc3)nc2c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 39.5 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.63 mmol) in DMSO (4 mL) was added benzyl(methyl)amine (92 mg, 0.76 mmol), and DIEA (163 mg, 1.26 mmol). The resulting solution was stirred for 2 hours at 85° C. Then the mixture was quenched of water (100 mL) and extracted with dichloromethane (3×50 mL) The organic layers were combined and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[benzyl(methyl)amino]-2-(4-fluorophenyl)quinoxaline-6-carboxylate as yellow oil (100 mg, 39%).
Reaction SMILES: Br[CH2:2][C:3]([CH3:18])([CH3:17])[CH2:4][O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7].[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:17][C:3]([CH3:18])([CH2:2][O:24][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])[CH2:4][O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7]
Reactant: CCCC1CCC(C(=O)OCC(C)(C)CBr)CC1
Reactant: C=C(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C(C)C(=O)OCC(C)(C)COC(=O)C1CCC(CCC)CC1

Procedure:
4-Propyl-cyclohexanecarboxylic acid 3-bromo-2,2-dimethyl-propyl ester (4.3 g, 13.3 mmol), methacrylic acid (3.4 g, 39.9 mmol) and potassium carbonate (6.9 g, 50.0 mmol) are stirred at 100° C. in dimethyl sulphoxide (100 ml) for 3d. A solid precipitate is removed by filtration and washed with diethyl ether. The filtrate is washed with water, removed, dried and evaporated to dryness. Purification is achieved by flash column chromatography using petrol as eluant to give 22 as a liquid.