Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.O>O1CCCC1>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:8]([S:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:9]#[N:10]
Reactant: COc1ccc(C(C#N)SC2CCCCC2)cc1OC
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)(CCCCCBr)SC2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.57 g of product from Example 82 in 180 ml of anhydrous tetrahydrofuran, under argon, is added 1.3 g of 50% sodium hydride in oil. The mixture is stirred at room temperature for 1 hour; followed by the addition of 10.6 ml of 1,5-dibromopentane and the stirring is continued for 4 hours at room temperature. The reaction mixture is poured into 450 ml of water and extracted with diethyl ether. The organic layer is washed with saturated sodium chloride, dried, filtered and concentrated in vacuo to give 23 g of a crude oil. The oil is purified by chromatography (silica gel: hexane to 10% ethyl acetate/hexane) to give 8.9 g of the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:10])[CH:3]=[CH:2]1.N1C=CC=CC=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH:10][S:18]([CH3:17])(=[O:20])=[O:19])[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc2cc[nH]c12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc2cc[nH]c12
Yield: 94 %

Procedure:
Stir 1H-indol-7-ylamine with pyridine (1 equivalent) and methanesulfonyl chloride (1 equivalent) in dichloromethane for 12 hrs. Wash the reaction with 1N hydrochloric acid and water, dry over magnesium sulfate, and evaporate. Recrystallize the residue from isopropanol to obtain the title product as a purple solid (94%). MS (ES+), 210 (M), MS (ES−), 209 (M−1). LC/MS shows 95% purity.
Reaction SMILES: Cl.Cl.[C:3]1([CH2:9][O:10][NH:11][CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][NH:14][CH2:13]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[O:29]=[C:30](Cl)OC(Cl)(Cl)Cl.CN(C1C=CC=CN=1)C>C(#N)C>[C:3]1([CH2:9][O:10][N:11]2[CH:12]3[CH2:13][N:14]([NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=43)[C:30]2=[O:29])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc(CONC2CNNc3ccccc32)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1N2CC(c3ccccc3N2)N1OCc1ccccc1
Reaction time: 1 h
Yield: 135.7 %

Procedure:
3.13 g of the compound obtained in stage C are dissolved in 1.9 l of acetonitrile. 4.81 g (6.6 ml) of triethylamine are added dropwise over 10 minutes. 0.943 g (575 μl) of diphosgene is subsequently added slowly at 0° C., followed by 1.27 g of dimethylaminopyridine. The temperature is subsequently allowed to return to ambient temperature. After one hour, the acetonitrile is evaporated and the residue is treated with NaH2PO4 (1M aqueous solution). Extraction is carried out with a heptane/AcOEt 1:2 mixture and washing is carried out with water. The organic phase is dried over MgSO4 and evaporated to dryness. This residue is crystallized from ether at 0° C. 1.82 g of the expected compound (68%) are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]([O:10][CH3:11])=[O:9])[N:6]2[C:12](=[O:25])[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C@H:5]2[S:4][CH2:3]1.[N+](=[CH2:28])=[N-]>O1CCOCC1.CCOCC>[CH3:28][O:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:13]([N:14]3[C:18](=[O:19])[C:17]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]4[C:15]3=[O:24])[C:12](=[O:25])[N:6]2[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1C(=O)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)C1=C(OC)CS[C@@H]2C(N3C(=O)c4ccccc4C3=O)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 3-oxo-7-phthalimidocepham-4-carboxylate (b) thus prepared by above methods is dissolved in dioxane, mixed with a solution of diazomethane in ether, and stirred for 1 hour at room temperature. The reaction mixture is evaporated under reduced pressure to give methyl 3-methoxy-7-phthalimido-3-cephem-4-carboxylate in nearly quantitative yield. Recrystallization from a mixture of acetone and ether gives ure crystals, m.p. 225-227° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[OH:12].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[O:12][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: Oc1cc2ccncc2cc1Br
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccncc4cc3Br)c2cc1OC
Temperature: 140 °C
Reaction time: 7 h
Yield: 44.6 %

Procedure:
7-Bromo-6-hydroxyisoquinoline (11 mg), 4-chloro-6,7-dimethoxyquinoline (31 mg), and 4-dimethylaminopyridine (17 mg) were suspended in o-dichlorobenzene (2 ml), and the mixture was stirred at 140° C. for 7 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (9 mg, yield 48%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[C:10](OCC)=[O:11])=[CH:5][CH:4]=1)#[N:2].[CH3:16][C@H:17]1[CH2:22][C@@H:21]([OH:23])[C@H:20]([CH:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1>CC(OC)(C)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:15])[C:10]([O:23][C@@H:21]2[CH2:22][C@H:17]([CH3:16])[CH2:18][CH2:19][C@H:20]2[CH:24]([CH3:26])[CH3:25])=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(=O)c1ccc(C#N)cc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: COC(C)(C)C
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)C(=O)c1ccc(C#N)cc1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
A mixture of ethyl (4-cyanophenyl)(oxo)acetate (35.2 g, 173 mmol), (1R,2S,5R)-(−)-menthol (41.0 g, 262 mmol), and titanium ethoxide (3.6 mL, 17 mmol) was heated to 80 ° C. under vacuum for 60 hours. The mixture was diluted with MTBE (1.5 L), washed sequentially with 10% HCl (2×300 mL), saturated aqueous NaHCO3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2% ethyl acetate/hexanes to provide the desired product (50.0 g, 92% yield). 1H NMR (CDCl3) δ 8.12 (m, 2H), 7.82 (m, 2H), 5.01 (ddd, 2H), 2.15 (m, 1H), 1.91 (m, 1H), 1.72 (m, 2H), 1.55 (m, 2H), 1.16 (m, 2H), 0.97(d, 3H), 0.91 (d, 3H), 0.83 (d, 3H).
Reaction SMILES: C(OC(NCCCl)=O)(C)(C)C.[NH2:12][NH2:13].F[C:15]1[C:28]2[C:27](=O)[C:26]3[CH:25]=[N:24][CH:23]=[CH:22][C:21]=3[C:20](=[O:30])[C:19]=2[C:18]([O:31][S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[CH:17][CH:16]=1.ClC1C2C(=O)C3C=NC=CC=3C(=O)C=2C(OS(C2C=CC(C)=CC=2)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:38]1([CH3:41])[CH:39]=[CH:40][C:35]([S:32]([O:31][C:18]2[CH:17]=[CH:16][C:15]3[NH:13][N:12]=[C:27]4[C:26]5[CH:25]=[N:24][CH:23]=[CH:22][C:21]=5[C:20](=[O:30])[C:19]=2[C:28]=34)(=[O:33])=[O:34])=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2ccncc2C3=O)cc1
Reactant: NN
Agent: CC(C)(C)OC(=O)NCCCl
Agent: Cc1ccc(S(=O)(=O)Oc2ccc(Cl)c3c2C(=O)c2ccncc2C3=O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)Oc2ccc3[nH]nc4c3c2C(=O)c2ccncc2-4)cc1

Procedure:
(2-N-tert-butoxycarbonylaminoethyl)hydrazine is prepared by reaction of N-t-butoxycarbonyl-2-chloro-ethylamine with hydrazine following a procedure adapted from J. Med. Chem. 7, 493, (1964). Under a nitrogen atmosphere a solution of (2-N-tert-butoxycarbonylaminoethyl)hydrazine (9.2 g) in anhydrous THF (10 mL) is added during 30' to the stirred 9:1 mixture of 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy)benzo [g]isoquinoline-5,10-dione of Preparative Example 15b (3.0 g) in THF (25 mL) containing N,N-diisopropylethylamine (1.38 mL). A slightly exothermic reaction ensues, and the reaction temperature increases from 21° C. to 24° C. After stirring for one hour at room temperature the obtained precipitate is recovered by suction, washed with THF/n-hexane 1/1 (15 mL) and dried at 40° C. under vacuum, to give 2-[2-(N-tert-butoxycarbonylamino)ethyl[-5-(p-toluenesulfonyloxy)iso-quino[8,7,6-cd]indazole-6(2H)-one (1.33 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[O:12][CH2:13][CH3:14])[CH3:2].[Br:16]Br>O.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([Br:16])[C:8]([Cl:11])=[CH:7][C:6]=1[O:12][CH2:13][CH3:14])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1ccc(Cl)cc1OCC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)c(Cl)cc1OCC
Reaction time: 72 h
Yield: 64 %

Procedure:
To a solution of 4-chloro-2-ethoxy-benzoic acid ethyl ester (1.46 g, 6.4 mmol) in 13 mL of water and methylene chloride (1:1 mixture) was added bromine (360 uL, 7 mmol). The reaction was stirred for three days. The organic layer was separated. It was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 5-bromo-4-chloro-2-ethoxy-benzoic acid ethyl ester (1.26 g, 64%). LC-MS: 307.1 [(M+H)+].
Reaction SMILES: CN(C=O)C.[CH2:6]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][C:17]=2[C:24]([F:27])([F:26])[F:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:6]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[O:23][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])=[CH:20][CH:19]=[CH:18][C:17]=2[C:24]([F:27])([F:25])[F:26])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Oc1c(Cc2ccccc2)cnc2c(C(F)(F)F)cccc12
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cccc2c(OCCCCCCBr)c(Cc3ccccc3)cnc12
Yield: 85.8 %

Procedure:
A DMF (3 mL) solution of 3-benzyl-8-(trifluoromethyl)quinolin-4-ol (500 mg, 1.65 mmol), 1,6-dibromohexane (3.22 g, 13.20 mmol), and potassium carbonate (455.7 mg, 3.30 mmol) was stirred at room temperature overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane:ethyl acetate), and the title compound (660 mg, yield 86%) was obtained as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[NH2:13][C@H:14]([CH2:16][OH:17])[CH3:15].C(N(CC)CC)C>ClCCl>[OH:17][CH2:16][CH:14]([NH:13][C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9])[CH3:15]
Reactant: C[C@H](N)CO
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CO)NC(=O)c1cn(C)nc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
At 0° C., a solution of 38.9 g 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.2 mol) in 100 ml dichloromethane is added dropwise to a stirred solution of 15 g alaninol (0.2 mol) and 25 g triethylamine (0.25 mol) in 400 ml dichloromethane. The reaction mixture is stirred for 1 h at ambient temperature and then allowed to stand for 3 h at ambient temperature. After removal of the solvent the residue is purified by flash chromatography over silica gel 400 g (eluent: ethyl acetate/methanol 19:1). 42 g (90% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide is obtained in form of a solid (mp. 81-87° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:8][S:9]([NH:12][C:13](=O)OC(C)(C)C)(=[O:11])=[O:10])([O-:3])=[O:2].[C:23]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][NH:8][S:9]([NH:12][CH2:13][CH3:23])(=[O:11])=[O:10])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc([N+](=O)[O-])c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CCO
Solvent: C1CCOC1
Product: CCNS(=O)(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude tert-butyl N-(3-nitrobenzylsulfamoyl)carbamate, triphenylphosphine (2 g) and diisopropyl azodicarboxylate (DIAD, 1.6 g) were dissolved in THF (20 mL) and ethanol (0.47 ml). The solution was stirred at ambient temperature overnight. The reaction solution was evaporated to dryness. The residue was dissolved in methanol (10 mL) and treated with 4.0 M HCl in dioxane (10 mL). It was stirred at rt overnight and then evaporated. The residue was diluted with ethyl acetate (100 mL) and washed with NaHCO3 aq. (2×100 mL). The organic solution was evaporated and purified by flash column chromatography (EtOAc/hexane=1/2, 1/1) to give N-(3-nitrobenzyl)-N′-ethylsulfamide. 1H NMR (DMSO-d6): δ 1.02 (t, J=7.2 Hz, 3H), 2.82 (p, J=6.9 Hz, 2H), 4.14 (d, J=6.6 Hz, 2H), 6.93 (t, J=5.4 Hz, 1H), 7.54 (t, J=6.3 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 8.10 (d, J=8.1 Hz, 1H), 8.20 (s, 1H); LCMS: purity: 1.2 g, 88.4%; MS (m/e): 260.16 (MH+).
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[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:25]([C:30]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[C:35]([Cl:42])[CH:34]=2)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[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:37]([C:36]3[CH:40]=[CH:41][C:33]([NH:32][C:30]([C:25]4[C:24]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:31])=[CH:34][C:35]=3[Cl:42])=[O:38])[CH2:6][C:5]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1Cl
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
To a solution of 0.52 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.39 g of N,N-diisopropylethylamine in 25 ml of methylene chloride is added 1.1 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried (Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through hydrous magnesium silicate two additional times to give upon concentration in vacuo 1.10 g of the desired product as a residue. M+=516,518,520.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:22][C:23]([N:25]([CH3:36])[C:26]1[CH:35]=[CH:34][C:29]2[N:30]=[C:31]([CH3:33])[O:32][C:28]=2[CH:27]=1)=[O:24]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([CH2:22][C:23]([N:25]([CH3:36])[C:26]3[CH:35]=[CH:34][C:29]4[N:30]=[C:31]([CH3:33])[O:32][C:28]=4[CH:27]=3)=[O:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ccccc12
Reactant: Cc1nc2ccc(N(C)C(=O)CBr)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(N(C)C(=O)Cn3nc(-c4cccc(Cl)c4)c4ccccc4c3=O)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
To a solution of 4-(3-chlorophenyl)phthalazin-1(2H)-one (0.5 g, 1.94 mmol) in DMF (20 mL) was added NaH (60%) (0.116 g, 2.91 mmol) portionwise at 0° C. After stirring for 30 min, 2-bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl) acetamide (0.55 g, 1.94 mmol) in DMF (2 mL) was added dropwise and the reaction mixture warmed to rt overnight. The reaction was quenched with water and the solid collected by filtration. The crude was purified by column chromatography (60-70% EtOAc/hexane) to give 2-(4-(3-chlorophenyl)-1-oxophthalazin-2(1H)-yl-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (0.22 g), (MS: ESI +ve, 459.17 [M+H]). 1H NMR: (400 MHz, DMSO) δ: 2.63 (s, 3H), 3.24 (s, 3H), 4.73 (s, 2H), 7.44-7.46 (d, J=8.0, 1H), 7.55-7.66 (m, 4H), 7.69-7.74 (q, 2H), 7.93 (s, 3H), 8.29-8.31 (d, J=7.2, 1H). Representative compounds of the invention were prepared in a similar manner to examples 1 from 4-chlorophthalazin-1(2H)-one, the corresponding boronic acid or ester, and the appropriate alkylating agent (scheme 1).
Reaction SMILES: [C:1](OC)([O:5][CH3:6])([O:3]C)[CH3:2].[CH3:9][C:10]([CH3:14])=[CH:11][CH2:12]O.P(=O)(O)(O)O>CO>[CH3:9][C:10]([CH3:14])([CH:11]=[CH2:12])[CH2:2][C:1]([O:5][CH3:6])=[O:3]
Reactant: COC(C)(OC)OC
Reactant: CC(C)=CCO
Agent: O=P(O)(O)O
Solvent: CO
Product: C=CC(C)(C)CC(=O)OC
Yield: 40.5 %

Procedure:
A mixture of trimethyl orthoacetate (120 g; 1 mole), 3-methylbut-2-enol (21.5 g; 0.25 mole) and orthophosphoric acid (1.5 g; 0.015 mole) was placed in a flask equipped with a stirrer and a 10 cm fractionating column packed with Fenske rings. The mixture was heated, with stirring, to a temperature of 95° to 110° C. and maintained at this temperature for a period of 2 hours while the methanol formed was collected by distillation. The excess trimethyl orthoacetate was distilled from the reaction mixture over a period of 1 hour during which time the temperature of the reaction mixture was raised to 140°-145° C. The reaction mixture was heated with stirring, at a temperature of 140°-145° C. for a period of 1 hour and then product was distilled to give methyl 3,3-dimethylpent-4-enoate (14.4 g; 40.6%); bp 95°-99° C. at 140 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24](=[O:27])[N:25]([CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:13])([CH3:1])[CH:3]3[OH:12])[N:26]=2)=[CH:17][CH:16]=1
Reactant: CC1(C)Oc2ccncc2C2OC21
Reactant: O=c1ccc(-c2ccc(Cl)cc2)n[nH]1
Product: CC1(C)Oc2ccncc2C(n2nc(-c3ccc(Cl)cc3)ccc2=O)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 6-(4-chloro-phenyl)-2H-pyridazin-3-one as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>ClCCl>[CH3:10][S:11]([O:9][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:13])=[O:12]
Reactant: OCc1cccnc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cccnc1F

Procedure:
A solution of (2-fluoropyridin-3-yl)methanol (400 mg, 3.1 mmol), methanesulfonyl chloride (0.37 mL, 4.7 mmol) and triethylamine (0.88 mL, 6.30 mmol) in dichloromethane (10 mL) was stirred at rt for 16 h. The mixture was then diluted with dichloromethane and washed with H2O, then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give (2-fluoropyridin-3-yl)methyl methanesulfonate.
Reaction SMILES: [Br:1]C1C(C(OC)=O)=NC(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=CN=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:31]1[N:32]=[CH:33][C:34]([NH:39][C@@H:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@@H:41]2[OH:49])=[N:35][C:36]=1[O:37][CH3:38]>>[Br:1][C:33]1[C:34]([NH:39][C@@H:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@@H:41]2[OH:49])=[N:35][C:36]([O:37][CH3:38])=[C:31]([C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[Cl:23])[N:32]=1
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Reactant: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1-c1ccc(Cl)cc1Cl
Product: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(Br)nc1-c1ccc(Cl)cc1Cl

Procedure:
Following the procedure for the preparation of methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate but substituting (1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxypyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 3.09–3.13, 3.29–3.34, 3.92, 4.81, 5.60–5.63, 5.99, 7.33–7.42, 7.49; MS (ESI+) for C20H16BrCl2N3O2 m/z 479 (M+H)+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=2)[N:14]=[C:13]([S:22][CH3:23])[N:12]=1.C[C:25]1[CH:30]=[CH:29][C:28]([N:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[NH2:32])=[CH:27][CH:26]=1>O1CCOCC1>[CH3:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([S:22][CH3:23])[NH:12][C:11]2=[N:32][N:31]([C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CSc1nc(Cl)c2cc(C)ccc2n1
Reactant: CCOC(=O)N(N)c1ccc(C)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N(N=c1[nH]c(SC)nc2ccc(C)cc12)c1ccccc1

Procedure:
N,N-Diisopropylethylamine (0.104 mL, 0.6 mmol) was added to a solution of 11b (0.071 g, 0.3 mmol) and 10a, (0.057 g, 0.3 mmol) in 5 mL of dioxane and the solution was heated at reflux for 48 h; during which a white precipitate fell out. The white slurry was filtered and the precipitate was washed with dioxane to give 12 as a white solid. (0.110 g, 100%). mp. 229.7° C.;
Reaction SMILES: Br([O-])(=O)=O.[Na+].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1.CC[O:17]CC>C(#N)C.O>[F:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:17])=[O:12])=[CH:9][CH:8]=1
Reactant: OCc1ccc(F)cc1
Reactant: CCOCC
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 40 h
Yield: 86 %

Procedure:
A mixture of the Ceiv catalyst from Example 47 (0.08 g), sodium bromate (0.3 g) and 4-fluorobenzyl alcohol (0.256 g, 2 mmol) in acetonitrile:water (1:1, 10 ml) was stirred at 80° C. for 40 h under an atmosphere of nitrogen. On cooling ether (70 ml) was added and the catalyst was filtered off. The organic layer was separated and the aqueous phase was extracted with ether (2×50 ml). The combined organic extracts were washed with water (25 ml), dried with anhydrous magnesium sulphate and concentrated to give 4-fluorobenzoic acid as a white solid (0.24 g, 86%). M.p. 182° C., lit. 185° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:9].C([Li])CCC.CN([CH:18]=[O:19])C>CCOCC.CCCCCC>[CH3:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Cc1cncc(C)c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cncc(C)c1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-3,5-dimethylpyridine (0.70 g, 3.76 mmol) in ether (10 mL) was cooled to −78° C. and then 2.50 M n-butyllithium in hexane (1.50 mL) was added to the reaction flask dropwise. After stirring at −78° C. for 1 h, DMF (1.75 mL, 22.6 mmol) was added to the reaction flask slowly. The reaction solution was allowed to warm to room temperature overnight. The reaction was quenched with 10 mL saturated NH4Cl solution and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate once. The combined organic solutions were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (40% to 50% ethyl acetate/hexanes) to afford the desired product as a solid. (280 mg, 55%). 1H NMR (400 MHz, CDCl3): δ 10.62 (s, 1H), 8.43 (s, 2H), 2.57 (s, 6H).