Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=1.[CH:13]1([CH2:16][NH2:17])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:13]1([CH2:16][NH:17][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: NCC1CC1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(NCC2CC2)nc1
Yield: 95.5 %

Procedure:
Ethyl 2-chloropyrimidine-5-carboxylate (500 mg, 2.68 mmol), cyclopropylmethylamine (0.28 mL, 3.22 mmol) and DIPEA (0.58 mL, 3.35 mmol) were dissolved in DMF (4 mL) and the reaction mixture was heated using a microwave reactor at 100° C. for 20 min. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (50 mL) and sat aq NaHCO3 (40 mL). The organic fraction was dried (MgSO4) and concentrated in vacuo to give the title compound (566 mg, 95.5%) as a yellow solid. LCMS (ES+): 222.1 [MH]+. HPLC: Rt 5.79 min, 92.9% purity.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][C:9]([O:16][OH:17])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12]>>[CH3:6][C:5]([O:17][O:16][C:9]([CH3:15])([CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH2:4][C:2](=[O:1])[CH3:3])[CH3:7]
Reactant: CC(C)(C)CC(C)(C)OO
Reactant: CC(=O)C=C(C)C
Product: CC(=O)CC(C)(C)OOC(C)(C)CC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 49 g (0.50 mole) of mesityl oxide and 10 g of Amberlyst 15® sulfonic acid type ion-exchange resin was stirred at 0°-5° C., while 78 g (0.45 mole) of 84% 1,1,3,3-tetramethylbutyl hydroperoxide was added slowly. The reaction mixture was allowed to warm to 25° C. and the stirring continued for 16 hours. The ion-exchange resin was separated by filtration. Iodometric assay showed that substantially all of the hydroperoxide had reacted. The infrared spectrum and G.L.C. showed the presence of the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[N:9]1[CH:10]=[C:6]([CH2:4][OH:3])[N:7]=[CH:8]1
Reactant: CCOC(=O)c1cn(-c2ccc3ccccc3n2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cn(-c2ccc3ccccc3n2)cn1

Procedure:
Following the general method described in example 298, 1-quinolin-2-yl-1H-imidazole-4-carboxylic acid ethyl ester was reacted with lithium aluminum hydride followed by hydrolytic workup and chromatography. The title compound was obtained as an off-white crystalline material. Mp. 136-137° C. (EtOH), MS: m/e=225 (M+).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[Cl:25])[C:6]=1[CH3:26].COC(=O)CC1C2C(=NC=CC=2)NC=1C.[H-].[Na+].BrCC1C=CC(S(C)(=O)=O)=CC=1Cl.[I-].[Na+]>CN(C=O)C>[Cl:25][C:16]1[CH:17]=[C:18]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:19]=[CH:20][C:15]=1[CH2:14][N:7]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[C:5]([CH2:4][C:3]([OH:27])=[O:2])=[C:6]1[CH3:26]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2Cl)c2ncccc12
Agent: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[1-(2-Chloro-4-methanesulfonyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To an ice cooled (0° C.) stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((2.25 g, 1.1 mmol) in dry DMF (15 ml) is added sodium hydride (0.484 g of a 60% dispersion in mineral oil, 12.1 mmol). After stirring at room temperature for 3 hours, the reaction mixture is re-cooled to 0° C. and treated with 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene (5.0 g, 17.6 mmol) and sodium iodide (2.64 g, 17.6 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is poured onto water (300 ml) and extracted with 1:1 ethyl acetate/diethyl ether. The organic portions are washed with brine, dried (Na2SO4) and concentrated in vacuo and the resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:4 increasing to 1:2) to yield the titled product. (MH+407)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]#[N:22])[C:9]=2[CH3:23])=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:26][N:25]=[N:24][N:22]=3)[C:9]=2[CH3:23])=[CH:6][CH:7]=1
Reactant: Cc1c(C#N)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2nnn[nH]2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 97.5 %

Procedure:
A mixture of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonitrile (500 mg, 1.39 mmol), sodium azide (1.08 g, 16.6 mmol) and ammonium chloride (890 mg, 16.6 mmol) dissolved in dimethylformamide (3 ml) was placed in a microwave synthesizer tube, and subjected to microwave irradiation in a Biotage® Initiator was set at 180° C. After 20 minutes, the mixture was quenched with water and extracted with ethyl acetate. The solvent of the extracted organic layer was evaporated off and the residue was purified by reverse phase preparative HPLC, to obtain 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-1H-tetrazole (550 mg, 98%) as white solid.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17]C)=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].Cl>CO.O>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCOc1cccc(C(=O)O)c1

Procedure:
A solution of methyl 3-decyloxybenzoate (9.64 g, 0.033 mol) and sodium hydroxide (6.60 g, 0.165 mol) in methanol (150 ml) and water (15 ml) was heated under reflux for 2 h. The reaction mixture was then allowed to cool, followed by addition of dilute HCl (100 ml). The crude product was filtered off, washed with water and then dried in vacuo. The material was recrystallised to yield colourless crystals.
Reaction SMILES: [C:1]([C:6]1[CH:16]=[CH:15][C:9]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]>CCO>[CH2:4]([O:3][C:1]([C:6]1[CH:16]=[CH:15][C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:7]=1)=[O:2])[CH3:5]
Reactant: CCOC(=O)c1ccc(C=CC(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1ccc(CCC(=O)O)cc1
Yield: 45.1 %

Procedure:
a solution of 4-carbethoxycinnamic acid (4.9 g) in EtOH (120 ml) was hydrogenated over 5% RH/C (485 mg) at atmosphere pressure for 21 hr. The solution was filtered and stripped. The residue was crystallized from cyclohexane to afford 2.23 g (46%) of the title compound as white crystals; mp 108.5°-110.5°.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH:18]([CH3:20])[O:17][N:16]=2)=[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:14]([C:15]2[CH2:19][CH:18]([CH3:20])[O:17][N:16]=2)=[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:12]=[CH:11][C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)=NO1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1CC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2Cl)=NO1

Procedure:
5.7 g (51 mmol) of thionyl chloride were added dropwise at room temperature to a solution of 13.0 g (41 mmol) of 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoic acid, 1 ml of dimethylformamide and 250 ml of dry toluene. The mixture was subsequently refluxed until the reaction was complete. After cooling, the solvent was distilled off. This gave 14.2 g of 2-chloro-3-(5-methyl-4,5-dihydroisoxazol-3-yl)-4-methyl-benzoyl chloride in quantitative yield.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([F:22])([F:21])[O:20][C:16]=2[CH:15]=1)[C:9]([O:11]C)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:14]1[CH:24]=[CH:23][C:17]2[O:18][C:19]([F:21])([F:22])[O:20][C:16]=2[CH:15]=1)[C:9]([OH:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC(F)(F)O2)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccc2c(c1)OC(F)(F)O2)C(=O)O
Reaction time: 2 h
Yield: 106 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoate (1850 mg, 5 mmol) in 50 mL of THF at 0° C. was added LiOH (0.2 M, 26 ml, 5 mmol) over 10 minutes. The reaction was stirred for 2 hours and was then washed with ether (200 mL), acidified to pH 4 with 2 N HCl and extracted with ethyl acetate (4×100 mL). The organics were washed with water and brine and dried over sodium sulfate. Concentration provided (S)-2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoic acid (1.75 g, 98% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC1SC(C(Cl)=O)=C(C)N=1)C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:42][CH:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:44]#[N:45]>C(N(CC)CC)C>[C:44]([CH:43]([NH:42][C:15]([C:11]1[S:10][C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:13][C:12]=1[CH3:14])=[O:17])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)#[N:45]
Reactant: Cc1nc(NCc2ccccc2)sc1C(=O)O
Reactant: N#CC(N)c1ccccc1
Agent: Cc1nc(NCc2ccccc2)sc1C(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(NCc2ccccc2)sc1C(=O)NC(C#N)c1ccccc1
Yield: 38.8 %

Procedure:
1.2g of 2-benzylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-benzylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.1g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 0.89g of amino-phenylacetonitrile hydrochloride and 2.3ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.68g (Yield 39%) of the title compound.
Reaction SMILES: [CH:1]1([B-](F)(F)F)[CH2:3][CH2:2]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](Br)=[C:21]([Cl:26])[N:20]=1)=[O:18]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(PC12CC3CC(CC(C3)C1)C2)CCC>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH:1]2[CH2:3][CH2:2]2)=[C:21]([Cl:26])[N:20]=1)=[O:18]
Reactant: COC(=O)c1ccc(Br)c(Cl)n1
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCPC12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(C2CC2)c(Cl)n1
Temperature: 100 °C
Yield: 58.9 %

Procedure:
To a mixture of palladium(II)acetate (17.9 mg, 79.8 μmol), butyl-1-adamantylphosphine (42.9 mg, 120 μmol), potassium cyclopropyltrifluoroborate (597 mg, 4.03 mmol) and cesium carbonate (3.9 g, 12.0 mmol) under an argon atmosphere was added a solution of 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (CAN 1214353-79-3, 1 g, 3.99 mmol) in toluene (25.2 ml) and water (2.8 mL) under an argon atmosphere. The reaction mixture was heated to 100° C. for 20 h, diluted with water (17.5 ml), poured onto 100 ml ice/brine and extracted with i-PrOAc (2×100 mL). The combined extracts were dried over sodium sulfate and concentrated in vacuo to give a yellow liquid. This crude material was purified by column chromatography (70 g SiO2, n-heptane/i-PrOAc 0-10% over 120 min) to give the title compound (497 mg, 59%) as yellow solid, MS (EI): m/e=212.0 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH2:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[NH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1.Cl>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:14][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([NH2:16])=[CH:18][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1ccc(N)cc1
Yield: 21.6 %

Procedure:
(S)-2-(4-Amino-benzoylamino)-3-(4-bromo-phenyl)-propionic acid methyl ester (415 mg) was prepared from (S)-2-amino-3-(4-bromo-phenyl)-propionic acid methyl ester-hydrochloride (1.5 g, 5.1 mmol) and 4-amino-benzoic acid (698 mg, 5.1 mmol) as described in Procedure A, except for an adapted work-up. After reaction completion, the reaction mixture was poured onto 100 mL of 1N HCl and 100 mL of EtOAc. The organic layer was washed with 1N HCl (2×), 10% sodium carbonate, dried over sodium sulfate and evaporated. The crude material was purified over silica gel (DCM-EtOAc, 9-1).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:8][C:9]1[CH:32]=[CH:31][C:12]2[C:13]3[N:17]([CH2:18][CH2:19][O:20][C:11]=2[CH:10]=1)[CH:16]=[C:15]([C:21]1[N:22]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:23]=[CH:24][N:25]=1)[N:14]=3)[CH:5]([CH3:7])[CH3:6].O.[OH-].[Li+].Cl.C[N:39](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CO.O>[CH3:6][CH:5]([CH3:7])[CH:4]([O:8][C:9]1[CH:32]=[CH:31][C:12]2[C:13]3[N:17]([CH:16]=[C:15]([C:21]4[N:22]([CH2:26][C:27]([F:28])([F:30])[F:29])[N:23]=[CH:24][N:25]=4)[N:14]=3)[CH2:18][CH2:19][O:20][C:11]=2[CH:10]=1)[C:3]([NH2:39])=[O:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)C(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CC(C)C(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 3-methyl-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid methyl ester in methanol (5 mL) was added water (0.5 mL) and lithium hydroxide monohydrate (22 mg, 0.57 mmol). The reaction mixture was heated at 50° C. for 16 h then HCl (1N, aqueous) added until pH˜4. The reaction mixture was concentrated in vacuo. The resultant residue was dissolved in DMF (3 mL) and HATU (220 mg, 0.57 mmol), ammonium chloride (46 mg, 0.86 mmol) and triethylamine (120 μL, 0.86 mmol) added. The reaction mixture was stirred at RT for 1 h before being concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and the mixture washed with water, extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give 467 as a white solid (121 mg, 36%). LCMS: RT=4.05 min, [M+H]+=451; 1H NMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.3 Hz), 8.03 (1H, s), 7.96 (1H, s), 7.47 (1H, br s), 7.25 (1H, br s), 6.74 (1H, dd, J=8.3, 2.5 Hz), 6.51 (1H, d, J=2.5 Hz), 5.86 (2H, q, J=8.9 Hz), 4.50-4.40 (4H, m), 4.22 (1H, dd, J=6.2 Hz), 2.08 (1H, oct, J=6.3 Hz), 0.96 (3H, d, J=6.3 Hz), 0.94 (3H, d, J=6.4 Hz)
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([CH2:15][C:16]([CH3:24])([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH3:27]I>O1CCOCC1>[CH2:7]([O:6][P:4]([C:9]([CH3:27])([CH2:15][C:16]([CH3:24])([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CI
Reactant: CCOC(=O)CC(C)(C)CC(C(=O)OCC)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CC(C)(C)CC(C)(C(=O)OCC)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethyl 2-diethylphosphono-4,4-dimethyladipate (3.6 parts) (See Example 9) was added dropwise to a suspension of sodium hydride (0.6 parts, 50% in oil) in dry dioxan (100 parts by volume) containing methyliodide (14.2 parts) over 2 hr. at room temperature. The resulting solution was stirred at room temperature for 18 hr. then heated to reflux for 2 hr., cooled, the solids removed by filtration and the filtrate concentrated in vacuo. Distillation of the residual oil gave 3 parts of diethyl 2-diethylphosphono-2,4,4-trimethyladipate, boiling at 137°-8° C./0.03 mm having a 31P chemical shift of -26 ppm and having the following elemental analysis by weight.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[Cl:16][C:17]1[N:26]=[C:25]([CH3:27])[C:24]([Cl:28])=[C:23]([CH3:29])[C:18]=1/[C:19](=[N:21]/O)/[NH2:20]>CN(C)C(=O)C>[Cl:16][C:17]1[C:18]([C:19]2[N:20]=[C:5]([C:4]3[C:3]([N+:13]([O-:15])=[O:14])=[C:2]([OH:1])[C:10]([O:11][CH3:12])=[CH:9][CH:8]=3)[O:7][N:21]=2)=[C:23]([CH3:29])[C:24]([Cl:28])=[C:25]([CH3:27])[N:26]=1
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1O
Reactant: Cc1nc(Cl)c(/C(N)=N/O)c(C)c1Cl
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2nc(-c3c(Cl)nc(C)c(Cl)c3C)no2)c([N+](=O)[O-])c1O
Temperature: 135 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
To a stirred suspension of 3-hydroxy-4-methoxy-2-nitrobenzoic acid (0.900 g, 4.22 mmol) in N,N-dimethylacetamide (10.35 mL) at room temperature was added 1,1-carbonyldiimidazole (1.540 g, 9.506 mmol) in 7.65 ml of N,N-dimethylacetamide dropwise. After stirring for three hours, (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide (1.19 g, 5.107 mmol) was added in 2.7 ml of N,N-dimethylacetamide in one portion. The resulting mixture was stirred for one hour and forty five minutes then heated at 135° C. for one hour. The reaction mixture was poured onto ice/2N HCl mixture. The precipitate was filtered off, washed with water and dried under vacuum to give a yellow solid. Recrystallisation from dichloromethane/isopropanol gave 3-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-6-methoxy-2-nitrophenol as a yellow solid (0.317 g, 18%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1>[CH2:21]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCc1ccccc1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)c1ccccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
24 g of 3-bromocarbazole was dissolved in 100 ml of tetrahydrofuran. To this was added 14 g of potassium carbonate followed by 14 g of benzylchloride and allowed the reaction to stir at room temperature overnight. The reaction mixture was poured into water and the precipitated white solid was filtered, washed with methanol and dried under vacuum to obtain 30 g 9-benzyl-3-bromocarbazole (89%).
Reaction SMILES: [Cl:1][C:2]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([Cl:17])[C:3]=1[CH:4]=[N:5][NH:6][C:7]([NH2:9])=[NH:8]>Cl.C(O)(=O)C>[ClH:1].[ClH:1].[NH2:14][C:13]1[C:2]([Cl:1])=[C:3]([C:10]([Cl:17])=[CH:11][CH:12]=1)[CH:4]=[N:5][NH:6][C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)NN=Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: CC(=O)O
Product: N=C(N)NN=Cc1c(Cl)ccc(N)c1Cl
Yield: 182.9 %

Procedure:
A hot solution of stannous chloride dihydrate (12.8 g, 56.7 mmol) in concentrated hydrochloric acid (15 cm3) was slowly added to a hot stirred solution of (2,6-dichloro-3-nitrobenzylideneamino)-guanidine (2.0 g, 7.2 mmol) in glacial acetic acid (20 cm3). The solution was cooled and the precipitated white solid collected, dissolved in methanol (30 cm3) and the solution saturated with hydrogen sulphide. After filtering off the inorganic salts the filtrate was concentrated and then diluted with diethyl ether to yield a white solid which was recrystallised from methanol-diethyl ether affording (3-amino-2,6-dichlorobenzylideneamino)-guanidine dihydrochloride (1.4 g) m.p. 218°-220° C. (dec).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[O:60][N:59]=[C:58]([C:61](Cl)=[O:62])[CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:58]2[CH:57]=[C:56]([CH3:55])[O:60][N:59]=2)=[O:62])[CH2:49][CH2:48]1
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 56 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as starting materials in 56% yield. LCMS for C29H30ClN8O3 (M+H)+: m/z=573.2.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CCOC(C)=O>CN(C=O)C>[NH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1ccccc1Nc1ccccc1
Yield: 92.6 %

Procedure:
To a stirring solution of N-phenyl-o-phenylene diamine (20 g, 180.55 n M) in 200 ml of DMF at RT was added K2CO3 (16.5 g, 120 mM) followed by tert-butyl bromoacetate (21.17 g 108.55 mM). The resulting mixture was stirred at RT until TLC (Hex:AcOEt 3:1) showed completion of reaction. The mixture was filtered to remove the K2CO3 and then diluted with 800 mL of EtOAc and 200 mL of Et2O. This solution was washed successively with H2O (2×400 mL), brine (1×400 mL), 1 N HCl (2×400 mL), and H2O (1×400 mL), and the organics dried (MgSO4) and concentrated to give a greenish-black oil. The resultant oil was purified by silica gel flash column chromatography using hexane/EtOAc 4/1 and the combined filtrates evaporated in vacuo to give 30 g of product.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[O:6][CH:7]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH2:9]([NH:11][CH2:2][C:3]1[N:4]=[C:5]([CH3:8])[O:6][CH:7]=1)[CH3:10]
Reactant: Cc1nc(CBr)co1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1coc(C)n1

Procedure:
prepared by reaction of 4-bromomethyl-2-methyl-oxazole (prepared according to Pattenden G. et al, Org. & Biomolecular Chem., 2003, 1, 23, 4173-4208) with 2M ethylamine in THF.