Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[NH:5][SH:6](=[O:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[CH:13]=[C:12]([S:14](=[O:17])(=[O:16])[NH2:15])[C:11]([Cl:18])=[CH:10][C:8]=2[N:9]=1>C(COC)OC>[ClH:3].[Cl:18][C:11]1[C:12]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:13][C:7]2[SH:6](=[O:25])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:5][C:4]([NH:2][CH3:1])=[N:9][C:8]=2[CH:10]=1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)N=C(Cl)N[SH]2(=O)c1ccccc1
Reactant: CN
Solvent: COCCOC
Product: CNC1=Nc2cc(Cl)c(S(N)(=O)=O)cc2[SH](=O)(c2ccccc2)N1
Product: Cl

Procedure:
To a stirred mixture of 5.14 g. (0.066 mole) of 40% aqueous methylamine solution and 50 ml. of glyme is added, over a 30 minute period, a solution of 13.5 g. (0.035 mole) of 3,6-dichloro-1-phenyl-7-sulfamyl-1,2,4-benzothiadiazine -1-oxide in 150 ml. of glyme. The reaction mixture is heated under reflux for 10 hours, cooled, concentrated to dryness, and suspended in 100 ml. of 10% hydrochloric acid. Filtration of the solid material yields the product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C@@H:19]([CH3:20])[CH2:18][NH:17][CH2:16][C@@H:15]2[CH3:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C@@H:19]([CH3:20])[CH2:18][N:17]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:16][C@@H:15]2[CH3:21])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccnc1Cl
Reactant: C[C@H]1CNC[C@H](C)N1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ncccc2Cl)C[C@H](C)N1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 27.7 %

Procedure:
To a solution of (2S,6S)-1-[(4-tert-butylphenyl)sulfonyl]-2,6-dimethylpiperazine (120 mg, 0.39 mmol) and 2,3-Dichloropyridine (115 mg, 0.78 mmol) in anhydrous 1,4-Dioxane (0.2 mL) was added diisopropylethylamine (0.201 mL, 1.16 mmol). The mixture was subject to microwave irradiation at 200° C. for 1 hour. Reaction was half complete as determined by TLC. The reaction mixture was diluted with ethyl acetate and washed with saturated NH4Cl (aq.), 10% HCl (aq.), water and brine. Organic layer was dried over MgSO4. Solvent evaporation followed by flash column chromatography afforded (2S,6S)-1-[(4-tert-butylphenyl)sulfonyl]-4-(3-chloropyridin-2-yl)-2,6-dimethylpiperazine in 27.7% yield (45 mg) as off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][Cl:6].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.C(N(CC)CC)C>C1C=CC=CC=1>[ClH:6].[ClH:6].[CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH2:5][N:33]1[CH2:32][CH2:31][N:30]([CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=2)[CH2:35][CH2:34]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: COc1ccc(CCl)c(OC)c1OC
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1OC
Product: Cl
Temperature: 25 °C
Yield: 98.5 %

Procedure:
1.3 g (6.0 millimoles) of 2,3,4-trimethoxybenzyl chloride [see Monatsh., 95 (3), 942 (1964)], 1.7 g (5.9 millimoles) of bis(4-fluorophenyl)methylpiperazine and 1.2 ml (8.6 millimoles) of triethylamine were heated under reflux for 6 hours in 50 ml of benzene. The reaction mixture was allowed to cool to room temperature, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of 2 ml of conc. hydrochloric acid and 20 ml of ethanol was added to the resulting oily product, and the mixture was concentrated under reduced pressure. Ether was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol-ether gave 1.6 g of 1-(2,3,4-trimethoxybenzyl)-4-[bis(4-fluorophenyl)methyl]piperazine dihydrochloride as colorless crystals. The product showed the same property values as the compound obtained in Example 4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[K+].Cl.Cl[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18]>CS(C)=O>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN(C)CCOc1cccc([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
3-Nitro phenol (1 g, 7.19 mmol) was added to a solution of potassium hydroxide (1.6 g, 28.76 mmol) in anhydrous DMSO (6 ml) at room temperature. After 30 min, (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.03 g, 7.19 mmol) was added and the reaction mixture was heated at 80-90° C. for 12 hr. The reaction mixture was cooled to room temperature and diluted with ice water. The product was extracted with toluene and the organic layer was washed with 5% sodium hydroxide solution, then brine and dried. Evaporation under reduced pressure gave dimethyl-[2-(3-nitro-phenoxy)-ethyl]-amine (600 mg, 40%) as oil.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[CH2:6]([O:8][C:9](=[O:26])[C:10](=[CH:22]OCC)[C:11]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21])=[O:12])[CH3:7]>C(O)C>[CH2:6]([O:8][C:9](=[O:26])[C:10](=[CH:22][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:11]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21])=[O:12])[CH3:7]
Reactant: CC(C)(C)N
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1F
Solvent: CCO
Product: CCOC(=O)C(=CNC(C)(C)C)C(=O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
Tert-butylamine (6.2 mL, 84.7 mmoles) was added to a solution of 13.15 g (43.5 mmoles) of 3-(2,4,5-trifluorophenyl)-3-oxo-2-(ethoxymethylene)-propanoic acid ethyl ester in 19 mL of dry ethanol at -15° C. After 5 minutes, the mixture was stirred at room temperature for one hour, and then concentrated to dryness. The crude residue (10.87 g) was crystallized from 25 mL of hexane to afford 7.22 g of titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][CH:13]=4)[C:4]=2[CH:3]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1.C1CCCCC1>[CH3:22][C:15]1([CH3:23])[C:14]2[C:9]3=[C:10]([C:4]4[CH:3]=[C:2]([B:29]([OH:32])[OH:30])[CH:7]=[CH:6][C:5]=4[N:8]3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=3)[CH:11]=[CH:12][CH:13]=2
Reactant: COB(OC)OC
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cccc1c32
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2ccccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Reaction time: 1 h

Procedure:
93.9 g (259 mmol) of 3-bromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine are dissolved in 1500 ml of dry THF. 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., and, after 1 h, 37 ml of trimethyl borate (336 mmol) are added dropwise. The mixture is allowed to come to room temperature over the course of 1 h, and the solvent is removed. The residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification. The yield is 77 g (235 mmol), corresponding to 91% of theory.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[N:13]#[C:14][Br:15].O>CO>[BrH:15].[N:1]1[CH:5]=[CH:4][N:3]2[C:2]=1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[N:8]=[C:14]2[NH2:13]
Reactant: Nc1ccccc1-c1ncc[nH]1
Reactant: N#CBr
Solvent: CO
Solvent: O
Product: Br
Product: Nc1nc2ccccc2c2nccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
To a solution of 2-(1H-imidazol-2-yl)aniline (0.06 g. 0.38 mmol) in methanol (3 ml) was added cyanogen bromide (0.05 g, 0.45 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting precipitate was collected by filtration, washed with acetone, and dried under reduced pressure to give imidazo[1,2-c]quinazolin-5-amine hydrobromide (0.06 g, 61% yield) as a white solid.
Reaction SMILES: [CH:1]#[CH:2].[CH3:3][C:4]([CH3:6])=O>>[CH3:3][CH:4]([CH2:6][CH2:1][CH2:2][CH:4]([CH2:6][CH2:1][CH2:2][CH:4]([CH2:6][CH2:1][CH2:2][CH2:3][CH:4]([CH2:6][CH2:1][CH2:2][CH:4]([CH2:6][CH2:1][CH2:2][CH:4]([CH3:6])[CH3:3])[CH3:3])[CH3:2])[CH3:3])[CH3:3])[CH3:1]
Reactant: C#C
Reactant: CC(C)=O
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C

Procedure:
Ethynylation of 194 g of citronelliodene acetone was carried out with acetylene in the same manner as in example 20 except that citronellidene acetone was used in place of pseudoionone and 278 g of a crude product was thus obtained. This product was subjected to oxydative-coupling, hydrogenation and hydrogenolysis in sequence in the same manner as in example 20 and squalane was thus obtained in a yield of 36.3 % from citronellidene acetone to squalane.
Reaction SMILES: CC(O)=O.CC(O)=O.[Pd:9].[C:10]([OH:14])(=[O:13])[CH2:11][CH3:12]>>[C:10]([O-:14])(=[O:13])[CH2:11][CH3:12].[Pd+2:9].[C:10]([O-:14])(=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)O
Reactant: [Pd]
Solvent: CC(=O)O
Product: CCC(=O)[O-]
Product: [Pd+2]

Procedure:
5 gm commercial palladium(II) acetate trimer (Aldrich) was added to 40 g of propionic acid. The mixture was maintained at 40 degrees Celsius for 24 hours. Excess propionic acid was removed under vacuum at room temperature. The resulting yellow solid was used for making palladium inks.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:8].Cl.[NH2:10][C:11]1C=CC=[CH:13][CH:12]=1.N([O-])=O.[Na+].C(#N)C=C>O.CO>[Cl:8][CH:12]([CH2:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]#[N:10]
Reactant: Cl
Reactant: Nc1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: C=CC#N
Solvent: O
Product: N#CC(Cl)Cc1ccccc1
Yield: 88 %

Procedure:
55.8 g (0.6 mol) of aniline and 200 ml of a 25% hydrochloric acid aqueous solution were mixed to obtain a suspension of aniline hydrochloride. While cooling this solution to a temperature of from 0° to 10° C. from outside and stirring it, a solution prepared by dissolving 42.5 g (0.615 mol) of sodium nitrite in 85 ml of distilled water, was dropwise added over a period of about 4 hours. After the completion of the dropwise addition, the reaction mixture was stirred for about 1 hour at a temperature of from 0° to 10° C. To this solution, 200 ml of methanol and 95.4 g (1.8 mols) of acrylonitrile were added, and while stirring the mixture under cooling, 5 g of cuprous oxide powder was gradually added. The reaction mixture was stirred at a temperature of from 10° to 20° C. for 4 hours, and then methanol and unreacted acrylonitrile were distilled off by distillation. The residual solution was separated into an aqueous phase and an organic phase. The organic phase was subjected to distillation under reduced pressure, whereby 87 g (yield: 88%) of α-chloro-β-phenylpropionitrile was obtained. (b.p.: 105°-110° C./4 mmHg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([C@@H:21]3[CH2:27][CH2:26][C@@H:25]4[CH2:28][N:22]3[C:23](=[O:37])[N:24]4[O:29]CC3C=CC=CC=3)=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([C@@H:21]3[CH2:27][CH2:26][C@@H:25]4[CH2:28][N:22]3[C:23](=[O:37])[N:24]4[OH:29])=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)[C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)ccc2C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)[C@@H]3CC[C@@H]4CN3C(=O)N4O)ccc2C1
Reaction time: 8 h

Procedure:
To a solution of the product of Step 1 (79.6 mg, 0.157 mmol) in methanol (4 mL) and ethyl acetate (2 mL), was added 10% palladium on carbon (18 mg) and the reaction mixture was stirred under an atmosphere of hydrogen (balloon) overnight. LC/MS analysis showed the reaction was not quite complete so an additional 10% palladium on carbon (10 mg) was added and the reaction mixture was stirred under an atmosphere of hydrogen (balloon) for an additional 6 hours. The reaction mixture was filtered through a microfilter and the collected solid was washed well with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene to afford the title compound as a light brown oil which was used directly in the next step without purification
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH:11]1([CH2:14][OH:15])[CH2:13][CH2:12]1.[OH-].[K+]>CS(C)=O>[CH:11]1([CH2:14][O:15][C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: OCC1CC1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCC2CC2)cn1
Temperature: 80 °C
Yield: 34 %

Procedure:
A solution of 5-chloro-pyrazine-2-carboxylic acid (1.50 g, 9.46 mmol) in dry dimethylsulfoxide (5 ml) was treated at 25° C. with cyclopropyl-methanol (1.02 g, 14.1 mmol) and powdered potassium hydroxide (2.12 g, 37.4 mmol). The mixture was heated in a microwave oven at 80° C. for 90 minutes. For the workup, the reaction mixture was quenched with an aqueous solution of citric acid (10%), then extracted with ethyl acetate (5×30 ml), followed by the extraction with a 4:1-mixture of dichloromethane and methanol. The combined organic layers were washed with brine (200 ml), dried and evaporated ate reduced pressure. After lyophilization the 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid (34% yield) was obtained as a white solid. MS (ISP): m/z=195.0 [M+H]+.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(C)ccn1
Reactant: NO
Solvent: CO
Product: Cc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 72 h
Yield: 47 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (101 mg, 0.3 mmol) in MeOH (2 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×5 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:3 to 100:7) to furnish III as a colourless oil (46 mg, 47%).
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[C:12]([Br:24])[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:14]=2)[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=1)[CH3:6].[OH:32][CH2:33][C:34]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1>ClCCl.C1CCCCC1>[Br:24][C:12]1[N:13]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[N:14]=[C:15]2[C:11]=1[CH:10]=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=[C:7]2[CH:5]([O:32][CH2:33][C:34]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])[CH2:36][CH2:35]1)[CH3:6]
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2c(Br)n(COCC[Si](C)(C)C)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2c(Br)n(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(3-Bromo-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (1.29 g, 2.21 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.71 g, 2.43 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 8 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (60 μL, 0.44 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate and diluted with diethyl ether and the layers separated. The ethereal was washed with water (2×), 1 M potassium bisulfate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10% ethyl acetate/hexanes) gave 840 mg (53%) as a yellow film. 1H-NMR (CDCl3, 500 MHz) δ 7.82 (s, 1H), 7.54 (s, 1H), 7.24-7.27 (m, 2H), 7.18-7.22 (m, 3H), 5.51 (s, 2H), 5.07 (q, J=6.4 Hz, 1H), 3.74 (m, 2H), 3.44-3.51 (m, 2H), 3.27 (d, J=9.2 Hz, 1H), 3.24 (d, J=9.2 Hz, 1H), 2.99-3.03 (m, 2H), 2.11-2.16 (m, 2H), 1.82-1.88 (m, 2H), 1.50 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 0.70-0.83 (m, 2H), 0.08 (s, 9H). Mass spec.: 736.03 (MNa)+.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[NH2:42][C:43]1[CH:47]=[N:46][N:45]([CH2:48][C:49]2[O:50][CH:51]=[C:52]([C:54](=[O:56])[CH3:55])[N:53]=2)[N:44]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:54]([C:52]1[N:53]=[C:49]([CH2:48][N:45]2[N:44]=[C:43]([NH:42][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:47]=[N:46]2)[O:50][CH:51]=1)(=[O:56])[CH3:55]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(=O)c1coc(Cn2ncc(N)n2)n1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (590 mg, 2.72 mmol) in CH2Cl2 (20 mL) was treated at rt with DMAP (82 mg, 0.68 mmol), HOBt (441 mg, 3.62 mmol), EDC (1.3 g, 6.79 mmol) and DIPEA (1.8 mL, 10.86 mmol) and the resulting mixture was stirred for 30 min at rt. A solution of 1-(2-((4-amino-2H-1,2,3-triazol-2-yl)methyl)oxazol-4-yl)ethanone (WO 2009/077990, p. 105) (562 mg, 2.72 mmol) in CH2Cl2 (7.0 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (50 mL), the org. phase was washed with water (50 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a white solid: TLC: rf (4:6 hept-EA)=0.35. LC-MS-conditions 07: tR=0.88 min, [M+H]+=407.05.
Reaction SMILES: P([O-])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].Br[CH2:12][C:13]([OH:15])=O.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>COCCOC>[OH:15][C:13]1[CH:12]=[C:18]2[C:17]([C:6](=[O:5])[CH2:7][C:16]3([O:22]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:16][CH:21]=1
Reactant: CCOP([O-])OCC
Reactant: O=C1CCCCC1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1CC2(CCCCC2)Oc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl phosphite (4 mL, 31.0 mmol) in 1,2-dimethoxyethane (100 mL) was added 60% NaH (3.72 g, 93 mmol). When gas evolution had mostly ceased (10 min), a solution of bromoacetic acid (4.3 g, 30.9 mmol) in 1,2-dimethoxyethane (30 mL) was added slowly. When gas evolution had again ceased, cyclohexanone (3.2 mL, 30.9 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, then was quenched with ethanol (5 mL) and was poured into ice water. The aqueous layer washed with ether, acidified to pH 4 with conc. HCl, and then extracted with ether. The extracts were dried over Na2SO4, filtered and were evaporated in vacuo. The title compound was afforded as a yellow-orange oil, which was mixed in POCl3 (25 mL, 268.2 mmol) with resorcinol (3.39 g, 30.8 mmol) and ZnCl2 (5.9 g, 43.3 mmol). The mixture was stirred at room temperature for 5.5 h and was then poured onto ice. Extraction with ethyl acetate, followed by drying over Na2SO4, filtration and evaporation in vacuo, afforded the crude product as a dark orange oil. Chromatography on silica gel (7:3 hexane-ethyl acetate, eluant) yielded the title compound as an off-white solid, 3.14 g (44%). 1H NMR (300 MHz, DMSO-d6) δ 10.47 (br, 1H), 7.56 (d, J=8.5 Hz, 1H), 6.43 (m, 1H), 6.28 (d, J=2.4 Hz, 1H), 2.63 (s, 2H), 1.44-1.87 (m, 10H). MS (DCI+) m/z 233 (M+H).
Reaction SMILES: C(O)C.[CH2:4]([NH2:6])[CH3:5].[C:7](OC)(=[O:14])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>O>[CH2:4]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[CH3:5]
Reactant: COC(=O)c1ccncc1
Reactant: CCN
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1ccncc1
Reaction time: 8 h

Procedure:
A mixture of 200 ml of ethanol and 20 ml water was cooled in an ice bath and saturated with ethylamine for 0.5 hr. then 80 g of crude methyl isonicotinate was added with cooling. Ethylamine was again bubbled onto the reaction mixture for 10 min and then it was allowed to stand overnight at room temperature. It was then concentrated in vacuo to leave 82.82 g of a pale oil which became semisolid on cooling.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10]O)[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.S(Cl)([Cl:14])=O>>[ClH:14].[Cl:14][CH2:10][C:3]1[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]2=[N:1][CH:2]=1
Reactant: OCc1cnc2n1CCCC2
Reactant: O=S(Cl)Cl
Product: Cl
Product: ClCc1cnc2n1CCCC2

Procedure:
To 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl methanol (1.0 g), thionyl chloride (5 ml) was added at 0° C. After heating to reflux for 40 minutes, the mixture was concentrated under reduced pressure. To the residue was added ethyl acetate, and the precipitated crystals were collected by filtration. The crystals were washed with ethyl acetate, to give 3-(chloromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine hydrochloride (1.03 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Nc1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 24.8 %

Procedure:
To a sealed tube containing a clear, slightly yellow solution of 3-chloroaniline (2.5 g, 19.60 mmol) and methyl 2-bromopropanoate (3.93 g, 23.52 mmol) in DMF (39.2 mL) was added potassium iodide (0.325 g, 1.960 mmol) and potassium carbonate (4.06 g, 29.4 mmol). The vessel was sealed with a Teflon screw cap possessing an o-ring. The resulting suspension was warmed to 100° C. After 5 h, the resulting dark brown reaction mixture was stopped and cooled to rt. The reaction was filtered to remove the solid, rinsing with EtOAc. The filtrate was partitioned between EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give a brown liquid weighing 6.30 g. Purification by normal phase chromatography gave the desired product (1.04 g, 25%) as a clear, yellow oil. MS (ESI) m/z: 214.0 (M+H)+.