Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH:20]([CH3:23])[CH:21]=[CH2:22]>C(O)C>[CH2:23]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH2:1])[CH:11]=[CH:10]2)/[CH:20]=[CH:21]/[CH3:22]
Reactant: Nc1ccc2cccc(O)c2n1
Reactant: C=CC(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C/C=C/COc1cccc2ccc(N)nc12
Temperature: 65 °C
Reaction time: 48 h

Procedure:
A 250 mL round bottom flask was charged with 2.00 g (12.5 mmol) of 2-amino-8-hydroxyquinoline, 3.46 g (25.0 mmol), of K2CO3 and 63 mL of anhydr ethanol. Following the dissolution of 2-amino-8-hydroxyquinoline, 1.51 mL of 3-chloro-1-butene (15.0 mmol) was added in one portion, and the mixture was heated to 65° C. in an oil bath. After 48 h, the solvent was evaporated and the residue dissolved in EtOAc and washed with H2O. The combined aqueous layers were back-extracted with EtOAc. The organic layers were then pooled, dried, and filtered. The residue was then purified by column chromatography (SiO2; EtOAc/hexanes with 0.1% Et3N). The resultant material was then re-crystallized from Et2O to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.82 (m, 1H), 7.16 (m, 1H), 7.00 (m, 2H), 6.73 (m, 1H), 6.39 (m, 2H), 5.67–5.98 (m, 2H), 4.44–4.67 (m, 2H), 1.74 (m, 3H); MS (DCI/NH3) m/z 215 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:4](=[CH2:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:3].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:1][CH:2]([C:4](=[CH2:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:3])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: C=C(C(=O)OC)C(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C(=O)OC)C(C)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of methyl 2-(1-hydroxyethyl)acrylate (50 g) and pyridine (32.6 ml) in dichloromethane (200 ml) was added dropwise acetyl chloride (34.8 g) at 0° C. After the reaction mixture was stirred for 1 hour, the mixture was allowed to warm to room temperature, and quenched with water (500 ml). The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layer were washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and an aqueous sodium chloride in turn, and then dried over magnesium sulfate. The resultant solution was evaporated, and the residue was distilled in vacuo to give methyl 2-(1-acetoxyethyl)acrylate (28.2 g).
Reaction SMILES: [N:1]1([C:7](OC(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:29]=C(Cl)[N:27]=[CH:26][N:25]=1>ClCCl>[Cl:23][C:24]1[CH:29]=[C:7]([N:1]2[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]2)[N:27]=[CH:26][N:25]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Clc1cc(N2CCNCC2)ncn1
Temperature: 25 °C
Yield: 98 %

Procedure:
13.3 g tert-butyl 1-piperazinecarboxylate and 11.2 mL DIPEA were added to 10 g 4, 6 dichloro pyrimidine in 1000 mL dichlormethane was stirred over the weekend at RT. The solvent was removed. The residue was dissolved in 200 mL dichlormethane and 200 mL trifluoro acetic acid was added. The reaction was stirred at RT. The solvent was removed. The residue was dissolved in methanol and passed through HCO3 containing resin. The solvent was removed and the residue was purified by chromatographie on silica (dcyclohexane: ethylacetate 0-40%) to yield 13.07 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH2:12].[Br:13][C:14]1[CH:15]=[C:16]([C:22](OC)=[O:23])[N:17]([CH2:19][CH2:20]Br)[CH:18]=1>CS(C)=O>[Br:13][C:14]1[CH:15]=[C:16]2[C:22](=[O:23])[N:12]([CH2:11][C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[O:2][CH3:1])[CH2:20][CH2:19][N:17]2[CH:18]=1
Reactant: COC(=O)c1cc(Br)cn1CCBr
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CS(C)=O
Product: COc1ccc(CN2CCn3cc(Br)cc3C2=O)c(OC)c1
Temperature: 150 °C
Yield: 85.3 %

Procedure:
(2,4-Dimethoxyphenyl)methanamine (Aldrich; 4.36 mL, 28.9 mmol) was added to a stirred solution of methyl 4-bromo-1-(2-bromoethyl)-1H-pyrrole-2-carboxylate (Example 165a; 3.60 g, 11.58 mmol) in DMSO (15 mL) at RT. The reaction was heated at 150° C. in an oil bath for 5 h. After it was cooled to RT, the brown mixture was partitioned between 10 mL of 2.0 N aq. HCl and 200 mL of EtOAc. The layers were separated; the organic solution was washed with 2.0 N aq. HCl (5 mL) followed by brine (5 mL), dried (Na2SO4), and concentrated. Purification on a silica gel column (25-75% EtOAc in Hexanes) gave 7-bromo-2-(2,4-dimethoxybenzyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (3.61 g, 9.88 mmol, 85% yield) as an off-white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.15 (1H, d, J=1.8 Hz), 7.11 (1H, d, J=8.2 Hz), 6.68 (1H, d, J=1.8 Hz), 6.59 (1H, d, J=2.3 Hz), 6.50 (1H, dd, J=8.3, 2.4 Hz), 4.53 (2H, s), 4.12 (2H, dd, J=6.7, 5.2 Hz), 3.81 (3H, s), 3.76 (3H, s), 3.57 (2H, dd, J=6.7, 5.0 Hz). m/z (ESI, +ve) 365/367 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:14]#[N:15])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[CH3:2].[C:17]1([CH3:25])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Mg]Cl>>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:25])[CH3:2]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: CCOC(=O)C(C#N)=Cc1cccc(Br)c1
Product: CCOC(=O)C(C#N)C(c1cccc(Br)c1)c1ccccc1C

Procedure:
In analogy to example 74, step 2, from 3-(3-bromo-phenyl)-2-cyano-acrylic acid ethyl ester and o-tolylmagnesium chloride was prepared the title compound as a colorless oil, MS (ESI−): m/z=370.04 (([M−H]−), 1Br).
Reaction SMILES: OO.[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH3:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][CH2:22]3)=[CH:18][C:16]=2[N:17]=1.C(O)(C(F)(F)F)=[O:28].N>C(Cl)Cl.C(Cl)(Cl)Cl>[O-:25][N+:14]1[C:15]2[CH:24]=[C:23]3[C:19](=[CH:18][C:16]=2[N+:17]([O-:28])=[C:12]([NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:6][CH2:5][O:4][CH3:3])[CH3:26])[N:13]=1)[CH2:20][CH2:21][CH2:22]3
Reactant: COCCN(C)CCCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COCCN(C)CCCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 4.7 %

Procedure:
H2O2 (70%, 3.0 mL, ca. 60.4 mmol) was added dropwise to a stirred solution of TFM (8.4 mL, 60.4 mmol) in DCM (80 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., and added to a solution of 1-oxide 52 (2.0 g, 6.04 mmol) and TFA (1.0 mL, 13.0 mmol) in CHCl3 (80 mL) at 0° C. and the solution stirred at 20° C. for 18 h. The solution was made basic with dilute aqueous NH3 solution and extracted with CHCl3 (3×100 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-18%) of MeOH/DCM, to give 1,4-dioxide 53 (99 mg, 5%) as a red solid: mp 77-79° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.26 (br s, 1H, NH), 3.66 (t, J=6.3 Hz, 2H, CH2), 3.59 (t, J=5.6 Hz, 2H, CH2), 3.36 (s, 3H, OCH3), 3.03-3.12 (m, 4H, H-6, H-8), 2.66-2.71 (m, 4H, 2×CH2), 2.39 (s, 3H, NCH3), 2.19 (p, J=7.4 Hz, 2H, H-7), 1.91 (p, J=6.6 Hz, 2H, CH2); 13C NMR δ 155.6, 149.5, 145.7, 138.0, 129.7, 115.8, 111.6, 70.5, 58.9, 56.8, 55.9, 42.5, 40.5, 33.4, 32.4, 25.9, 25.6; HRMS (FAB+) calcd for C17H26N5O3 (MH+) m/z 348.2036, found 348.2032.
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])C.[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].C(OC(=O)C)C>CS(C)=O>[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17]
Reactant: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Reactant: Nc1ccccc1Br
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Nc2c(Nc3ccccc3Br)c(=O)c2=O)c(O)c1
Temperature: 25 °C
Yield: 3.3 %

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanoanilino)-3-cyclobutene-1,2-dione (0.7 g, 2.71 mmol) and 2-bromoaniline (0.47 g, 2.73 mmol) were heated in 6 ml DMSO for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added and precipitates formed. The filtrate was partitioned between ethylacetate and water. The organic layer was dried over sodium sulfate and concentrated. After Gilson HPLC, 34 mg (3%) of purified product was obtained. LC/MS (H+) 386
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([NH:10][NH2:11])=O)=[CH:3][CH:2]=1.Cl[C:13]1[N:14]=[N:15][C:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:17][CH:18]=1>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[N:14]3[N:15]=[C:16]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH:17]=[CH:18][C:13]3=[N:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: NNC(=O)Cc1ccncc1
Reactant: Clc1ccc(-c2cccs2)nn1
Product: c1csc(-c2ccc3nnc(Cc4ccncc4)n3n2)c1

Procedure:
The title compound was prepared as described in Example 17 from 4-pyridineacetic acid hydrazide (1.81 mmol) and 3-chloro-6-thiophen-2-yl-pyridazine (0.58 mmol) as a pale yellow solid. 1H NMR (CD3OD) δ 8.50 (2H dd, J=4.6 Hz, 1.4 Hz), 8.22 (1H d, J=9.6 Hz), 7.94 (1H, dd, J=3.8 Hz, 1.2 Hz), 7.93 (1H, d, J=9.8 Hz), 7.74 (1H, dd, J=5.0 Hz, 1.0 Hz), 7.52 (2H, m), 7.23 (1H, dd, J=5.3 Hz, 3.8 Hz), 4.69 (2H, s). ESI-MS (m/z): Calcd for C15H11N5S: 293.1; found 294.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:27][CH2:26]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.N[C@@H:32](CCN1CC(OC2C=CC(Cl)=C(C)C=2)C1)CO>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:27][CH2:26]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[CH:29][C:30]=1[CH3:32]
Reactant: Cn1nc(C2CC2)cc1NC(=O)N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Reactant: Cc1cc(OC2CN(CC[C@H](N)CO)C2)ccc1Cl
Product: Cc1cc(OC2CN(CC[C@@H](CO)NC(=O)Nc3cc(C4CC4)nn3C)C2)ccc1Cl

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 83 except using (S)-2-amino-4-[3-(4-chloro-3-methyl-phenoxy)-azetidin-1-yl]-butan-1-ol in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[NH:8][C:9](=[O:18])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:6]=2[CH:5]=1.[CH2:21]([N:23]([CH2:37][CH3:38])[C:24](=[O:36])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)[CH3:22].O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[N:8]([S:32]([C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:24]([N:23]([CH2:37][CH3:38])[CH2:21][CH3:22])=[O:36])=[CH:31][CH:30]=3)(=[O:34])=[O:33])[C:9](=[O:18])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:6]=2[CH:5]=1
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)n2c(=O)n(-c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
0.075 g of sodium hydride as a 60% dispersion in oil is added to a solution of 0.5 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-2H-benzimidazol-2-one in 40 ml of DMF and the mixture is stirred for 30 minutes at RT. 0.6 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride is then added and the mixture is stirred for 4 hours at RT. The reaction mixture is poured into iced water, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.45 g of the expected product. M.p.=222° C.
Reaction SMILES: [OH:1]O.[OH-].[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:17][CH:16]=[C:15]2[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:9]=[CH:10][C:11]=1[C:12]#[N:13]>CO>[C:12]([C:11]1[CH:10]=[CH:9][C:8]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:17][CH:16]=[C:15]2[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:7][C:6]=1[Cl:5])(=[O:1])[NH2:13]
Reactant: OO
Reactant: COc1ccc(-c2ccc(CCC(=O)O)n2-c2ccc(C#N)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2ccc(CCC(=O)O)n2-c2ccc(C(N)=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
An 8 ml vial was loaded with a mixture of 30% H2O2 (50 uL), 3N NaOH (0.15 ml) and MeOH (0.125 ml). To this mixture 3-[1-(3-chloro-4-cyanophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl]propanoic acid (40 mg, 0.105 mmol) was added at room temperature. The reaction mixture was stirred at rt for 45 minutes, TLC showed the starting material to be consumed. The reaction mixture was diluted with water, acidified to pH=2, stirred for 10 minutes, and filtered off. The solid was washed with water and dried to give 30 mg of 3-(1-(4-carbamoyl-3-chlorophenyl)-5-(4-methoxyphenyl)-1H-pyrrol-2-yl)propanoic acid, 73% yield.
Reaction SMILES: [C-]#N.[Na+].[Br:4][C:5]1[CH:6]=[C:7]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14]Br)[CH:8]=[CH:9][CH:10]=1.[CH3:20][N:21](C)C=O>O>[Br:4][C:5]1[CH:6]=[C:7]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][C:20]#[N:21])[CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)C=O
Reactant: BrCc1ccccc1Sc1cccc(Br)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1ccccc1Sc1cccc(Br)c1

Procedure:
12.4 G. sodium cyanide (0.25 mole) is added to a solution of 58.6 g. 2-(3-bromophenylthio)benzyl bromide (0.164 mole) in 200 cc. dimethylformamide (DMF). The reaction is slightly exothermic. The resulting solution is allowed to stir for an hour without cooling, then is diluted with a large volume of water and extracted with ether three times. Ether extracts are washed several times with water, dried over sodium sulfate and the ether evaporated off. The crude yield of 2-(3-bromophenylthio)benzyl cyanide is 49.6 g.; the product is an oil which is hydrolyzed as such.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]([O:19][CH3:20])(=[O:18])[C:15]([CH3:17])=O.C([O-])(=O)C.[Na+]>CO>[CH3:20][O:19][C:14](=[O:18])[C:15](=[N:10][NH:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:17]
Reactant: NNc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)=NNc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
(4-Chloro-2-nitro-phenyl)hydrazine hydrochloride (30 g, 0.14 mol) prepared in Step A and methyl pyruvate (14.4 mL, 0.16 mol) were dissolved in methanol (300 mL), and sodium acetate (14.2 g, 0.17 mol) was added thereto. The reaction solution was stirred for 8 h at room temperature, and the resulting yellow solid was filtered, washed with water and methanol, and dried to give the title compound (30 g, Yield 82%).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH2:25])(=[S:24])[CH3:23].N1C=CC=CC=1>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:25]=[C:22]([CH3:23])[S:24][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(N)=S
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Yield: 31.1 %

Procedure:
To 2-bromo-1-(4-fluorophenyl)-2-(4-(methylsulfonyl)phenyl)ethanone (1.10 g) in ethanol (15.0 mL) were added thioacetamide (0.266 g) and pyridine (0.300 mL). After refluxing for 2 h, the reaction mixture was extracted with EtOAc, 25% NH4OAc and purified by flash chromatography (50% EtOAc in hexane then 90% Et2O in hexane) to yield the title compound (0.320 g).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH:3]=1.C(OO)(=[O:12])C>C(OCC)(=O)C>[CH3:1][C:2]12[O:12][CH:7]1[CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]2
Reactant: CC(=O)OO
Reactant: CC1=CCC(CO)CC1
Solvent: CCOC(C)=O
Product: CC12CCC(CO)CC1O2

Procedure:
Epoxidation of 12.6 g (0.1 mol) of (4-methylcyclohex-3-enyl)methanol was carried out with a 5 percent by weight solution of peracetic acid in ethyl acetate at 65° C. Purification of the product by distillation yielded 12 g of (6-methyl-7-oxabicyclo[4.1.0]hept-3-yl)methanol with a purity of 98%.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH:13]([CH3:15])[CH3:14].[C:16]12([CH2:26][C:27](Cl)=[O:28])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:16]12([CH2:26][C:27]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]3[CH:13]([CH3:15])[CH3:14])=[O:28])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: CC(C)c1nc2ccccc2c(=O)n1N
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)c1nc2ccccc2c(=O)n1NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 22 h
Yield: 41.9 %

Procedure:
3-Amino-2-isopropyl-4(3H)-quinazolinone (Aldrich, 97.5 mg, 0.48 mmol) was dissolved in chloroform (5 mL). 1-Adamantaneacetyl chloride (107.0 mg, 0.50 mmol) and pyridine (100 μL, 1.24 mmol) were added, and the reaction was allowed to stir at ambient temperature for 22 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Waters Nova-Pak® HR C18 6 μm 60 {acute over (Å)} Prep-Pak® cartridge column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound as a white solid (76.4 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21-1.26 (m, 6H), 1.60-1.75 (m, 12H), 1.94-1.99 (m, 3H), 2.09-2.20 (m, 2H), 3.09-3.18 (m, 1H), 7.50-7.55 (m, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.82-7.88 (m, 1H), 8.12 (dd, J=7.9, 1.2 Hz, 1H), 10.80 (s, 1H) ppm; MS (DCI/NH3) m/z 380 (M+H)+; Elemental Analysis: Calculated for C23H29N3O2: C, 72.79; H, 7.70; N, 11.07. Found: C, 72.79; H, 7.81; N, 11.07.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:23]1([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH:35]([NH:38][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:36][CH2:37]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1cc2c(Oc3ccccc3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3ccccc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-phenoxy-1H-indole-2-carboxylic acid 129 (preparation see below) and amine 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][C:12]1[S:13][CH:14]=[CH:15][N:16]=1
Reactant: COc1ccc(O)c(Cl)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Oc2nccs2)c(Cl)c1
Temperature: 160 °C
Yield: 87.9 %

Procedure:
A mixture of 2-chloro-4-methoxy-phenol (7.93 g, 0.05 mol), 2-bromothiazole (9.0 g, 0.055 mol) and potassium carbonate (7.6 g, 0.055 mol) in dimethyl sulfoxide was heated at 160° C. under nitrogen for 4 hours. The solution was cooled and treated with water, and the aqueous phase was extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give 30 g of the crude material, which was purified on a silica gel (ethyl acetate/hexane 5-35%) to afford 10.62 g of the product as a light yellow oil (88% yield), 1H NMR (300 MHz, CDCl3) δ ppm 3.81 (s, 3H) 6.80 (d, J=4.04 Hz, 1H) 6.85 (dd, J=9.19, 2.94 Hz, 1H) 7.01 (d, J=2.94 Hz, 1H) 7.19 (d, J=3.68 Hz, 1H) 7.27 (d, J=8.82 Hz, 1H). MS (ESI), m/z 241.9 (M+H)+.
Reaction SMILES: [Mg].II.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1.[O:13]=[C:14]1[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15]1.Cl>CCOCC.C1COCC1>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:14]2([OH:13])[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15]2)=[CH:7][CH:6]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: ClCc1ccc(Cl)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O)C1CC(O)(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
In a dry flask, under argon, magnesium (1.7 g, 70.11 mmol), a crystal of I2 and just enough Et2O to cover the magnesium was heated to reflux until the purple color dissipated (ca. 10 min.). Approximately 10% of a solution of 4-chlorobenzyl chloride (11.3 g, 70.11 mmol) in Et2O (20 mL) was added all at once and reflux was continued until the solution became brown. While maintaining a gentle reflux, the remainder of the 4-chlorobenzyl chloride solution was slowly added. After the addition was complete, heating was continued for 0.5 h. The solution was cooled to room temperature and added to a solution of 3-oxocyclobutanecarboxylic acid (2 g, 17.53 mmol) in THF (30 mL) pre-cooled to 0° C. Once the addition was complete, the resulting solution was allowed to warm to room temperature with continued stirring for 16 h. The reaction mixture was then poured into a solution of ether and 1 M HCl. The layers were separated and the aqueous phase was extracted with ether (3×). The combined extracts were concentrated, dissolved in 1 M NaOH and washed with ether. The aqueous phase was re-acidified with 2 M HCl and extracted with Et2O, dried over MgSO4 and concentrated to give the subject compound as a white solid (2.5 g, 59%) of white solid. 1H NMR (CDCl3, 500 MHz) δ 7.44 (d, J=8.24 Hz, 2H), 7.35 (d, J=8.24 Hz, 2H), 3.02 (s, 2H), 2.90-2.84 (m, 1H), 2.66-2.62 (m, 2H), 2.47-2.42 (m, 2H). ESI MS found for C12H13ClO3 m/z [239.1 (M−1)].
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:2][C:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.N1CCCCC1.[NH2:20][C:21]1[C:22]([CH:27]=O)=[N:23][CH:24]=[CH:25][N:26]=1>C1(C)C=CC=CC=1>[N:23]1[CH:24]=[CH:25][N:26]=[C:21]2[N:20]=[C:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:2]([C:1]([O:11][CH2:12][CH3:13])=[O:10])=[CH:27][C:22]=12
Reactant: Nc1nccnc1C=O
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2nccnc2nc1C(=O)OCC
Yield: 27.9 %

Procedure:
Diethyl oxalacetate, (4.7 g, 0.025 mol) and piperidine (1.66 g, 1.93 mL) are added to 3-aminopyrazine-2-carboxaldehyde (2.4 g, 0.0195 mol) dissolved in 250 mL of toluene. After the reaction mixture is refluxed for two hours, the toluene is removed under reduced pressure to give a dark red oily residue. The product is purified by column chromatography on silica gel (hexane:EtOAc, 4:1), affording 3.1 g (58% yield), of the crude desired product. Crystallization from ether-hexane (4:1) gives analytically pure compound 1.5 g (28%) having a melting point 83°-85° C.