Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCNC2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-3-carbonyl)-piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (78) (1.41 g; 2.39 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 5 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (0.97 g) as a white solid.
Reaction SMILES: Br[C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[C:9]([O-:17])(=[S:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cs+]>CN(C=O)C.CCOCC>[C:9]([S:16][C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [O-]C(=S)c1ccccc1
Reactant: CC(C)[C@H](Br)C(=O)O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)[C@@H](SC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.5 %

Procedure:
To a solution of (S)-(−)-2-bromo-3-methylbutyric acid (4.20 g, 23.2 mmol) in DMF (41 mL) was added cesium thiobenzoate (6.08 g, 22.5 mmol). The mixture was stirred at rt for 20 h. The resulting solution was diluted with ether (200 mL) and washed with H2O (4×40 mL). The ethereal layer was dried (Na2SO4), and concentrated. The crude residue was recrystallized from hexanes to afford (R)-2-benzoylthio-3-methylbutanoic acid as a pale yellow solid (4.05 g, 75%); 1H NMR (300 MHz, CDCl3) δ 1.09 (d, J=7.4 Hz, 3H), 1.11 (d, J=7.4 Hz, 3H), 2.40 (m, 1H), 4.37 (d, J=5.9 Hz, 1H), 7.45 (t, J=7.4 Hz, 2H), 7.57 (t, J=7.4 Hz, 1H), 7.97 (d, J=7.4 Hz, 2H), 11.9 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 19.8, 20.6, 30.5, 53.1, 127.6, 128.8, 133.9, 136.3, 177.9, 190.3; IR (neat) 3100, 2967, 1709, 1669 cm−1; [α]D22=+95.6 (c 1, CH2Cl2). All spectral data was identical to that previously published (Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1986, 51, 3664).
Reaction SMILES: F[C:2]1([O:9][C:10]#[C:11][CH3:12])[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][CH2:3]1.[Br:13]C1C=CC(F)=CC=1O>>[Br:13][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:9][CH2:10][C:11]#[CH:12]
Reactant: Oc1cc(F)ccc1Br
Reactant: CC#COC1(F)C=C(F)C=CC1
Product: C#CCOc1cc(F)ccc1Br
Yield: 87 %

Procedure:
This compound was prepared analogously to 2,4-difluoro-2-prop-ynyloxy-benzene but using 2-bromo-5-fluorphenol (15 g, 78 mmol) to give 1-bromo-4-fluoro-2-prop-2-ynyloxy-benzene 15.6 g (87%)
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])[CH:11]=1)C.[Li+].[OH-].Cl>C1COCC1.CO>[CH2:29]([N:23]([CH2:22][C:13]1[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=1[C:10]1[CH:11]=[C:6]([CH2:5][C:4]([OH:36])=[O:3])[CH:7]=[N:8][CH:9]=1)[C:24]([CH:26]1[CH2:28][CH2:27]1)=[O:25])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1
Temperature: 25 °C

Procedure:
To (5-{2-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester (0.043 g, 0.09 mmol) in THF (3 mL) and MeOH (0.3 mL) was added 1N aqueous LiOH (3 mL), and the reaction was stirred at room temperature. The mixture was neutralized with 1N aqueous HCl to pH 4-5 and extracted three times with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by preparative HPLC to give Compound 17.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH2:7][C:8]([CH3:16])(C)[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([OH:6])=[O:5].N[CH2:18]C(CCCCCC(C)C)C(O)=O.C1(C(OC2C(C(C)(C)C)=CC(C)=CC=2C(C)(C)C)=O)CC1>>[NH2:1][CH2:2][CH:3]([CH2:7][CH:8]([CH2:16][CH3:18])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[C:4]([OH:6])=[O:5]
Reactant: CC(C)CCCC(C)(C)CC(CN)C(=O)O
Reactant: CC(C)CCCCCC(CN)C(=O)O
Agent: Cc1cc(C(C)(C)C)c(OC(=O)C2CC2)c(C(C)(C)C)c1
Product: CCC(CCCC(C)C)CC(CN)C(=O)O

Procedure:
A procedure similar to that of 2-Aminomethyl-4,4,8-trimethyl-nonanoic acid was utilized to prepare 2-Aminomethyl-8-methyl-nonanoic acid from 2,6-di-t-butyl-4-methylphenyl cyclopropylcarboxylate. m/z 230.2 (M+).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[C:5]([OH:19])[CH:4]=1.[CH3:20][S-:21].[Na+]>CO>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[O:10][C:11]3[C:3]([CH2:2][S:21][CH3:20])=[CH:4][C:5]([OH:19])=[CH:6][C:7]=3[CH:8]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(-c2cc3cc(O)cc(CBr)c3o2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a solution of benzyl bromide 4 (0.052 g, 0.161 mmole) in 5 mL methanol was added sodium thiomethoxide (0.013 g, 0.177 mmole). After stirring at R.T. for 1 hour, the solvent was evaporated and the residue was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 4:1) to afford 0.025 g (54%) of thioether 10 as a white solid: Mp=188–190° C.; 1H NMR (DMSO-d6) δ 9.82 (s, 1 H), 9.14 (s, 1 H), 7.69 (d, 2 H, J=8.5 Hz), 7.01 (s, 1 H), 6.86 (d, 2 H, J=8.5 Hz), 6.77 (d, 1H, J=2.1 Hz), 6.63 (d, 1 H, J=2.1 Hz), 3.91 (s, 2 H), 2.05 (s, 3 H); MS 285 (M−H)−
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:9]=2[C:8]=1[Br:17].O>CCOCC>[Br:17][C:8]1[C:9]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:10]=2[S:11][CH:7]=1
Reactant: Cc1ccc2c(Br)c(Br)sc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Cc1ccc2c(Br)csc2c1
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A solution of n-butyl lithium (22.3 ml. of 1.6M solution in hexane) was added dropwise to a stirred solution of 2,3-dibromo-6-methylbenzo[b]thiophene (11.76 g.) in dry ether (150 ml.) at 0° under an atmosphere of dry nitrogen. The resulting solution was stirred at 0° for 1 hour and then water (50 ml.) was added. The mixture was stirred for a few minutes and then the ether layer was separated, dried (Na2SO4) and evaporated to give an oil. The oil was distilled to give 3-bromo-6-methylbenzo[b]thiophene (5.80 g.), b.p. 112°-114° C. @ 0.2 m.m., m.p. 51°-53° C. (from methanol).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[C:7]([Cl:12])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:7]1[N:8]([CH3:11])[N:9]=[C:10]2[C:6]=1[CH:5]=[CH:4][CH:3]=[C:2]2[C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][C:18]=1[Cl:20]
Reactant: Cn1nc2c(Br)cccc2c1Cl
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cn1nc2c(-c3ccc(Cl)cc3Cl)cccc2c1Cl
Temperature: 88 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A mixture of 7-bromo-3-chloro-2-methyl-2H-indazole (0.079 g, 0.32 mmol), 2,4-dichlorophenyl boronic acid (0.122 g, 0.641 mmol), 2 mL of ethylene glycol dimethyl ether, 2 mL of a 2 M aqueous Na2CO3 solution, and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.010 mmol) was stirred at 88° C. overnight, then diluted with 10 mL of ethyl acetate. The mixture was washed with two 5 mL portions of a saturated aqueous NaCl solution, dried, filtered, and concentrated to a yellow oil. Column chromatography (0→5% EtOAc/hexanes) afforded of 3-chloro-7-(2,4-dichloro-phenyl)-2-methyl-2H-indazole (26: R=Me; Ar=2,4-dichlorophenyl; 0.063 g; 63%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=O.S(Cl)(Cl)=O.[NH2:22][CH:23]([C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1)CC1C=CC=CC=1.[OH-].[Na+]>ClCCl>[CH3:17][O:16][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([NH:22][CH2:23][C:31]1[CH:32]=[CH:33][C:34]([C:35]([OH:37])=[O:36])=[CH:38][CH:39]=1)=[O:10]
Reactant: NC(Cc1ccccc1)c1ccc(C(=O)O)cc1
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=CC(=O)NCc2ccc(C(=O)O)cc2)cc(OC)c1OC
Yield: 113.1 %

Procedure:
3,4,5-trimethoxycinnamic acid (2.38 g, 10 mmol), thionylchloride (4.72 g, 40 mmol), dichloromethane (10 ml), 4-(1-amino-2-phenylethyl)benzoic acid (2.41 g, 10 mmol), and 10 ml of 1 mol/L sodium hydroxide are used according to the method for the production of compound III in Method one to obtain 4.20 g of 4-[(3,4,5-trimethoxycinnamoyl)aminomethyl]benzoic acid (intermediate M-42) as a white solid, with a yield of 91.2%.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[Cl:13]N1C(=O)CCC1=O>CN(C)C=O>[Cl:13][C:7]1[CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[F:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Solvent: CN(C)C=O
Product: Nc1c([N+](=O)[O-])cc(Cl)c(F)c1F
Temperature: 85 °C

Procedure:
2,3-Difluoro-6-nitroaniline (15.4 g, 88.7 mmol), N-chlorosuccinimide (14.9 g, 111.4 mmol) and N,N-dimethylformamide (250 mL) were combined and were heated to 80-90° C. for several hours, after which time the mixture was poured into ice water. The product was extracted with ethyl acetate which was then washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and the solvents were removed in vacuo to leave a yellow, viscous oil. 1H NMR (DMSO-d6) δ: 8.03 (dd, J=7.3, 2.2 Hz, 1H, Ar—H), 7.65 (br s, 2H, NH2).
Reaction SMILES: Cl[C:2]1[NH:14][C:5]2=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[O:21]2)[CH2:17][CH2:16]1.O>CN1C(=O)CCC1>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:9]=[C:4]2[N:3]=[C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22](=[O:29])[O:21]4)[CH2:17][CH2:16]3)[NH:14][C:5]2=[N:6][CH:7]=1
Reactant: FC(F)(F)c1cnc2[nH]c(Cl)nc2c1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1OC2(CCN(c3nc4cc(C(F)(F)F)cnc4[nH]3)CC2)c2ccccc21

Procedure:
Heat a solution of 2-chloro-6-trifluoromethyl-3-H-imidazo[4,5-b]pyridine (0.1 g, 0.45 mmol) and spiro[isobenzofuran-1,4′-piperidin]-3-one (0.2 g, 0.90 mmol) in dry NMP (5 mL) at 100° C. for 10 hours. Pour the cooled mixture into water (20 mL) and extract twice with EtOAc (20 mL). Wash the combined extracts with brine (20 mL), dry, and evaporate in vacuo. Purify by preparative TLC (4% MeOH—CH2Cl2) to obtain 1′-(6-trifluoromethyl-3-H-imidazo[4,5-b]pyridine-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>COC(O)C.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Agent: COC(C)O
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Br)c3)c2cc1[N+](=O)[O-]

Procedure:
A mixture of 3.52 g (9.7 mmol) of 4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile and 2.0 g (10.7 mmol) of 3-bromo-4-fluoro aniline in 150 ml of methoxyethanol was refluxed under nitrogen for 5.5 hours. The reaction mixture was diluted with ethyl acetate and wash with sodium bicarbonate solution and sodium chloride solution. The organic layer was dried with sodium sulfate and then solvent was removed under vacuum. The residue was chromatographed on silica gel eluting with mixture of ethyl acetate and hexane to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]2[CH2:21][CH2:22][CH2:23][C:18]([OH:24])([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([OH:11])[CH:13]=3)[CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Oc1cccc(C2(O)CCCNC2)c1
Product: O=C(c1ccc(F)cc1)N1CCCC(O)(c2cccc(O)c2)C1

Procedure:
The compound of Example 55 was prepared according to the general preparation protocol A from 4-fluorobenzoyl chloride and 3-(3-hydroxyphenyl)-piperidine-3-ol.
Reaction SMILES: O1CCN(CCOC2C=CC(C3C=CC(CC#N)=NC=3)=CC=2)CC1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][C:43]([CH2:46][C:47](OC)=[O:48])=[N:44][CH:45]=3)=[CH:36][CH:35]=2)[CH2:27][CH2:26]1.[CH2:51]([NH2:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[O:25]1[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][O:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:58][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:48])=[N:44][CH:45]=3)=[CH:38][CH:39]=2)[CH2:29][CH2:30]1
Reactant: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reactant: NCc1ccccc1
Agent: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Product: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1

Procedure:
In another aspect, the invention relates to the process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide comprising the steps of coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; and reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:14]2[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=2[S:12][C:11]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:2].B1([O-])OO1.[OH2:29].[OH2:30].O.O.[Na+]>C(O)(=O)C.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:14]2[N:15]=[C:16]([S:19]([CH3:20])(=[O:30])=[O:29])[N:17]=[CH:18][C:13]=2[S:12][C:11]=1[C:21]([O:23][CH3:24])=[O:22])[CH3:2]
Reactant: O
Reactant: CCOc1ccccc1-c1c(C(=O)OC)sc2cnc(SC)nc12
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: CCOc1ccccc1-c1c(C(=O)OC)sc2cnc(S(C)(=O)=O)nc12
Temperature: 70 °C
Yield: 82.4 %

Procedure:
A mixture of 330 mg of methyl 7-(2-ethoxyphenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate, prepared by analogy to the method described in example 4, and 634 mg of sodium perborate tetrahydrate in 15 ml of acetic acid is microwave-heated at 70° C. in a sealed tube for 1 h 30. The mixture is diluted with 5 volumes of water and the resulting precipitate is filtered off and washed with water. The solid is taken up with dichloromethane and 100 ml of a solution of sodium thiosulfate. The pH is adjusted to pH 8-9 by adding solid potassium carbonate and the aqueous phase is extracted with dichloromethane. The organic phases are dried over magnesium sulfate, filtered, and then concentrated under vacuum. This crude is purified on 40 g of silica, elution being carried out with dichloromethane, so as to obtain 296 mg of methyl 7-(2-ethoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.C(Cl)(=O)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[CH:29]([NH:32][CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:30]>C(Cl)Cl.CN(C=O)C>[CH:29]([N:32]([CH:33]([CH3:35])[CH3:34])[C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:16][CH:15]=1)([CH3:31])[CH3:30]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CC(C)NC(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1ccc(C(=O)N(C(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-(2-methylphenyl)benzoic acid (4.00 g, 18.8 mmol) in DCM (150 mL) was added oxalyl chloride (10.00 g, 78.8 mmol) followed by 5 drops of DMF. The reaction mixture was stirred at RT for 3 h until a clear solution resulted. The solvent was removed in vacuo. The residue was dissolved with DCM (100 mL) and treated with aq. potassium carbonate (3.41 mL, 56.5 mmol). The reaction mixture was cooled to 0° C., and a solution of diisopropylamine (5.33 mL, 37.7 mmol) in DCM (50 mL) was added dropwise. The resulting mixture was stirred at RT over 12 h. The resulting mixture was quenched by the slow addition of saturated aqueous Na2CO3 (100 mL). The organic phase was separated and aqueous phase was extracted with dichloromethane (3×60 mL). The combined organic phases were washed with brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure to give N,N-diisopropyl 4-(2-methylphenyl)benzamide as an off-white solid. MS (ESI, pos.ion) m/z: 296 (M+1)
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].C(N(CC)CC)C.[CH2:28]([CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])=[O:38])[CH2:33][CH2:32]1)[C:29]#[CH:30]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[Cl:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[O:39][C:37]([N:34]1[CH2:33][CH2:32][CH:31]([CH2:28][C:29]#[C:30][C@@:9]2([N:8]3[C:18]4[N:19]=[CH:2][N:3]=[C:4]([NH2:20])[C:5]=4[N:6]=[CH:7]3)[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]2[OH:11])[CH2:36][CH2:35]1)=[O:38]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccccc2Cl)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnc2c1ncn2[C@]1(C#CCC2CCN(C(=O)Oc3ccccc3Cl)CC2)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-iodoadenosine (0.602 g, 1.531 mmol) in freshly degassed DMF (20 mL) was added degassed triethylamine (1.20 mL, 8.54 mmol), Pd(PPh3)4 (85 mg, 0.074 mmol), CuI (catalytic), and 2-chlorophenyl 4-(prop-2-ynyl)piperidine-1-carboxylate (0.588 g, 2.117 mmol). The mixture was stirred at room temperature under and inert atmosphere for 20 h. Silica bound Pd(II) scavenger Si-thiol (400 mg) and Pd(0) scavenger Si-TAAcOH (619 mg) were added and stirring continued a further 72 h. The suspension was filtered through celite and the resulting solution evaporated to dryness. The crude was purified by column chromatography, eluting with a gradient of DCM/MeOH (0-4%) to afford the pure product as a white solid: yield 0.733 g, 88%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1O)=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4].P(Br)(Br)([Br:22])=O>C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH:17]([CH3:19])[CH3:18])=[N:7][C:8]2[C:13]([C:14]=1[Br:22])=[CH:12][C:11]([Cl:16])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1O
Reactant: O=P(Br)(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Br
Yield: 51 %

Procedure:
To a stirred solution of 6-chloro-4-hydroxy-2-isopropyl-quinoline-3-carboxylic acid methyl ester (800 mg, 2.86 mmol) in DCM (15 ml) was added POBr3 (1.23 g, 4.3 mmol) at 25° C. and the resulting reaction mixture was refluxed for 6 h. The reaction mixture was diluted with cold water, extracted with DCM, washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (eluting with 5% EtOAc in hexane on 100-200 mesh silica gel column chromatography) to afford pure 4-bromo-6-chloro-2-isopropyl-quinoline-3-carboxylic acid methyl ester (500 mg, 51%) as an off white solid. LC-MS: 343 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Nc1ccccc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc3ccccc3nc2-c2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
For example, in synthetic route `A2` of FIG. 2, 4,4'-difluorobenzil, 1,2-phenylenediamine and chloroform are charged together in a reaction vessel and stirred. A catalytic amount of trifluoroacetic acid is added slowly and the reaction mixture heated to about 50° C. with continued stirring. After about 16 h, the mixture is cooled to provide 2,3-bis(4-fluorophenyl)quinoxaline after removal of the chloroform. Recrystallization results 2,3-bis(4-fluorophenyl)quinoxaline having a melting point of 127-1290° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1)(=[O:4])=[O:3].O.[OH-].[Li+]>CO.O>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)Cc1ccc(NS(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
The solution of ethyl 2-(4-(methylsulfonamido)phenyl)acetate (200 mg, 0.77 mmol) and lithium hydroxide hydrate (130.4 mg, 3.11 mmol) in MeOH/H2O (10 mL, 1:1) was stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure. The residue was used for the next step without purification. LC-MS: m/z (M+H)=230.4