Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[O:23].C1(C)C=CC=CC=1>O1CCCC1>[OH:23][CH:22]([C:13]1[S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:21]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C=O
Reactant: c1ccc(-c2csc3ccccc23)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A solution of butyllithium (1.6 M, 3.75 mL, 6 mmol) was added at −20° C. to a solution of 3-phenyl-1-benzothiophene (3a) (1.18 g, 5.61 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere. After 1 hour, a solution of ethyl glyoxylate in toluene (50%, 1.2 mL, 6 mmol) was added. The reaction mixture was slowly warmed to room temperature for 2 hours, quenched with water (5 mL) and concentrated in vacuo. The residue was partitioned between dichloromethane (40 mL) and water (15 mL). The organic layer was washed with water (2×15 mL), brine (15 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired alcohol (3b) as a white solid (340 mg, 1.09 mmol, 20%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@@H:13]([NH2:15])[CH2:12]1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>CS(C)=O.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:12][C@@H:13]([NH:15][C:22]2[C:17]([Cl:16])=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:14]1
Reactant: Clc1nccnc1Cl
Reactant: N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Clc1nccnc1N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Reaction time: 6 h
Yield: 32.4 %

Procedure:
To a round bottomed flask was added cis-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (0.5306 g, 1.816 mmol), 2,3-dichloropyrazine (0.271 g, 1.816 mmol, Pfaltz & Bauer, Inc.), and triethylamine (0.758 ml, 5.45 mmol, Sigma-Aldrich Chemical Company, Inc.) to stir at 75° C. in DMSO (1.816 ml) to stir for 6 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic extract was washed with water, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (0.1952 g, 0.588 mmol, 32.4% yield). LCMS showed product peak at 1.625 min (m+1=332.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.06-2.20 (m, 2 H) 2.75-2.87 (m, 2 H) 3.98-4.11 (m, 1 H) 4.11-4.22 (m, 1 H) 7.03 (td, J=7.53, 1.17 Hz, 1 H) 7.19-7.28 (m, 2 H) 7.40 (d, J=7.24 Hz, 1 H) 7.60 (d, J=2.54 Hz, 1 H) 7.69 (dd, J=7.82, 0.78 Hz, 1 H) 8.05 (d, J=2.74 Hz, 1 H) 8.32 (d, J=6.65 Hz, 1 H)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].[OH:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])[O:15][CH2:16][CH2:17][OH:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCCl
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCO)cc1OCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 2-(2-chloroethoxy)-4-fluoro-1-nitro-benzene (91.3 g, 6 mmoles), 2-hydroxyethanol (0.57 g, 7.2 mmoles), and cesium carbonate (2.34 g, 7.2 mmoles) in DMF were stirred together at room temperature for 1 hour, diluted with water and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound (0.63 g, 2.4 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:13]=1[C:14]#[N:15])([O-:11])=[O:10]>>[N:1]1([CH2:6][CH2:7][O:8][C:16]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=2[C:14]#[N:15])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OCCn1cccc1
Product: N#Cc1c(OCCn2cccc2)cccc1[N+](=O)[O-]
Yield: 42.5 %

Procedure:
Prepared as in Example 160d from 2-(1H-pyrrol-1-yl)ethanol and 2,6-dinitrobenzonitrile, in 42.5% yield. MS 258 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)#N.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[Mg]Br.S(=O)(=O)(O)[OH:20]>O1CCCC1.C1(C)C=CC=CC=1>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)=[O:20]
Reactant: Br[Mg]c1cccs1
Reactant: N#Cc1cccc2cc[nH]c12
Reactant: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(c1cccs1)c1cccc2cc[nH]c12
Temperature: 35 °C
Reaction time: 4.5 h
Yield: 38 %

Procedure:
2 g of 7-cyanoindole (14.1 mmol) in tetrahydrofuran (10 ml) and toluene (15 ml) was introduced in a round flask at 20° C. under inert gas atmosphere. 2-Thienyl magnesium bromide [produced from 6.21 g of 2-bromothiophene (36.8 mmol) and 1.2 g of magnesium (49.4 mmol) in tetrahydrofuran (53 ml)] was added to the above within 5 minutes. The temperature of the reaction mixture was then maintained for 1 hour at 35° C. and then for another 4.5 hours at 45° C. Then the pH of the mixture was adjusted to 0.5 with a 10 percent sulfuric acid and stirred at 45° C. for 45 minutes. It was extracted after neutralization with 30 percent NaOH. Then the organic phase was washed twice with common salt solution (50 ml) and then concentrated by evaporation to a dark brown oil (3.52 g). The latter was dissolved in ethyl acetate (50 ml), then treated with activated carbon and then this solution was concentrated to 20 ml. All of this was cooled to -50° C. for crystallization. 1.2 g of crystallized product was obtained corresponding to a yield of 38 percent relative to 7-cyanoindole used. The product had a melting point of 128.7° to 129.5° C. (light brown crystals). Other data concerning the product was:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1.O=CCCCNC(=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]=[O:17])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCO)CC1
Agent: O=CCCCNC(=O)c1ccccc1
Product: COc1ccccc1N1CCN(CC=O)CC1

Procedure:
[4-(2-Methoxy-phenyl)-piperazin-1-yl]-acetaldehyde (28B) is prepared from 28A as described for 1E.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:12].[O-]CC.[Na+]>C(O)C>[C:13]12([C:11](=[O:12])[CH:10]=[CH:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-fluorobenzaldehyde (6.01 ml, 56.10 mmol, Aldrich) and 1-adamantyl methyl ketone (10.00 g, 56.10 mmol) in absolute ethanol (100 ml) was treated with a solution of sodium ethoxide in ethanol (21% by weight solution; 2.08 ml, 5.61 mmol). A precipitate soon fell out of solution. After stirring at room temperature for 48 hours, the mixture was cooled to -10° C. and the precipitate was collected by filtration. The solid was washed with cold ethanol, dried in vacuo and recrystallized from hexane. The title compound was obtained as an off-white solid (9.20 g, 57.8%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:34][C:20]3=[N:21][CH:22]=[C:23]([C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([OH:30])=O)[CH:24]=[C:19]3[C:18]=2[C:35](=[O:38])[NH:36][CH3:37])=[CH:13][CH:12]=1.[CH3:39][C:40]([NH2:43])([CH3:42])[CH3:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:40]([NH:43][C:28]([C:27]1[CH:26]=[C:25]([C:23]2[CH:24]=[C:19]3[C:18]([C:35]([NH:36][CH3:37])=[O:38])=[C:17]([C:14]4[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=4)[O:34][C:20]3=[N:21][CH:22]=2)[CH:33]=[CH:32][CH:31]=1)=[O:30])([CH3:42])([CH3:41])[CH3:39]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)O)c3)cc12
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC(C)(C)C)c3)cc12
Reaction time: 2 h
Yield: 28.8 %

Procedure:
DIEA (31 μL, 0.18 mmol) was added to a stirring solution of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoic acid (23 mg, 0.059 mmol), 2-methylpropan-2-amine (20 μL, 0.059 mmol), and HATU (27 mg, 0.071 mmol) in DMF (0.6 mL) at room temperature. It was allowed to stir for 2 hours. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 5-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide (8 mg, 0.017 mmol, 29% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.74 (1H, d, J=2.14 Hz), 8.55-8.61 (1H, m), 8.39 (1H, d, J=2.44 Hz), 8.16 (1H, s), 8.07 (2H, dd, J=8.85, 5.19 Hz), 7.94 (1H, s), 7.92 (1H, d, J=7.63 Hz), 7.86 (1H, d, J=7.93 Hz), 7.59 (1H, t, J=7.63 Hz), 7.43 (2H, t, J=8.85 Hz), 2.87 (3H, d, J=4.58 Hz), 1.42 (9H, s). LC-MS retention time: 1.68 min; m/z (MH+): 446. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Phenomenex Gemini C1 C-18, 4.6×150 mm, 3 mm, Rt=13.66 min, purity=98%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=13.69 min, purity=98%.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:17]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cnc2ccccc2c1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and 3-bromoquinoline (purchased from the Aldrich Chemical Co.) were coupled according to the procedure described in Example 1A to provide the title compound.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C@@H:12]2[CH2:17][O:16][C@@H:15]([CH2:18][OH:19])[O:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[C:21](Br)([F:23])[F:22].[CH:25](O)=O>>[F:22][C:21]([F:23])=[CH:25][O:19][CH2:18][C@H:15]1[O:16][CH2:17][C@H:12]([CH:9]2[CH2:8][CH2:7][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)[CH2:13][O:14]1
Reactant: O=CO
Reactant: CCCCCC1CCC([C@H]2CO[C@H](CO)OC2)CC1
Reactant: FC(F)(Br)Br
Product: CCCCCC1CCC([C@H]2CO[C@H](COC=C(F)F)OC2)CC1

Procedure:
27.0 g of trans/trans-[5-(4-pentylcyclohexyl)-1,3-dioxan-2-yl]methanol are firstly esterified using formic acid as described in Example 1 and then treated with dibromodifluoromethane. Conventional work-up gives trans/trans-2-(2,2-difluorovinyloxymethyl)-5-(4-pentylcyclohexyl)-1,3-dioxane.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=5)[N:30]([CH3:38])[N:29]=4)[N:26]=3)[N:21](COCC[Si](C)(C)C)[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=5)[N:30]([CH3:38])[N:29]=4)[N:26]=3)[NH:21][CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(Cl)ccc21
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(C#N)CC4)C(C)(C)C)c3n2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.3 %

Procedure:
In a round-bottomed flask, 2-(5-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (0.158 g, 0.193 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.6 ml, 7.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was redissolved in dichloromethane (1 ml) and ethylenediamine (0.8 ml, 11.7 mmol) was added. The solution was stirred at room temperature for 1 h then quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with EtOAc/hexanes (gradient 0-100% EtOAc) to afford 26 mg (24%) of 2-(5-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as an off-white solid. MS: (M+H)+=533; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.92 (br. s., 1H), 9.09 (s, 1H), 8.73 (d, J=6.8 Hz, 1H), 8.61 (t, J=8.1 Hz, 1H), 8.46 (d, J=9.1 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.50 (d, J=9.1 Hz, 1H), 5.20 (d, J=9.4 Hz, 1H), 4.19 (s, 3H), 3.97-4.12 (m, 1H), 3.35-3.91 (m, 2H), 3.01-3.23 (m, 2H), 1.39-2.07 (m, 4H), 1.04 (d, J=6.4 Hz, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[OH:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=O)[N:10]1[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[N:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=2)[N:20]=1.O.C(OCC)(=O)C>CN(C)C=O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:8])[N:10]1[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[N:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=2)[N:20]=1
Reactant: CN(C)CCCN
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3NCCCN(C)C)nc2n1
Yield: 32.3 %

Procedure:
3-Dimethylaminopropylamine (5.1 g) is added at a temperature in the region of 20° C. to a solution of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (12.4 g) in anhydrous dimethylformamide (200 cc), and the reaction mixture is heated to reflux for 8 hours. After being cooled, the reaction mixture is poured into a mixture of water (1200 cc) and ethyl acetate (500 cc) and filtered to remove an insoluble product. The aqueous phase is separated after settling has occurred and then extracted with ethyl acetate (2×250 cc). The organic phases are combined, washed with water (5×80 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After recrystallization in ethyl acetate, 3-(3-dimethylaminopropylamino)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (5.1 g), m.p. 128° C., is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[C:29]([NH:32][CH2:33][CH2:34][NH2:35])(=[O:31])[CH3:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[C:29]([NH:32][CH2:33][CH2:34][NH:35][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)(=[O:31])[CH3:30]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: CC(=O)NCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CC(=O)NCCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with N acetylethylenediamine using BOP reagent in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=460.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH2:15][CH2:16][O:17][CH3:18]>[OH-].[Na+].O>[CH3:18][O:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: COCCCCl
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCCOc1cc(C)c(C(C)=O)c(C)c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (800 mg, 4.9 mmol, 1.0 equiv) and 1-chloro-3-methoxypropane (528.97 mg, 4.9 mmol, 1.0 equiv) in 50% aqueous NaOH solution (10.0 mL) was stirred at 140° C. for 16 h. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was separated, dried over MgSO4(s), and concentrated under reduced pressure to give 1-(4-(3-methoxypropoxy)-2,6-dimethylphenyl)ethanone (987.8 mg, 4.2 mmol) as yellow oil in 86% yield: 1H NMR (DMSO-d6, 500 MHz) δ 6.56 (s, 2 H), 4.02-4.04 (m, 2H), 3.53-3.55 (m, 2 H), 3.36 (s, 3 H), 2.45 (s, 3 H), 2.23 (s, 6 H), 2.02-2.04 (m, 3H); ESI-MS: m/z 237.7 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:21])(=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1)=[O:4].[CH3:22][NH:23][C:24]([NH:26][CH3:27])=[S:25]>>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:25][C:24](=[N:23][CH3:22])[N:26]2[CH3:27])=[CH:6][C:7]=1[S:12](=[O:21])(=[O:20])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccc(Cl)c(S(=O)(=O)Nc2ccccc2)c1
Reactant: CNC(=S)NC
Product: Br
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Nc3ccccc3)c2)N1C

Procedure:
5.2 g of 2-bromo-4'-chloro-3'-phenylsulfamoylacetophenone and 1.5 g of 1,3-dimethylthiourea were reacted as prescribed in Example 23 and the precipitated end product was filtered off. Colorless crystals, melting point: 82° C (decomposition).
Reaction SMILES: [CH3:1][O:2][CH:3](P(=O)(OCC)OCC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].[N+:26]([C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[C:32]2=O)([O-:28])=[O:27].S([O-])(O)(=O)=O.[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[C:32]1[C:31]2[C:35](=[CH:36][CH:37]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=2)[NH:34][C:33]1=[O:38])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Reactant: CCOP(=O)(OCC)C(OC)c1ccc(OC)cc1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccc(OC)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
6.3 g (22 mmol) of diethyl [methoxy-(4-methoxyphenyl)-methyl]-phosphonate are dissolved in 40 ml of DMF under a nitrogen atmosphere. 5.1 g (45 mmol) of potassium tert.butoxide are added batchwise at −40° C. and the mixture is then stirred for another 30 minutes at −10° C. Then 3.84 g (20 mmol) of 5-nitroisatine are added. The mixture is stirred for 1 hour at ambient temperature and then poured onto ice water containing 20 ml of saturated potassium hydrogen sulphate solution. The precipitate is suction filtered and chromatographed over silica gel (dichloromethane/methanol=10:1).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(2-methanesulfonyl-ethyl)-piperazine (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C35H45N6O4SCl2 [(M+H)+] 715.2595, observed 715.259.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Mg].BrC(Br)C.[C:14](Cl)(=[O:18])[C:15]([Cl:17])=[O:16]>C1COCC1.CCOCC>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14](=[O:18])[C:15]([Cl:17])=[O:16]
Reactant: Cc1ccccc1Br
Reactant: O=C(Cl)C(=O)Cl
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccccc1C(=O)C(=O)Cl
Reaction time: 1 h
Yield: 95.8 %

Procedure:
In a stream of argon gas, 2-bromotoluene (8.55 g, 0.05 mol) in dry THF (60 ml) was dropwise added to a mixture of magnesium (2.43 g, 0.1 mol) and dibromoethane (0.1 ml) in dry THF (10 ml) at 50° to 60° C. for 13 minutes. The reaction mixture was stirred at 60° to 65° C. for 1 hour, diluted with dry THF (30 ml) and cooled below 20° C. This mixture was dropwise added to oxalyl chloride (7.62 g, 0.06 mol) in dry ether (150 ml) below -50° C. over 8 minutes, followed by stirring at -75° C. for 1 hour, and filtered in a stream of argon gas at room temperature. The filtrate was concentrated under reduced pressure at room temperature. The precipitated crystals were filtered in a stream of argon gas and washed with dry ether. The filtrate and the wash liquid were combined together and the solvent was distilled off under reduced pressure to give crude 2-(2-methylphenyl)glyoxyloyl chloride (8.75 g; yield, 95.8%) as a pale brown oil.