Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([OH:27])[CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[C:6](=[O:12])[NH:7]4)[CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: Oc1ccc2cccnc2c1
Product: O=c1[nH]c2nccc(Oc3ccc4cccnc4c3)c2c2ccccc12
Yield: 68.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 182 using 83 (50 mg, 0.22 mmol) and quinolin-7-ol (63 mg, 0.43 mmol) to provide 229 (51 mg, 69% yield) as a tan solid. LC-MS (M+H=340, obsd.=340).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][C:8]([CH3:10])=[O:9])=[N:4][N:3]=1.[CH:11]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=1[O:21][CH3:22])=O.N1CCCCC1.C(O)(=O)C>ClCCl>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:13]=1[CH:11]=[C:7]([C:5]1[S:6][C:2]([CH3:1])=[N:3][N:4]=1)[C:8](=[O:9])[CH3:10])[C:17]#[N:18]
Reactant: COc1cc(C#N)ccc1C=O
Reactant: CC(=O)Cc1nnc(C)s1
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cc(C#N)ccc1C=C(C(C)=O)c1nnc(C)s1

Procedure:
1.34 g (8.32 mmol) of 1-(5-methyl-1,3,4-thiadiazol-2-yl)acetone [T. Saito et al., J. Heterocycl. Chem. 20, 73-75 (1983)] and 1.30 g (8.32 mmol) of the compound from example 3A are dissolved in 20 ml of dichloromethane, and 0.165 ml (1.66 mmol) of piperidine and 0.100 ml (1.66 mmol) of acetic acid are added. The reaction mixture is heated under reflux with an inverse water trap overnight. The volatile components are removed in a rotary evaporator, and the crude product is purified by column chromatography (silica gel; eluent: initially dichloromethane, then cyclohexane/ethyl acetate 4:1→1:1). 1.17 g (47% of theory) of the title compound are obtained as a mixture of the E/Z isomers which can be crystallized from ethyl acetate/n-pentane. 530 mg of the title compound are obtained as a crystalline solid in this way.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 85 °C

Procedure:
Methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl-3-methoxy-6-[[[2-(dimethylamino)-2-oxoethyl]methylamino]carbonyl]- (117 mg, 0.21 mmol) was dissolved into THF/MeOH (1:1, 2 mL) and 1M NaOH (aq.) (0.5 mL, 0.5 mmol). The reaction mixture was heated in a sealed tube with microwave irradiation at 85° C. for 20 min. The reaction was cooled, neutralized with 1M HCl (aq.) (0.5 mL, 0.5 mmol) and concentrated to remove organic solvents. The residue was slurried with H2O and the solids were collected by filtration, flushed with H2O, and purified by preparative HPLC to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[[[2-(dimethylamino)-2-oxoethyl]methylamino]carbonyl]- (71 mg, 0.13 mmol, 63%) as a yellow solid. Mixture of amide rotamers: 1HNMR (500 MHz, CD3OD) δ 8.24 (br s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.18-6.88 (m, 2H), 7.14 (dd, J=8.4, 2.2 Hz, 1H), 5.14 (br s, 1H), 4.49-4.12 (m, 2H), 3.97-3.88 (m, 1H), 3.93 (s, 3H), 3.15-2.83 (m, 7H), 2.56 (s, 1.5H), 2.42 (s, 1.5H), 2.23-1.73 (m, 6H), 1.59-1.17 (m, 4H). LCMS: m/e 530 (M+H)+, ret time 1.40 min, column A, 2 minute gradient.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:20]1[CH2:19][CH2:18][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:22][CH2:21]1)=[O:5]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Temperature: 150 °C
Yield: 28.1 %

Procedure:
To a solution of 2-fluorobenzaldehyde (Aldrich) (1 g, 8.1 mmol) in DMF (14 mL) was added 1-Boc-piperazine (Lancaster) (2.3 g, 12 mmol). The resulting solution was treated with copper (Aldrich Chemical Company) (50 mg, 0.8 mmol) and K2CO3 (Aldrich) (5.1 g, 37 mmol). The suspension was heated in a sealed tube at 150° C. for 18 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted twice with EtOAc and the combined EtOAc layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude compound was purified on a Biotage 40 M column (12% EtOAc in hexanes) to give tert-butyl 4-(2-formylphenyl)piperazinecarboxylate (0.66 g) as a yellow oil. MS m/z: 291 (M+H). Calc'd for C16H22N2O3: 290.36.
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[C:25]([C:28]#[N:29])[CH:26]=[CH:27][C:15]=3[N:14]=2)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.C(=O)([O-])[O-:31].[K+].[K+]>CS(C)=O.O.OO.CCOC(C)=O>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16]3[CH:24]=[C:25]([C:28]([NH2:29])=[O:31])[CH:26]=[CH:27][C:15]=3[N:14]=2)[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(C#N)cc2n1-c1ccccc1
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(C(N)=O)cc2n1-c1ccccc1
Reaction time: 1 h
Yield: 168.5 %

Procedure:
To a solution of (S)-2-(1-(9H-purin-6-ylamino)ethyl)-1-phenyl-1H-benzo[d]imidazole-6-carbonitrile 122 (70 mg, 0.18 mmol) in DMSO (2 mL) was added potassium carbonate (10 mg, 0.07 mmol) followed by hydrogen peroxide (30%, 0.2 mL). After 1 h stirring, additional potassium carbonate (10 mg, 0.07 mmol) in water and hydrogen peroxide 90.2 mL) were added and stirring was continued for 1 h. The solution was then diluted with water (30 mL) and EtOAc was added. A precipitate formed and was filtered off affording 137 as a white solid (47 mg, 64%). LCMS: RT 2.41 min [M+H]+ 399.1. 1H NMR (DMSO, 400 MHz): δ 8.20-8.07 (2H, m), 8.03-7.92 (2H, m), 7.81 (1H, d, J=9.19 Hz), 7.76-7.50 (6H, m), 7.24 (1H, s), 5.51 (1H, bs), 1.58 (3H, d, J=6.84 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:49])([CH3:48])[C:10]([NH:12][C@H:13]([CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)[C:14]([NH:16][C:17]1[N:18]=[C:19]([CH:22]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[C:23]([O:25]CC)=[O:24])[NH:20][CH:21]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O1CCOCC1>O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:49])([CH3:48])[C:10]([NH:12][C@H:13]([CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:41][CH:40]=1)[C:14]([NH:16][C:17]1[N:18]=[C:19]([CH:22]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[C:23]([OH:25])=[O:24])[NH:20][CH:21]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(c1ccc2ccccc2c1)c1nc(NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)c[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)Nc1c[nH]c(C(C(=O)O)c2ccc3ccccc3c2)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution consisting of ethyl 2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)acetate (1.52 grams, 2.28 mmol), lithium hydroxide (0.11 grams, 4.56 mmol), dioxane (10 mL), and water (10 mL) was stirred at ambient temperature until complete as determined by hplc (30 minutes). The reaction mixture was concentrated to dryness and the residue was dissolved in water (20 mL). The aqueous solution was adjusted to a pH of 3 using a 10% sodium bisulfate solution and extracted with ethyl acetate (3×25 mL). The organic layers were combined, dried using sodium, sulfate, filtered, and concentrated to give 1.34 grams (92%) of 2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methyl propanoylamino}-3-indol-3-ylpropanoylamino)imidazolyl]-2-(2-naphthyl)acetic acid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:24]>CN(C)C=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:6][CH2:5][C:1]([OH:24])([CH3:3])[CH3:2])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCC(C)(C)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of Example 244A (75 mg, 0.23 mmol) in N,N-dimethylformamide (2 mL) was treated with NaH 60% dispersion in oil (9.5 mg, 0.23 mmol) followed by Example 308A (60 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 18 hours, poured into water and extracted with ethyl acetate. The organic layer was washed with H2O (2×50 mL), dried over MgSO4, filtered, concentrated under reduced pressure and dried under vacuum (˜1 mm Hg) to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.17 (s, 6H), 1.32 (s, 9H), 1.76-1.91 (m, 2H), 3.79 (s, 3H), 4.14-4.31 (m, 2H), 4.43 (s, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 7.44 (dd, J=9.0, 2.9 Hz, 1H), 7.76 (d, J=3.1 Hz, 1H); MS (ESI) m/z 411 (M+H)h Anal. Calculated for C20H27ClN2O3SC, 58.45; H, 6.62; N, 6.82. Found C, 58.30; H, 6.51; N, 6.71.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24])[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: FCc1cccc(Br)n1
Product: O=C1c2ccccc2C(=O)N1CCC#Cc1cccc(CF)n1
Yield: 64.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (336 mg, 1.77 mmol, Example 190(E)) and 2-(but-3-ynyl)isoindoline-1,3-dione (320 mg, 1.61 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 75:25) to yield 320 mg (1.04 mmol, 65%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)isoindoline-1,3-dione as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C@@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(C(CCCC)C(O)=O)C>O>[CH3:16][C@H:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:17])=[O:2])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H]1CCCN1[C@@H](C)c1ccccc1
Agent: CCCCC(CC)C(=O)O
Solvent: O
Product: C[C@@H](c1ccccc1)N1CCC[C@H]1C(=O)O
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To N-[(S)-α-methylbenzyl]-(S)-proline methyl ester (4.46 g) obtained in Example 3 were added water (9.33 g) and 2-ethylhexanoic acid (3.25 g). The mixture was heated up to 60° C. and stirred at that temperature for 12 hours. The resulting mixture was washed with heptane to yield an aqueous N-[(S)-α-methylbenzyl]-(S)-proline solution.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[C:20]([CH3:21])=[C:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:34])[CH:17]=2)[CH:12]=1)=O.C(OCC)(=O)C>O1CCCC1>[CH2:32]([S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([F:34])[CH:17]=3)[CH:12]=[C:11]([CH2:9][OH:8])[C:20]=2[CH3:21])=[CH:24][CH:25]=1)(=[O:30])=[O:31])[CH3:33]
Reactant: CCS(=O)(=O)c1ccc(Cc2c(C)c(C(=O)OC)cc3ccc(F)cc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(Cc2c(C)c(CO)cc3ccc(F)cc23)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
A suspension of lithium aluminum hydride (399 mg, 10.5 mmol) in tetrahydrofuran (25 mL) was cooled to 0° C. under a stream of argon. A solution of 4-(4-ethanesulfonyl-benzyl)-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester (870 mg, 2.18 mmol) in tetrahydrofuran (30 mL) was added slowly drop-wise to the 0° C. suspension. The reaction mixture was stirred at 0° C. for 15 minutes. The reaction mixture was warmed to room temperature and it was stirred at room temperature for 15 minutes. The reaction mixture was cooled again to 0° C. Ethyl acetate was added drop-wise to quench the unreacted lithium aluminum hydride. A saturated aqueous solution of potassium sodium tartrate was added. The organic phase was separated, dried over MgSO4, filtered, and concentrated to afford 780 mg (96%) of [4-(4-ethanesulfonyl-benzyl)-6-fluoro-3-methyl-naphthalen-2-yl]-methanol as an oily white solid. This product was used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.98 (dd, J=8.9, 6.2 Hz, 1 H), 7.90 (s, 1 H), 7.73 (d, J=8.2 Hz, 2 H), 7.67 (d, J=12.4 Hz, 1 H), 7.34 (dd, J=8.9, 2.1 Hz, 1 H), 7.29 (d, J=8.2 Hz, 2 H), 5.27 (t, J=5.1 Hz, 1 H), 4.66 (d, J=5.1 Hz, 2 H), 4.58 (s, 2 H), 3.20 (q, J=7.2 Hz, 2 H), 2.31 (s, 3 H), 1.04 (t, J=7.2 Hz, 3 H). HRMS (ES+) cald. for C21H21FO3S [(M+Na)+] 395.1087, obsd. 395.1088.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[S:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)[CH:6]=CC=1)#N.[OH-:20].[K+].Cl.[CH2:23]([OH:25])[CH3:24]>>[S:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[CH:10]=[CH:9][C:5]1[CH:6]=[C:24]([CH:1]=[CH:3][CH:4]=1)[C:23]([OH:20])=[O:25]
Reactant: CCO
Reactant: N#Cc1cccc(C=Cc2nc3ccccc3s2)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: O=C(O)c1cccc(C=Cc2nc3ccccc3s2)c1
Yield: 81 %

Procedure:
2-(2-(3-Cyanophenyl)ethenyl)benzthiazole (3.00 g, 11.5 mmol) was dissolved in 50 ml of ethanol. After 10 ml of 30% aqueous potassium hydroxide solution was added, the resulting mixture was heated under reflux for 19 hours. The reaction mixture was cooled, neutralized with 5% hydrochloric acid, extracted with ethyl acetate, and dried. The solvent was then distilled out to produce a crude product. This crude crystal was washed with ether to afford the indicated compound (2.60 g) with a yield of 81%.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C)C=O.[CH:14]1([CH2:17][N:18]2[CH:26]=[N:25][C:24]3[C:19]2=[N:20][C:21]([C:33]2[CH:34]=[N:35][C:36]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[N:37][CH:38]=2)=[N:22][C:23]=3[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:16][CH2:15]1>C(OCC)(=O)C>[Cl:1][C:26]1[N:18]([CH2:17][CH:14]2[CH2:16][CH2:15]2)[C:19]2[C:24]([N:25]=1)=[C:23]([N:27]1[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1)[N:22]=[C:21]([C:33]1[CH:38]=[N:37][C:36]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[N:35][CH:34]=1)[N:20]=2
Reactant: CC(C)(C)OC(=O)NCc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CC4)c3n2)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reaction time: 4.5 h
Yield: 56.1 %

Procedure:
N-Chlorosuccinimide (0.92 g, 6.89 mmol) was added to an N,N-dimethylformamide solution (60 ml) of tert-butyl {5-[9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-yl}methylcarbamate (2.14 g, 4.59 mmol) at room temperature. The resulting mixture was stirred for 4.5 hours followed by the addition of N-chlorosuccinimide (0.12 g, 0.92 mmol) and the resulting mixture was further stirred for 2.5 hours. The reaction mixture was poured into ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=17:3 to 3:1) to give the title compound (1.29 g, 56%, two steps combined) as a colorless amorphous substance.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=O)=[CH:6]1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35][NH:36][C:18]([C:7]1[C:8](=[O:17])[C:9]([O:15][CH3:16])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:21][CH3:22])[CH:6]=1)=[O:20]
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Reactant: NCc1ccc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(OC)c(=O)c(C(=O)NCc2ccc(F)cc2F)cn1CC(OC)OC
Reaction time: 0.17 h

Procedure:
1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.300 g, 0.95 mmol), prepared as described in WO2011/119566 A1, was evaporated once from dry toluene, suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.329 mL, 1.90 mmol), 2,4-difluorobenzylamine (0.125 mL, 1.05 mmol) and HATU (0.433 g, 1.14 mmol). The reaction mixture was stirred for 10 minutes and concentrated. The residue was purified by flash chromatography on silica gel (10 to 60% ethyl acetate:dichloromethane) to afford the compound methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate, 1-B. 1H-NMR (400 MHz, DMSO-d6) δ 10.28 (t, J=6.0 Hz, 1H), 8.46 (s, 1H), 7.42 (dd, J=15.4, 8.6 Hz, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 4.52 (m, 3H), 4.22 (d, J=4.4 Hz, 2H), 3.92 (s, 3H), 3.80 (s, 3H), 3.29 (d, 6H). LCMS-ESI+ (m/z): [M+H]+ calculated for C20H23F2N2O7: 441.15; found: 441.2.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][CH2:4][CH2:5][O:6][CH:7](O)[CH3:8].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>O>[OH:1][CH2:8][CH2:7][O:6][CH2:5][CH2:4][NH:3][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(O)OCCN
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(NCCOCCO)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of sodium hydroxide (2.2 g, 0.055 moles) in distilled water (100 ml), aminoethoxyethanol (5.25 g, 0.05 moles) was added and the solution was cooled to 0° C. on an ice bath. Under stirring on the ice bath, p-chloro-benzoylchloride (8.75 g, 0.5 moles) was added thereto drop by drop. The stirring was continued for 3 hours at room temperature and the separated precipitate was filtered off by suction. The mother liquid was extracted with chloroform (3×100 ml). The organic phase was separated, dried with sodium sulfate, filtered and evaporated on a rotary evaporator. The precipitated N-O-di-((4-chloro)-benzoyl)-amino-ethoxyethanol was dissolved in dioxan (50 ml) and sodium hydroxide (22 ml of a 1N solution) was added thereto. The solution was stirred for 2 hours at 40° C., water (50 ml) was added thereto and it was extracted with ethyl acetate (5×50 ml). The organic phase was separated, dried with sodium sulfate, filtered and evaporated on a rotary evaporator. The obtained product was crystallized from diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:14][CH:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:14]([CH:7]1[C:6]([CH3:13])([CH3:12])[C:5]2[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:15]=[CH:16][CH3:17]
Reactant: C=CC(C)O
Reactant: CC1(C)CC(=O)c2cc(F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(F)ccc2C1(C)C
Yield: 26 %

Procedure:
A solution of 10.0 g of 6-fluoro-3,3-dimethyl-1-indanone, 11.1 ml of 3-buten-2-ol and 200 mg of p-toluenesulfonic acid in 200 ml of 2,2-dimethoxypropane was boiled under reflux for 96 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 8:1). In addition to 11.9 g of educt, there were obtained 3.38 g (26%) of (RS)-2-(2-buten-1-yl)-6-fluoro-3,3-dimethyl-1-indanone as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(=O)(=O)(O)O.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(C)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1OC(C)=O
Temperature: 0 °C
Reaction time: 72 h

Procedure:
A solution of the product from step (i) (5.87 g) in acetic anhydride (4.32 g) was treated with concentrated sulphuric acid (0.5 ml) and stirred for 72 hours. The mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium bicarbonate, dried (MgSO4) and evaporated. Yield 5.5 g.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][S:21][CH2:20]2)=[C:12]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]=1>O>[ClH:9].[ClH:9].[NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:23][CH2:22][S:21][CH2:20]3)=[C:12]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Clc1nc(NCc2ccccc2)c2ncn(C3CCSC3)c2n1
Solvent: O
Product: Cl
Product: NC1CCC(Nc2nc(NCc3ccccc3)c3ncn(C4CCSC4)c3n2)CC1
Reaction time: 3 h
Yield: 131.1 %

Procedure:
400 mg of trans-1,4-diaminocyclohexane is taken to a temperature of 60 to 70° C., then 119 mg of the product obtained in Stage 2 above is added and the reaction medium is taken to a temperature of 130 to 140° C. for 3 hours, then left to return to ambient temperature, 5 ml of water is added followed by extracting with 3×10 ml of ethyl acetate, washing with 10 ml of water and 5 ml of an aqueous solution of sodium chloride, drying and evaporating to dryness. After purification on silica eluting with methanol/ ammonium hydroxide (NH4OH) in a proportion of 98/2, followed by salification with 1.4N hydrochloric acid in ethanol, leaving to crystallize for 2 days at ambient temperature, separating, washing with 10 ml of ethanol and drying at a temperature of approximately 50° C. In this way 112 mg of expected product is obtained in the form of crystals white/cream.