Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[F:1][C:2]1[C:9]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: BrCc1ccccc1
Reactant: O=Cc1cccc(O)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccc2)c1F

Procedure:
2-Fluoro-3-hydroxybenzaldehyde (16.49 g) was dissolved in dimethylformamide (200 ml) and stirred under an argon atmosphere. Sodium hydride was added (60% in mineral oil, 5.18 g) and the mixture was stirred for 30 minutes. Benzyl bromide was added (16.8 ml) and the mixture was stirred overnight. Reaction mixture was concentrated in vacuo and the resulting residue was partitioned between diethyl ether (200 ml) and water (200 ml). Combined organic extracts were washed with water (400 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, using a gradient of 0-10% ethyl acetate/iso-hexane as eluent to give the product as a yellow solid (18.41 g) 1H NMR (DMSO-d6) δ 5.20(s, 2H), 7.2-7.6(m, 8H), 10.21(s, 1H)
Reaction SMILES: BrC1C=C2C(=CC=1)C(=O)N([C@H](C(C)C)C(OC)=O)C2.[Br:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=O)=[C:23]([CH2:31]Br)[CH:22]=1.Cl.[NH2:34][CH:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37]>>[Br:20][C:21]1[CH:22]=[C:23]2[C:24](=[CH:29][CH:30]=1)[C:25](=[O:27])[N:34]([C@@H:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:31]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: COC(=O)C(N)CC(C)C
Agent: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)N1Cc2cc(Br)ccc2C1=O

Procedure:
The compound of example 386 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and methyl 2-amino-4-methylpentanoate hydrochloride.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@@H:13]([OH:31])[C@H:14]([CH:29]=[CH2:30])[C:15]([N:17]2[C@@H](C3C=CC=CC=3)COC2=O)=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:34]N>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@@H:13]([OH:31])[C@H:14]([CH:29]=[CH2:30])[C:15]([NH:17][NH2:34])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: NN
Reactant: C=C[C@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: C=C[C@H](C(=O)NN)[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 99.8 %

Procedure:
(4S)-3-{(2S)-2-[(S)-[3,5-Bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enoyl}-4-phenyl-1,3-oxazolidin-2-one (20 g, 42.5 mmol) and hydrazine (2.71 g, 85 mmol) in THF (100 mL) was stirred at room temperature for 1 hour. The reaction was diluted with ethyl acetate:hexanes (2:1, 200 mL) and was partitioned with water (100 mL). The organic was washed with brine (100 mL) and was dried over sodium sulfate, filtered, and concentrated. The crude product was triturated with IPA (30 mL) to remove the chiral auxiliary. The filtrate was concentrated to yield (2S)-2-[(S)-[3,5-bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enehydrazide (14.5 g, 42.4 mmol), which was used without further purification. 1H NMR (500 MHz, CDCl3) δ7.81 (s, 3H), 7.83 (s, 1H), 7.0 (br s, 1H), 5.9 (m, 1H), 5.42 (d, J=3.3 Hz, 1H), 5.29 (d, J=10.3 Hz, 1H), 5.03 (d, J=17.1 Hz, 1H), 3.1 (dd, J=9.4, 3.5 Hz, 1H).
Reaction SMILES: [NH2:1][CH:2]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Br:15])=[CH:10][N:9]=1)C(OCC)=O>Cl>[ClH:14].[Br:15][C:11]1[CH:12]=[C:13]([Cl:14])[C:8]([CH2:2][NH2:1])=[N:9][CH:10]=1
Reactant: CCOC(=O)C(N)c1ncc(Br)cc1Cl
Agent: Cl
Product: NCc1ncc(Br)cc1Cl
Yield: 182.4 %

Procedure:
A stirred solution of ethyl 2-amino-2-(5-bromo-3-chloropyridin-2-yl)acetate (0.5 g, 1.7 mmol) in 3 N HCl (25 mL) was heated at reflux for 4 h. The reaction mixture was washed with diethyl ether and H2O. The combined ether layer was concentrated under reduced pressure to afford the title compound as an off-white solid (400 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.70 (br s, 2H), 8.45 (s, 1H), 4.56 (m, 2H); ESIMS m/z 221.15 ([M+H]+).
Reaction SMILES: [I:1]I.[CH3:3][C:4]1([CH3:10])[CH2:8][C:7](=[O:9])[CH:6]=[CH:5]1>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.CCOCC>[CH3:3][C:4]1([CH3:10])[CH2:8][C:7](=[O:9])[C:6]([I:1])=[CH:5]1
Reactant: II
Reactant: CC1(C)C=CC(=O)C1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C=C(I)C(=O)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a cold (4° C.) solution of iodine (4.5 g, 18 mmol) in carbon tetrachloride (15 mL) and pyridine (15 mL), was added over 1 min. a solution of 4,4-dimethyl-2-cyclopenten-1-one (930 mg, 8.4 mmol) in carbon tetrachloride (15 mL) and pyridine (15 mL). The resulting red-brown solution was stirred at r.t. for 22 h. The reaction was diluted with Et2O (200 mL), washed successively with water (50 mL), 1.0 N HCl (50 mL), water (50 mL), and aqueous Na2S2O5 20% w/v, then dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 10% EtOAc/hexanes to give the title compound as a white solid.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:13][C@H:14]1[CH2:25][CH2:24][C:23]2[S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]([O:26][CH:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH2:29][CH2:28]4)[C:16]=3[C:15]1=2)[C:10]([NH2:12])=[O:11])(C(C)(C)C)(C)C.Cl>CO>[OH:8][CH:9]([CH2:13][C@H:14]1[CH2:25][CH2:24][C:23]2[S:22][C:21]3[N:20]=[CH:19][N:18]=[C:17]([O:26][CH:27]4[CH2:28][CH2:29][CH:30]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[CH2:31][CH2:32]4)[C:16]=3[C:15]1=2)[C:10]([NH2:12])=[O:11]
Reactant: CC(C)(C)[Si](C)(C)OC(C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21)C(N)=O
Agent: Cl
Solvent: CO
Product: NC(=O)C(O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A 100-mL round-bottom flask was charged with a solution of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]propanamide (197 mg, 0.35 mmol, 1.00 equiv) in methanol (10 mL). Hydrochloric acid (2 M, 0.8 mL) was added and stirring continued for 2 hr in a water/ice bath. After completion, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with 3×30 mL of DCM. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative TLC (DCM/MeOH:10/1) to afford the 2-hydroxy-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]propanamide (124 mg, 79%) as a white solid. MS (ES): m/z 447 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 5.28-5.25 (m, 1H), 4.17-4.06 (m, 51H), 3.74-3.72 (m, 5H), 3.37-2.98 (m, 2H), 2.72-2.28 (m, 10H), 2.11-2.08 (m, 2H), 1.79-1.46 (m, 5H).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[C:11]([NH:13][N+]([O-])=O)[CH:10]=[C:9]([Br:17])[N:8]=1.NC1C([N+:25]([O-:27])=[O:26])=NC=CC=1>CCOC(C)=O>[Br:17][C:9]1[C:10]([N+:25]([O-:27])=[O:26])=[C:11]([NH2:13])[CH:12]=[C:7]([Br:6])[N:8]=1
Reactant: O=[N+]([O-])Nc1cc(Br)nc(Br)c1
Reactant: Nc1cccnc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Temperature: 54 °C
Reaction time: 1 h

Procedure:
Concentrated sulphuric acid (250 ml) was heated in an oil bath until the temperature of the acid reached 47° C. 2,6-dibromo pyridin-4-yl-N-nitroamine (34.0 g, 114.5 mmol) was added in portions over 35 mins. The temperature of the mixture gradually rose throughout the addition period until it was 56° C. at the end. The mixture was stirred at 53-55° C. for 1 hour. Once the reaction was completed, the reaction mixture was cooled to in an ice-bath and poured on ˜2 L of crushed ice with stirring. The product precipitated and was filtered off. Combined with other batch 00110916-140-001 from an identical scale reaction. The crude, wet amino nitro pyridine was dissolved in 700 ml EtOAc and the water layer was separated. The organic layer was washed with water (2×150 ml), 1×150 ml aq. NaHCO3, brine (2×150 ml), dried (MgSO4) and concentrated under reduced pressure to give 28 g of the title compound.
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][NH2:6])#[N:2].[Cl:25][CH2:26][CH2:27][CH2:28][S:29](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:31])=[O:30]>>[Cl:25][CH2:26][CH2:27][CH2:28][S:29]([NH:6][CH2:5][CH:4]([CH2:3][C:1]#[N:2])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:31])=[O:30]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCOCC(CN)CC#N
Product: CCCCCCCCCCCCCCCCOCC(CC#N)CNS(=O)(=O)CCCCl

Procedure:
The crude 2-cyanomethyl-3-hexadecyloxypropylamine IVn1 prepared above is allowed to react by the same procedure as described in (4). The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: C([O:9][C@H:10]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][CH2:12][C@@H:11]1[C:18]1[N:22]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[N:21]=[CH:20][CH:19]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:17][C:14]1([F:16])[CH2:15][C@H:10]([OH:9])[C@@H:11]([C:18]2[N:22]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[N:21]=[CH:20][CH:19]=2)[CH2:12][CH2:13]1
Reactant: COCCOCn1nccc1[C@H]1CCC(F)(F)C[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCCOCn1nccc1[C@H]1CCC(F)(F)C[C@@H]1O
Yield: 90.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 107e by using the (1S*,2R*)-5,5-difluoro-2-[1-[(2-methoxyethoxy)methyl]-1H-pyrazol-5-yl]cyclohexyl benzoate (463 mg, 1.17 mmol) prepared in Example 155f, potassium carbonate (16 mg, 0.117 mmol) and methanol (10 mL), to yield the title compound (307 mg, 90%) as a colorless oil.
Reaction SMILES: ClCl.[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[C:8](=[C:18](Cl)[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:30](=[O:31])[C:29]4=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]4[C:27]3=[O:36])=[CH:21][CH:20]=2)[C:7]1=[O:38])(=[O:5])[CH3:4].[NH:39]1[CH:43]=[C:42]([C:44]2[CH:50]=[CH:49][C:47]([NH2:48])=[CH:46][CH:45]=2)[N:41]=[CH:40]1.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)/[C:8](=[C:18](/[NH:48][C:47]2[CH:46]=[CH:45][C:44]([C:42]3[N:41]=[CH:40][NH:39][CH:43]=3)=[CH:50][CH:49]=2)\[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]3[C:30](=[O:31])[C:29]4=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]4[C:27]3=[O:36])=[CH:21][CH:20]=2)/[C:7]1=[O:38])(=[O:5])[CH3:4]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Agent: Cl
Agent: ClCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C(=O)/C(=C(\Nc2ccc(-c3c[nH]cn3)cc2)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
A solution of 0.50 g (1 mmol) of the chlorine compound obtained in (b) in 20 ml of CH2Cl2 is added to a cold (Ti =-60° C.) stirred suspension of 0.35 g (1.5 mmol) of 4-(1H-imidazol-4-yl)aniline×2 HCl (melting point: 350° C.) and 0.77 ml (4.5 mmol) of Hunig's base in 20 ml CH2Cl2 and stirred overnight at ambient temperature. After evaporation in vacuo and evaporation twice with toluene in vacuo the residue obtained is triturated with EtOH.
Reaction SMILES: [C:1]1([C:7]2[S:15][C:14]3[C:13](=[O:16])[O:12][C:11](=[O:17])[NH:10][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(N(C)C)=O>[CH2:24]([N:10]1[C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:15][C:14]=2[C:13](=[O:16])[O:12][C:11]1=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=c1[nH]c2cc(-c3ccccc3)sc2c(=O)o1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1oc(=O)n(Cc2ccccc2)c2cc(-c3ccccc3)sc12
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution of 6-phenyl-1H-thieno[3,2-d][1,3]oxazine-2,4-dione (1 g, 4.1 mmol) and anhydrous sodium carbonate (477 mg, 4.5 mmol) diluted in 15 ml of anhydrous dimethylacetamide was stirred for one hour under nitrogen before adding benzyl bromide (785 mg, 4.5 mmol). The mixture was stirred overnight at room temperature. 912 mg (66.3%) of 1-benzyl-6-phenyl-1H-thieno[3,2-d][1,3]oxazine-2,4-dione were obtained as a pale yellow solid after filtration and washing the precipitate with acetone and pentane. NMR 1H (DMSO D6, 400 MHz) 7.8-7.76 ppm (m, 3H, Haro); 7.51-7.45 ppm (m, 3H, Haro); 7.43-7.41 ppm (m, 2H, Haro); 7.35-7.3 ppm (m, 2H, Haro); 7.28-7.24 ppm (m, 1H, Haro); 5.22 ppm (s, 1H, NCH2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH3:15]>CN1CCCN(C)C1=O>[C:5]([CH:4]([CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([O:2][CH3:1])=[O:8])(=[O:7])[CH3:6]
Reactant: COC(=O)/C=C(\C)[O-]
Reactant: CCCCBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CCCCC(C(C)=O)C(=O)OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
30 g (217 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate (Example 13A) suspended in 1,3-dimethyltetrahydro-2(1H)-pyrimidone and 1.24 g (7.5 mmol) of potassium iodide are treated dropwise with 29.8 g (217 mmol) of butyl bromide and the mixture is stirred at 80° C. for 1 h under reflux. The cooled mixture is then added to ice water and extracted with diethyl ether. The ether phase is washed with sodium thiosulphate solution, dried, concentrated and chromatographed. The eluent used is cyclohexane having an increasing ethyl acetate content.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]#[N:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:20]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:18])=[O:20])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnn2c(-c3cccc(F)c3)ccnc12
Product: NC(=O)c1cnn2c(-c3cccc(F)c3)ccnc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 131.5 g amount of 7-(m-fluorophenyl) pyrazolo[1,5-a]pyrimidine-3-carbonitrile (prepared as described in U.S. Pat. No. 4,236,005) was dissolved in 500 ml of concentrated sulfuric acid by stirring at room temperature for 18 hours. The solution was then carefully poured into ice water. The precipitate which formed was collected by filtration then washed with 1N sodium hydroxide until pH 7 was achieved, followed by washing with water to remove the excess base. The crystalline material was dried in vacuo to give 136.3 g of the desired product as yellow crystals, m.p. 247°-249° C.
Reaction SMILES: [N:1]1[C:9]([S:10][CH2:11][C:12]2[O:13][C:14](=[O:28])[C:15]3[C:20]([C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.BrCC1OC(=O)C2C(C=1C1C=CC=CC=1[F:47])=CC=CC=2.O.N1C(S)=C2C(NC=N2)=NC=1.C([O-])([O-])=O.[K+].[K+]>>[N:1]1[C:9]([S:10][CH2:11][C:12]2[O:13][C:14](=[O:28])[C:15]3[C:20]([C:21]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[F:47])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: O=c1oc(CBr)c(-c2ccccc2F)c2ccccc12
Reactant: O=c1oc(CSc2ncnc3[nH]cnc23)c(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: Sc1ncnc2[nH]cnc12
Agent: [K+]
Solvent: O
Product: O=c1oc(CSc2ncnc3[nH]cnc23)c(-c2ccccc2F)c2ccccc12
Yield: 73.5 %

Procedure:
The title compound was made in a similar way as that of the compound of example 10, 3-(bromomethyl)-4-(2-fluorophenyl)-1H-isochromen-1-one (intermediate C2, 37 mg, 0.111 mmol), 9H-purine-6-thiol hydrate (18.90 mg, 0.111 mmol) and K2CO3 (15.35 mg, 0.111 mmol) to give the title compound (33 mg, 73.5%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([CH2:23][CH3:24])([OH:22])[CH2:20][CH3:21].[CH3:26][Si:27]([CH3:30])([CH3:29])Cl.N1C=CN=C1.N1C=CC=CC=1>C(OCC)C>[CH3:25][C:2]1([CH3:1])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([CH2:23][CH3:24])([O:22][Si:27]([CH3:30])([CH3:29])[CH3:26])[CH2:20][CH3:21]
Reactant: C[Si](C)(C)Cl
Reactant: CCC(O)(CC)CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(CC)(CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C)O[Si](C)(C)C
Yield: 80.6 %

Procedure:
183 mg (0.52 mmol) of 51 is reacted with 171 mg (1.56 mmol) of trimethylchlorosilane, 140 mg (2.03 mmol) of imidazole and 0.21 ml of pyridine in 15 ml of diethyl ether analogously to 33., and 178 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:32]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)NCCc2ccc(-c3ccc(C(C)CNS(=O)(=O)C(C)C)cc3)cc2)c1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 18 mg (0.11 mmol) 3-methoxybenzoyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][NH:6][C:7]1[C:11]([O:12][CH3:13])=[CH:10][S:9][C:8]=1[CH3:14])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:13][O:12][C:11]1[C:7]([N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:24](=[O:25])[CH2:23][Cl:22])=[C:8]([CH3:14])[S:9][CH:10]=1
Reactant: CCOCCNc1c(OC)csc1C
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOCCN(C(=O)CCl)c1c(OC)csc1C

Procedure:
To a well stirred mixture of 6,05 g (0.03 mol) N-(2-ethoxyethyl)-4-methoxy-2-methyl-thiophene-3-amine, 4.15 g (0.03 mol) of K2CO3, 10 ml of water and 100 ml of CH2Cl2 is added dropwise without cooling the solution of 3.4 g (0.03 mol) of chloroacetyl chloride in 10 ml of CH2Cl2. After the exothermic reaction (27°) has subsided, stirring is continued for a further hour at ambient temperature.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[CH:24]=[C:23]([O:25]CC4C=CC(OC)=CC=4)[N:22]=[C:21]([NH:35][CH:36]([CH3:38])[CH3:37])[N:20]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[N:20]=[C:21]([NH:35][CH:36]([CH3:37])[CH3:38])[NH:22][C:23](=[O:25])[CH:24]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(COc2cc(-c3c[nH]c4ccc(-c5cncc(C6CC6)n5)cc34)nc(NC(C)C)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc(-c2c[nH]c3ccc(-c4cncc(C5CC5)n4)cc23)cc(=O)[nH]1
Temperature: 120 °C
Yield: 15.8 %

Procedure:
A glass microwave reaction vessel was charged with 4-(5-(6-cyclopropylpyrazin-2-yl)-1H-indol-3-yl)-N-isopropyl-6-(4-methoxybenzyloxy)pyrimidin-2-amine (25 mg, 0.049 mmol) and TFA (1 mL, 12.98 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 min, then the solvent was removed and the residue was purified with RP-HPLC (10-50% ACN in water with 0.1% TFA) to give 6-(5-(6-cyclopropylpyrazin-2-yl)-1H-indol-3-yl)-2-(isopropylamino)pyrimidin-4(3H)-one (3.0 mg, 7.76 μmol, 15.73% yield) as a TFA salt. MS (ESI, pos. ion) m/z: 387.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.82 (1 H, br. s.), 8.82-9.07 (2 H, m), 8.48 (1 H, s), 8.14 (1 H, d, J=2.3 Hz), 7.88 (1 H, d, J=8.2 Hz), 7.56 (1 H, d, J=8.8 Hz), 6.10 (1 H, br. s.), 4.20-4.36 (1 H, m), 2.19-2.31 (1 H, m), 1.27 (6 H, d, J=6.5 Hz), 1.04-1.14 (4 H, m)
Reaction SMILES: [C:1]1([C@H:7]([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>O>[N+:18]([C:4]1[CH:5]=[CH:6][C:1]([C@H:7]([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])=[CH:2][CH:3]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: C[C@H](CC(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: C[C@H](CC(=O)O)c1ccc([N+](=O)[O-])cc1

Procedure:
(R)-3-phenylbutanoic acid (10.0 g) was added to concentrated sulphuric acid (40 mL) at −5° C. under nitrogen. The resulting thick gel-like mixture was stirred vigorously and fuming nitric acid (2.8 mL) was added slowly over 20 minutes. The reaction mixture was poured onto a mixture of ice and water (500 mL) and the resulting white precipitate was collected by filtration, then washed thoroughly with water, and then dried to give the title compound (10.1 g) as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19](O)=[O:20].C1CCN2C(=NCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:24]([O:23][C:17]([C:18]1[C:19](=[O:20])[O:1][C:2]([CH3:16])([CH3:15])[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CC(=O)O
Reactant: CC(C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 62.6 %

Procedure:
A mixture of 2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one (2.87 g, 11.8 mmol), ethyl hydrogen malonate (2.02 g, 15.3 mmol), CMC (6.51 g, 15.4 mmol) and DMAP (0.35 g, 2.8 mmol) was dissolved in 100 mL of CH2Cl2. The mixture was stirred for 14 h at room temperature, then DBU (4 mL, 27 mmol) was added, stirred 1 h, then partitioned between CH2Cl2 and 1M HCl. The organic layer was washed with brine, filtered through cotton and evaporated. Purification by flash chromatography (90% ether/Hex) provided 2.50 g of the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][O:15][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-BOC-3-piperidinemethanol (0.50 g, 0.002 mmole) in DCM (10 mL) was added dropwise pyridine (2.42 mL, 0.03 mmole) followed by the addition of methanesulfonyl chloride (0.774 mL, 0.01 mmole). The reaction mixture continued stirring at RT overnight. The reaction mixture was quenched with water. The aqueous layer was extracted with EtOAc (3×5 mL). Combined organic layers were dried over Na2SO4 and concentrated to yield a crude oil, 68, which was used in the next step without further purification. LRMS: 193 (M+-BOC group).