Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]([OH:11])=O)[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)[CH3:2].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[CH3:35][N:36]([C@H:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52][CH2:51]1)[C:37]([C:39]1[N:40]=[C:41]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[S:42][CH:43]=1)=[O:38].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]([N:47]2[CH2:48][CH2:49][CH:44]([C:41]3[S:42][CH:43]=[C:39]([C:37]([N:36]([CH3:35])[C@H:50]4[C:59]5[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=5)[CH2:53][CH2:52][CH2:51]4)=[O:38])[N:40]=3)[CH2:45][CH2:46]2)=[O:11])[N:6]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)[CH3:2]
Reactant: CN(C(=O)c1csc(C2CCNCC2)n1)[C@@H]1CCCc2ccccc21
Reactant: CCc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CCCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-ethyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (170 mg, 0.76 mmol) (i.e. the product of Example 16, Step C) in ethyl acetate (5.0 mL) was treated with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 1.0 mL, 1.6 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a stirred suspension of N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride (i.e. the product of Example 6 Step C) (219 mg, 0.56 mmol), triethylamine (0.5 mL, 3.75 mmol) in ethyl acetate (5 mL). The reaction mixture was then stirred at room temperature for 12 h. The resulting suspension was concentrated in vacuo and purified by silica gel MPLC using ethyl acetate/hexanes as eluant to give 200 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: CNC([OH:5])C.[CH3:6][C:7]1([CH3:17])[C@H:12]2[CH2:13][C@@H:8]1[CH2:9][CH2:10][C@H:11]2[CH2:14][CH2:15]Br.[CH2:18]([N:20]([CH2:23]C)CC)[CH3:19]>>[CH3:23][N:20]([CH2:15][CH2:14][C@@H:11]1[CH2:10][CH2:9][C@H:8]2[CH2:13][C@@H:12]1[C:7]2([CH3:17])[CH3:6])[CH2:18][CH2:19][OH:5]
Reactant: CNC(C)O
Reactant: CCN(CC)CC
Reactant: CC1(C)[C@H]2CC[C@@H](CCBr)[C@@H]1C2
Product: CN(CCO)CC[C@@H]1CC[C@H]2C[C@@H]1C2(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3.4 ml N-methylaminoethanol and 7.3 ml triethylamine were added to 12.4 g 2-((1S,2S,5S)-6,6-dimethylbicyclo[3,1,1]hept-2-yl)-ethyl bromide, and the reaction mixture was stirred for 6 hours at room temperature. To work up the reaction mixture it was chromatographed over silica gel using dichloromethane/methanol (8:2) as solvent. 3.8 g N-methyl-N-[2-((1S,2S,5S)-6,6-dimethylbicyclo[3,1,1]hept-2-yl)-ethyl]-2-aminoethanol were obtained. Rf value=0.4. Furthermore, 7 g unreacted starting material were recovered.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1>>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1ccc(Br)cc1
Product: CC(C)c1ccc(Br)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 84 %

Procedure:
To fuming nitric acid (5 mL) cooled to 5° was added neat 4-bromoisopropylbenzene (1.0 g, 5.023 mmol) dropwise at such a rate that the reaction temperature remained below 10°. The reaction was stirred for 2 hours at 5-10°, quenched with ice (50 g), extracted with ethyl acetate (50 mL), and the organic extract was washed with water (2×25 mL) and brine (25 mL), then dried over magnesium sulfate filtered and concentrated by rotary evaporation. The residue was purified by silica gel flash chromatography eluting with 5:95 ethyl acetate/hexanes to afford the title compound as a light yellow solid (1.03 g, 4.22 mmol, 84%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.27 (d, J=6.99 Hz, 6 H) 2.75-3.23 (m, 1 H) 7.29 (dd, J=8.82, 2.21 Hz, 1 H) 7.63 (d, J=8.09 Hz, 1 H) 7.69 (d, J=2.21 Hz, 1 H); MS (DCI) m/z 261/263 (M+NH4)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:43])[CH2:9][CH2:10][C@@H:11]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([B:27]5[O:31]C(C)(C)C(C)(C)[O:28]5)[CH:22]=4)=[CH:17][CH:16]=3)[N:13]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:12]2=[O:42])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:43])[CH2:9][CH2:10][C@H:11]2[C:12](=[O:42])[N:13]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@@H:14]2[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([B:27]([OH:28])[OH:31])[CH:22]=3)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O)c5ccc(F)cc5)C(=O)N4c4ccccc4)cc3)c2)OC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(B(O)O)c3)cc2)N1c1ccccc1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
(3R,4S)-3-[(3S)-3-(4-Fluorophenyl)-3-hydroxypropyl]-1-phenyl-4-[3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl]azetidin-2-one (0.020 g, 0.034 mmol) was dissolved in ethanol (3 mL) and water (1 mL) at room temperature. Solid sodium carbonate (0.10 g, 1.2 mmol) was added and the mixture was rapidly stirred 2 h at room temperature. The solution was poured into 0.5 N hydrochloric acid (4 mL) and extracted with ethyl acetate. The organic phase was washed successively with water (2×) and brine, then dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by reverse-phase HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 40% to 75% acetonitrile-0.1% trifluoroacetic acid in water) to afford (4′-{(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)boronic acid as a white powder (0.012 g, 70%); 1H NMR (300 MHz, CD3OD) δ 7.83 (br s, 1H), 7.0-7.7 (m, 16H), 4.92 (d, J=2.7 Hz, 1H), 4.63 (t, J=6.2 Hz, 1H), 3.1-3.2 (m, 1H), 1.8-2.1 (m, 4H) ppm; MS [M+HCO2−]− 540.
Reaction SMILES: C[Al](C)C.[CH2:5]([NH:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH3:7].[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[C:17](=[O:31])[C:18]3[C:25]([C:26]([O:28]CC)=O)=[N:24][NH:23][C:19]=3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=1>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:33]=[CH:32][C:16]2[C:17](=[O:31])[C:18]3[C:25]([C:26](=[O:28])[N:8]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH3:7])=[N:24][NH:23][C:19]=3[C:20](=[O:22])[NH:21][C:15]=2[CH:14]=1
Reactant: CCCNCCC
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCN(CCC)C(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reaction time: 45 h
Yield: 31 %

Procedure:
To a solution of trimethylaluminum in toluene (4.68 mL, 9.38 mmol) was added dipropylamine (1.29 mL, 9.38 mmol) and the solution was stirred for 45 hours. A portion (1.9 mL) of this solution was added to a solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500 mg, 1.56 mmol) in toluene (2 mL). Additional toluene (7 mL) was added. The solution was stirred for 70 minutes at room temperature and then quenched with 1N hydrochloric acid (9.3 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organics were washed with 1N hydrochloric acid and water (25 mL) and concentrated by rotary evaporation. The crude residue was purified by chromatography eluting with hexanes:ethyl acetate (95:5-50:50) to give the title compound (31% yield, m.p. 270° C.).
Reaction SMILES: [CH2:1]1[O:5][CH2:4][O:3][CH:2]1[CH2:6][OH:7].N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>CCOCC>[C:15](=[O:16])([O:7][CH:6]1[CH2:2][O:3][CH2:4][O:5][CH2:1]1)[O:17][CH2:18][Cl:19]
Reactant: OCC1COCO1
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCCl)OC1COCOC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 6.4 %

Procedure:
Glycerol formal (14 g) was dissolved in anhydrous ether (400 ml) and, after adding pyridine (15 g) at −10° C., a solution of chloromethyl chloroformate (25 g) in anhydrous ether (50 ml) was added dropwise over the period of 10 minutes. After the reaction solution was stirred at room temperature for 20 hours, the deposited pyridine hydrochloride was removed by filtration. The filtrate was washed with a saturated sodium chloride aqueous solution (400 ml×2), and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by subjecting to silica gel chromatography (eluent: ethyl acetate/hexane=1/5→ethyl acetate/hexane=1/3) to obtain chloromethyl (1,3-dioxan-5-yl) carbonate (1.7 g) as a colorless oily product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7](O)[CH3:8].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>C1(C)C=CC=CC=1.O>[Cl:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][NH:32][CH:7]([CH3:8])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1Cl
Reactant: CC(O)Cc1cccs1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Cc1cccs1)NCc1ccccc1Cl
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(2-thienyl)-2-propanol (14.4 g) and triethylamine (10.5 g) in 60 ml of toluene, a solution of p-toluensulfonylchloride (19.0 g) into 40 ml of toluene is added dropwise. The mixture is stirred for 24 hours. The precipitate of triethylamine HCl is removed by filtration and the filtrate is added dropwise to a solution of 2-chlorobenzylamine (28.3 g, 0.2 moles) into 100 ml of toluene at the reflux temperature over the course of 12-14 hours. The heating is continued for an additional 6 hours. Thereafter the mixture is cooled to 80° C., 200 ml of water is added, and the mixture is further cooled to room temperature. The organic phase is separated and acidified with 3 M hydrochloric acid. The resulting hydrochloride is collected by filtration and washed with acetone to yield, after drying, 16.4 g (61.7%) of N-2-chlorobenzyl-1-methyl-2-(2-thienyl)ethylamine HCl having a m.p. 164-165° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)([OH:3])=[O:2].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:19][CH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(CCC(=O)O)cs1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CCc1csc(CBr)n1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a stirring solution of 4-carboxyethyl-2-methyl thiazole (30.3 g) in CCl4 (1 L) was added NBS (37.7 g) and AIBN (2.2 g). The resulting mixture was refluxed and irradiated with UV light for 4 hours. The mixture was cooled to room temperature and filtered. The solution was flash chromatographed (CH2Cl2) to yield 36.6 g of a red oil. This material was used without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]([O:7]C)=[O:6])[CH3:4].[CH:9]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([C:16]([NH:2][CH:3]([CH3:4])[C:5]([OH:7])=[O:6])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C(C)N
Reactant: O=C(Cl)C1CCCCCC1
Agent: Cl
Product: CC(NC(=O)C1CCCCCC1)C(=O)O

Procedure:
The preparation is carried out analogously to the procedure of Example 7A using 20 g (143 mmol) of methyl D,L-alaninate hydrochloride and 23.02 g (143 mmol) of cycloheptanoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].Cl.[NH2:15][OH:16].[OH-].[K+]>CO>[NH2:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([NH:15][OH:16])=[O:6])=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N)ccc1C(=O)NO
Yield: 46.4 %

Procedure:
Methyl 2-methoxy-4-aminobenzoate (10 g, 55.25 mmol) and hydroxylamine hydrochloride (15.36 g, 221 mmol) were taken up in MeOH (80 ml) and a solution of KOH (15.4 g, 275 mmol) in MeOH (55 ml) was added carefully. The resultant mixture was stirred at reflux for 36 hrs. The volatiles were removed in vacuo The residue was taken up in 1M NaOH (50 ml) and washed with ethyl acetate (EtOAc, 50 ml). Concentrated HCl was added slowly until precipitation of a solid (pH was 10). The solid was filtered off, washed with H2O, then methyl-tert-butyl ether (MTBE) and dried under vacuum. 1H NMR showed the solid contained approx. 1/3 molar equivalent of ethyl acetate. The solid was taken up in 1M NaOH (100 ml) and the EtOAc was removed in vacuo. Concentrated HCl was added carefully until precipitation of a solid (pH was 8). The solid was collected by filtration, washed with H2O, then MTBE and dried under vacuum to give 4.67 g (47%) of the title compound as a dark red solid.
Reaction SMILES: [Na].[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.Cl.CN(C)CCCN=C=NCC.[CH3:33][C@H:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35]1>N1C=CC=CC=1.CN(C)C=O.O>[F:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([N:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:42][C@@H:34]3[CH3:33])=[O:20])[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1
Reactant: C[C@H]1Cc2ccccc2N1
Reactant: O=C(O)Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOC(CF)C2)cc(=O)[nH]1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
In a three-necked flask under argon, 0.5 g of the sodium salt of [4-(2-fluoromethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid previously obtained (example 30b, step 3b) is placed in 7 ml of pyridine and 7 ml of dimethylformamide, and then N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride is added at ambient temperature, followed by 0.25 g of (S)-2-methylindoline (CAS 22160-09-4). The reaction medium is stirred at ambient temperature (20° C.) for 72 hours. 25 ml of water are added, extraction is carried out with 3 times approximately 25 ml of dichloromethane, washing is carried out with 25 ml of water, washing is carried out with twice approximately 15 ml of 1M hydrochloric acid solution, washing is carried out with 25 ml of water, washing is carried out with 25 ml of saturated NaCl solution, drying is carried out over MgSO4, filtration is carried out through a VF filter, and the resulting product is concentrated under vacuum. The compound obtained is chromatographed on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and ethanol (95/5, v/v). The fractions containing the expected compound are combined and evaporated. The compound obtained is triturated from 1 ml of dichloromethane and 10 ml of diisopropyl ether, filtered, and dried at ambient temperature (20° C.). (+)-6-(2-Fluoromethylmorpholin-4-yl)-2-[2-((S)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one is isolated (0.315 g).
Reaction SMILES: [C:1](=[N:9][OH:10])([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].[CH2:11]([Br:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Br-:18].[CH2:11]([N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1](=[N:9][OH:10])[CH3:2])[CH2:4]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=NO)c1cccnc1
Reactant: BrCc1ccccc1
Solvent: CCO
Product: CC(=NO)C1=CC=CN(Cc2ccccc2)C1
Product: [Br-]

Procedure:
7.4 g of 3-acetylpyridine oxime is dissolved in 80 cm3 of ethanol, 8 cm3 of benzyl bromide is added to it, with heating at reflux for 6 hours. The solvent is eliminated followed by crystallization from an ether/methanol mixture. 14.21 g of the expected product is obtained. m.p.=200°-201° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46]>C(Cl)Cl>[C:44]([NH:1][C@@H:2]1[C@H:6]([NH:7][C:8]2[N:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[C:23]([Cl:24])=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([O:27][CH3:28])[C:19]=4[Cl:29])[CH:14]=3)[N:9]=2)[CH2:5][C@@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1)(=[O:47])[CH:45]=[CH2:46]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4C[C@@H](C(=O)N(C)C)C[C@@H]4N)ncc3c2)c1Cl
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N[C@H]1C[C@H](C(=O)N(C)C)C[C@H]1Nc1ncc2cc(-c3c(Cl)c(OC)cc(OC)c3Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
(1S,3S,4R)-3-amino-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.050 g, 0.099 mmol) was taken up in CH2Cl2 (25 ml) and cooled to 0° C., followed by addition of DIEA (0.017 ml, 0.099 mmol) then acryloyl chloride (8.86 μl, 0.109 mmol) slowly. The reaction mixture was stirred at 0° C. for 30 minutes. After the reaction was complete, the reaction mixture was loaded directly onto silica and purified via flash chromatography (0-10% CH2Cl2/MeOH; 12 g column) to afford (1R,3S,4R)-3-acrylamido-4-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-N,N-dimethylcyclopentanecarboxamide (0.043 g, 0.077 mmol, 78% yield). MS (ES+) C27H29Cl2N5O4 requires: 558, found: 559 [M+H]+.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:29][CH2:30][C@@H:31]([OH:33])[CH3:32]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[CH:2][N:29]([CH2:30][CH:31]([OH:33])[CH3:32])[C:5]=3[C:6]=2[CH:7]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)CC2
Reactant: C[C@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(ccn1CC(C)O)CC2
Reaction time: 0.5 h

Procedure:
A solution of 3 g of (RS)-2-(2-oxoethyl)-7-methoxy-1-tetralone and 150 mg of p-toluenesulfonic acid in 130 ml in anhydrous toluene was heated on a water separator. A solution of 4.16 g of (S)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 3.0 g (84%) of (S)-1-(4,5-dihydro-8-methoxy-1H-benz[g]indol-1-yl-propan-2-ol were obtained as a brown oil which was used directly in the next reaction.
Reaction SMILES: [CH3:1][Mg]Br.COC(=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1.C([O:19][CH2:20][CH3:21])(=O)C.Cl>O1CCCC1.O>[OH:14][C:10]([CH3:11])([CH3:1])[CH2:9][C:8]1[CH:7]=[C:20]([OH:19])[CH:21]=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of methyl magnesium bromide (3 M, 12 mL, 36.06 mmol) cooled to 0° C. was added tetrahydrofuran (10 mL) and (3-hydroxy-phenyl)-acetic acid methyl ester (1 g, 6.01 mmol) as a solution in tetrahydrofuran (5 mL). The resulting mixture was warmed to room temperature stirred for 30 min and then poured carefully into a biphasic mixture of ethyl acetate and water. The water layer was made acidic (pH=1) with 1N aqueous hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo which afforded 3-(2-hydroxy-2-methyl-propyl)-phenol (1 g, 100%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([CH3:24])[CH2:21][C@H:20]1[C:25]([OH:27])=[O:26])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CC(N(C)C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:23][C@@H:22]([CH3:24])[CH2:21][C@H:20]1[C:25]([O:27][CH2:7][C:6]([C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9])=[O:26])=[O:18])([CH3:13])([CH3:14])[CH3:15]
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: C[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a mixture of p-bromophenacyl bromide (242 mg, 0.87 mmol) in DCM (1.5 mL) and DMA (1.5 mL), under nitrogen, was added (2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.87 mmol) and N,N-diisopropylethylamine (531.8 μL, 3.05 mmol) and the resulting mixture was stirred at 35° C. for 3 h, concentrated under vacuum, dissolved in DCM (30 mL), and washed with water (2×5 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title intermediate.
Reaction SMILES: C(Cl)(Cl)Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]([OH:17])=[C:15]([C:18]([CH3:20])=[O:19])[CH2:14][S:13]2)=[CH:8][CH:7]=1.S(Cl)(Cl)(=O)=O>O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][CH:14]=[C:15]([C:18]([CH3:20])=[O:19])[C:16]=2[OH:17])=[CH:10][CH:11]=1
Reactant: CC(=O)C1=C(O)C(c2ccc(F)cc2)SC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)c1csc(-c2ccc(F)cc2)c1O
Temperature: -11 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
A chloroform (6.3 mL) solution of 2-(4-fluorophenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (0.63 g, 2.38 mmol, purity: 90%) was cooled to −12° C., and to this solution, a chloroform (1.3 mL) solution of sulfuryl chloride (0.23 mL, 1.2 equivalent amounts) was dropwise added over a period of 6 minutes, followed by stirring at −11° C. for 2 hours. The temperature of the solution was raised to 3° C., and water (1.3 mL) was dropwise added, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a sodium hydroxide aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a yellow solid (0.28 g, yield: 50%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl-].[CH3:14][O:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:37]([CH2:44][CH:45]([CH3:52])[CH2:46][CH:47]([CH3:51])[CH2:48][CH2:49][CH3:50])[CH2:38][CH:39]([CH3:43])[C:40]([OH:42])=[O:41]>C1COCC1.CCCCCC>[CH3:52][CH:45]([CH2:46][CH:47]([CH3:51])[CH2:48][CH2:49][CH3:50])[CH2:44][C:37](=[CH:14][O:15][CH3:16])[CH2:38][CH:39]([CH3:43])[C:40]([OH:42])=[O:41]
Reactant: CCCC(C)CC(C)CC(=O)CC(C)C(=O)O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC(C)CC(C)CC(=COC)CC(C)C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of diisopropylamine (5.40 ml, 38.53 mmol) in 50 ml dry THF at -78° C. was mixed with 15.41 ml (38.53 mmol) of a 2.5M solution of n-butyllithium in hexane with stirring. After 15 minutes, (methoxymethyl)triphenyl-phosphonium chloride (13.87 g, 39.25 mmol, 97% purity) was slowly added. The temperature of the solution was raised to 0° C. and stirred for another 15 minutes. A solution of 4-oxo-2,6,8-trimethylundecanoic acid (10) (1.90 g, 7.85 mmol) in 20 ml of THF was then added to the reaction mixture and this mixture was stirred at room temperature for 11 hours.