Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]=3[C:41]([O:43]C(C)(C)C)=[O:42])[C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:49][C:2]([F:1])([F:48])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([N:19]([CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]=3[C:41]([OH:43])=[O:42])[C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])(=[O:18])=[O:17])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1c(CN(C(=O)OCc2ccccc2)S(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1c(CN(C(=O)OCc2ccccc2)S(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A solution of Example 9F (1.19 g, 1.72 mmol) in CH2Cl2 (35 mL) under N2 at −20° C. was treated with trifluoroacetic acid (13.3 mL, 0.172 mol) and allowed to stir at 0° C. 2 for 1 hour and then quenched with 2.6 M Na2CO3 (50 mL). The reaction mixture was reacidified to pH 3 with 1 M aq HCl, extracted with ethyl acetate. The combined ogranic layers were washed with brine, dried (Na2SO4), filtered, and concentrated (chasing with anhydrous toluene) to provide 1.096 g (100%) of the desired compound white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:13]=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([OH:11])[N:5]2[N:4]=1.[NH3:14]>>[NH2:14][CH2:2][C:3]1[N:13]=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([OH:11])[N:5]2[N:4]=1
Reactant: Cc1cc(O)n2nc(CCl)nc2n1
Reactant: N
Product: Cc1cc(O)n2nc(CN)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(Chloromethyl)-5-methyl-s-triazolo[1.5-a]pyrimidin-7-ol (1.0 g) (known from C.A. 104/09-068678) is dissolved in 20 ml of conc. aqueous ammonia and stirred at room temperature overnight. The precipitate formed is filtered off under suction. The mother liquor is concentrated and the residue is taken up in ethanol. The product thereby crystallizes. There is obtained 0.66 g of 2-(aminomethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-ol as a white powder of m.p. 204°-207° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33]N1C(=O)CCC1=O.O>O1CCCC1>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[Cl:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2)c1Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2Cl)c1Cl)(c1ccccc1)c1ccccc1
Reaction time: 24 h
Yield: 93.3 %

Procedure:
To a solution of 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)pyrrole (1.0 g) in tetrahydrofuran (10 ml) was added N-chlorosuccinimide (292 mg) at ambient temperature, and the mixture was allowed to stand for 1 day. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (10:1, V/V) to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-chloropyrrole (1.0 g) as an oil.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][O:60][CH:61]1[CH2:66][CH2:65][N:64]([CH2:67][C:68]2[CH:73]=[CH:72][C:71]([CH2:74][NH:75][CH3:76])=[CH:70][CH:69]=2)[CH2:63][CH2:62]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:75]([CH2:74][C:71]3[CH:70]=[CH:69][C:68]([CH2:67][N:64]4[CH2:65][CH2:66][CH:61]([O:60][CH3:59])[CH2:62][CH2:63]4)=[CH:73][CH:72]=3)[CH3:76])=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(OC)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(OC)CC4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(4-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (36 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [CH2:1]([Cl:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg:9].[CH:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[C:11]1=O)[CH2:17]2>CCOCC>[CH2:11]([Mg:9][Cl:8])[C:10]1[CH:19]=[CH:14][CH:15]=[CH:16][CH:17]=1.[C:2]1([CH:1]=[C:11]2[CH:12]3[CH2:18][CH:16]4[CH2:15][CH:14]([CH2:19][CH:10]2[CH2:17]4)[CH2:13]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Mg]
Reactant: ClCc1ccccc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Solvent: CCOCC
Product: C(=C1C2CC3CC(C2)CC1C3)c1ccccc1
Product: Cl[Mg]Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzylmagnesium chloride was prepared by reacting benzyl chloride (37.0 ml, 0.320 mol) with magnesium turnings (8.50 g, 0.350 mol) in 125 ml anhydrous ether (under N2). Then, a solution of 2-adamantanone (24.03 g, 0.160 mol) in 250 ml anhydrous ether was added gradually over a period of 60 minutes. The resulting suspension was stirred at room temperature for 18 hours, and then quenched by cautious addition of 250 ml 2N hydrochloric acid. The organic layer was separated, washed with water, then dried over MgSO4, and the solvent evaporated leaving, after crystallization from pentane, 32.47 g (84%) of 2-(phenylmethyl)-tricyclo[3.3.1.13,7 ]-decan-2-ol. Mp 58°-60° C. The decanol compound was then dehydrated using the method of Keul1 to produce 2-(phenyl-methylene)-tricyclo[3.3.1.13,7 ]decane. The dehydration procedure was as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:6]([CH3:7])[CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[NH2:17].C(N(CC)CC)C.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>>[CH3:1][C:2]1[CH:6]([CH3:7])[CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[NH:17][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC1=CC(C)C(C)=C1c1cc(C)cc(C)c1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC1=CC(C)C(C)=C1c1cc(C)cc(C)c1NC(=O)C(C)(C)C

Procedure:
2-(2,3,5-trimethylcyclopenta-1,4-dienyl)-4,6-dimethylphenyl(trimethylacetyl)a mine was prepared in the same manner as Example 11, except that 0.600 g (2.64 mmol) of 2-(2,3,5-trimethylcyclopenta-1,4-dienyl)-4,6-dimethylphenylamine, 0.321 g (3.17 mmol) of triethylamine, and 0.382 g (3.17 mmol) of pivaloyl chloride were used (0.727 g, 89%).
Reaction SMILES: [CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:19])[C:13]3[CH2:18][CH:17]=[CH:16][CH2:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([OH:24])=[O:23].S(=O)(=O)(O)[OH:26]>O>[CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[C@H:6]([NH:9][C:10]([CH:12]([NH2:19])[C:13]3[CH2:18][CH:17]=[CH:16][CH2:15][CH:14]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([OH:24])=[O:23].[OH2:26].[OH2:8]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)C3=CCC=CC3)[C@H]2SC1
Reactant: O=S(=O)(O)O
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(N)C3=CCC=CC3)[C@H]2SC1
Temperature: 52 °C
Reaction time: 1 h

Procedure:
A crystallisation reactor was charged with 3.0 g cephradine and 50 ml water and heated up to T=52° C. Immediately, the combined filtrates and washings were dosed with constant dosing rate in 60 minutes. The temperature was kept at T=52° C. and the pH at 4.80 by titration with 25% sulfuric acid. Then, the temperature was decreased to 25° C. in 30 minutes. The resulting suspension was filtered through a glass filter. The wetcake was washed with 30 ml water and 2×25 ml 80% acetone (acetone/water=80/20 v/v) and dried. 47.0 g cephradine hydrate, with a water content of 3.4%, was obtained.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:66]=[CH:65][C:16]([C:17]([O:19][C:20]2[CH:64]=[CH:63][C:23]([C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29](OC(=O)C4C=CC(OC(=O)C5C=CC(OCCCCCCCCCC=C)=CC=5)=CC=4)[CH:28]=3)=[O:25])=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:67]1(C=CC=C(O)C=1)O.[CH2:75]([O:87][C:88]1[CH:105]=[CH:104][C:91]([C:92]([O:94][C:95]2[CH:103]=[CH:102][C:98]([C:99]([OH:101])=[O:100])=[CH:97][CH:96]=2)=[O:93])=[CH:90][CH:89]=1)[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CC(=O)OCC>[CH2:75]([O:87][C:88]1[CH:105]=[CH:104][C:91]([C:92]([O:94][C:95]2[CH:103]=[CH:102][C:98]([C:99]([O:101][C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([O:26][C:24](=[O:25])[C:23]4[CH:22]=[CH:21][C:20]([O:19][C:17](=[O:18])[C:16]5[CH:65]=[CH:66][C:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:67])=[CH:14][CH:15]=5)=[CH:64][CH:63]=4)[CH:32]=3)=[O:100])=[CH:97][CH:96]=2)=[O:93])=[CH:90][CH:89]=1)[CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86]
Reactant: C=CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)Oc3cccc(OC(=O)c4ccc(OC(=O)c5ccc(OCCCCCCCCCC=C)cc5)cc4)c3)cc2)cc1
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Reactant: Oc1cccc(O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)Oc3cccc(OC(=O)c4ccc(OC(=O)c5ccc(OCCCCCCCCCCCC)cc5)cc4)c3)cc2)cc1

Procedure:
1,3-Phenylene bis(4-(4-(undec-10-enyloxy)benzoyloxy)benzoate) (BC3). Synthesized as described for the preparation of compound BC1. Quantities: resorcinol (0.13 g, 1.1 mmol), 17 (0.92 g, 2.2 mmol), DMAP (0.03 g, 0.2 mmol), DCC (0.92 g, 4.5 mmol). Yield 0.72 g (71%). EA: Found: C, 74.88; H, 7.22.C56H62O10 requires C, 75.14; H, 6.98%. 1H NMR: δH (CDCl3; 300 MHz): 1.24-1.43 (24 H, m, CH2), 1.84 (4 H, m, O—CH2—CH2—), 2.04 (4 H, m, CH2—CH═CH2), 4.06 (4 H, t, 3J=6.5 Hz, O—CH2), 4.95 (4 H, m, CH═CH2), 5.80 (2 H, m, CH═CH2), 6.99 (4 H, d, 3J=8.9 Hz, Ar—H), 7.19 (3 H, m, Ar—H), 7.38 (4 H, d, 3J=8.7 Hz, Ar—H), 7.50 (1 H, t, 3J=8.3 Hz, Ar—H), 8.16 (4 H, d, 3J=8.9 Hz, Ar—H), 8.28 (4 H, d, 3J=8.7 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 26.4, 29.3, 29.4, 29.5, 29.7, 29.8, 29.9, 34.2, 68.8, 114.5, 114.8, 116.2, 119.7, 121.4, 122.5, 127.0, 130.3, 132.3, 132.8, 139.6, 151.8, 155.9, 164.2, 164.5, 164.7. m/z (MALDI) 918.25 [M+Na]+, C56H62NaO10 requires 917.42.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[S:14][C:13]([N:16]3[CH2:21][N:20]([CH3:22])[CH2:19][N:18]([CH2:23][CH3:24])[C:17]3=[O:25])=[N:12][C:11]=2[CH:10]=[C:9]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][C:35]([CH2:43][CH3:44])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]3)=[N:30][CH:31]=2)[CH:8]=1.CN([CH:48]=[O:49])C>C1COCC1>[CH2:43]([C:35]1([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:36][CH2:37][N:32]([C:29]2[N:28]=[CH:27][C:26]([C:9]3[CH:8]=[C:7]([CH:48]=[O:49])[C:15]4[S:14][C:13]([N:16]5[CH2:21][N:20]([CH3:22])[CH2:19][N:18]([CH2:23][CH3:24])[C:17]5=[O:25])=[N:12][C:11]=4[CH:10]=3)=[CH:31][N:30]=2)[CH2:33][CH2:34]1)[CH3:44]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(Br)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
1.4M BuLi (600 μL, 0.84 mmol) was added to ethyl 1-[5-[7-bromo-2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-ethyl-piperidine-4-carboxylate (250 mg, 0.41 mmol) in THF (10 mL) at −90° C. and the reaction stirred for 10 mins before DMF (300 μL) was added and the mixture stirred for a further 20 mins. The reaction was quenched with sat. NH4Cl (aq) then allowed to warm to rt before extraction with EtOAc (3×). Combined EtOAc extracts were dried and the solvent evaporated to yield the crude product which was purified by flash chromatography on 12 g SiO2 using EtOAc/Cyclohexane gradient 0-0% 3CV, 0-100% 20CV, 100-100% 5CV to yield the desired product (105 mg, 46%). 1H NMR (CDCl3) δ 10.22 (s, 1H), 8.63 (s, 2H), 8.06 (d, J=1.7 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H), 5.21 (s, 2H), 4.56 (dt, J=13.8, 3.5 Hz, 2H), 4.33 (s, 2H), 4.23 (q, J=7.1 Hz, 2H), 3.51 (q, J=7.2 Hz, 2H), 3.23-3.13 (m, 2H), 2.67 (s, 3H), 2.25 (bd, J=13.4 Hz, 2H), 1.61 (q, J=7.6 Hz, 2H), 1.45 (ddd, J=13.5, 11.9, 4.2 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C:2]1=[O:10].C([O-])(O)=[O:12].[Na+].ClC1C=CC=CC=1C(OO)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH2:1]1[CH:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]2[CH2:3][C:2](=[O:10])[O:12]1
Reactant: O=C([O-])O
Reactant: O=C1CC2CCCCC2C1
Agent: O=C(OO)c1ccccc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CC2CCCCC2CO1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
To a stirred mixture of 3.16 g (23 mmol) of (3a alpha, 7a alpha )-octahydro-2H-inden-2-one, 17.3 g (207 mmol) of NaHCO3 and 300 mL of dichloromethane was added 9.29 g of 85% m. chloroperoxybenzoic acid in small portions over 15 min. The reaction mixture was stirred for 17 h at 20° C., then 200 mL of 10% aqueous Na2S2O3 was added and, after 15 min, the organic phase was separated. Extraction of the aqueous portion with 2×100 mL of dichloromethane, washing of the combined organic solutions with 10% Na2CO3 and concentration of the dried (MgSO4) solutions under vacuum 9ave 3.51 9 (95%) of racemic (4a alpha, 8a alpha)-octahydro-3H-2-benzopyran-3-one. TLC Rf 0.40 (SiO2, ethyl ether, iodine-brown).
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:8])[CH3:7])=[CH:4][C:3]2[CH2:9][CH2:10][C:11]3[C:16]([C:2]1=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[Al+3].[Cl-].[Cl-].[Cl-].[C:21](Cl)(=[O:23])[CH3:22].Cl>C(Cl)Cl>[S:1]1[C:5]([C:6](=[O:8])[CH3:7])=[CH:4][C:3]2[CH2:9][CH2:10][C:11]3[C:16]([C:2]1=2)=[CH:15][CH:14]=[C:13]([C:21](=[O:23])[CH3:22])[CH:12]=3
Reactant: CC(=O)Cl
Reactant: CC(=O)c1cc2c(s1)-c1ccccc1CC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCc1cc(C(C)=O)sc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
To a solution of 1-(4,5-dihydronaphtho[1,2-b]thiophen-2-yl)ethanone (5b) (30 g, 131 mmol) in 500 mL of DCM at 0° C., AlCl3 (52.6 g, 394 mmol) was added portion wise and after 15 min, acetyl chloride (18.69 ml, 263 mmol) was added dropwise at the same temperature over 30 min and the mixture was stirred at room temperature for 48 hr. The reaction mass was slowly added to ice water and acidified with 2 N HCl solution and extracted with DCM, and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound as an yellow solid (5c) (28.3 g, 80%). m/z 270.0 (M+).
Reaction SMILES: C([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)[N:5]=1)C.Cl>>[OH:15][CH:12]1[CH2:13][CH2:14][N:10]([C:6]2[N:5]=[C:4]([OH:3])[CH:9]=[CH:8][N:7]=2)[CH2:11]1
Reactant: CCOc1ccnc(N2CCC(O)C2)n1
Agent: Cl
Product: Oc1ccnc(N2CCC(O)C2)n1

Procedure:
1-(4-Ethoxypyrimidin-2-yl)pyrrolidin-3-ol (1.0 g, 4.8 mol) was combined with 6M HCl (24 mL, 144 mmol) and heated to reflux overnight. The mixture was concentrated in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][N:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[CH3:22][O:23][C:24]1(B(O)O)[N:29]=[CH:28][CH:27]=[CH:26][NH:25]1.C([O-])([O-])=O.[Na+].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.CCO>[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][N:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:26][N:25]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccnc(Br)c1
Reactant: COC1(B(O)O)N=CC=CN1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: COc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)ccn2)cn1

Procedure:
2-Bromo-N-(4-(trifluoromethoxy)phenyl)isonicotinamide (Stage 69.1, 70 mg, 0.194 mmol), 2-methoxypyrimidine boronic acid (45 mg, 0.291 mmol), Pd(PPh3)2Cl2 (5.44 mg, 7.75 μmol), Na2CO3 (71.9 mg, 0.678 mmol), water (194 μL), EtOH (129 μL) and DME (969 μL) were added to a vial, which was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 20 min. The RM was stirred with Si-Thiol (53.8 mg, 0.078 mmol) for 30 min. The resin was filtered off and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Biotage Silica gel column, 4 g, DCM/MeOH+1% NH4OH from 1.5% to 20% MeOH+1% NH4OH) to yield the title compound as an off-white solid. UPLC-MS (Condition 1) tR 2.58 min, m/z=391[M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 4.01 (s, 3H) 7.42 (d, J=8.56 Hz, 2H) 7.84 (dd, J=5.01, 1.35 Hz, 1H) 7.90 (m, J=9.30 Hz, 2H) 8.46 (s, 1H) 8.89 (d, J=5.14 Hz, 1H) 9.34 (s, 2H) 10.71 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1I.[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[CH:18]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:18]#[C:17][CH:19]1[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)C(=O)Nc1ncc(F)c(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2c(NC(=O)C(C)(C)C)ncc(F)c2Cl)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-5-fluoro-3-iodopyridin-2-yl)pivalamide (1 g, 2.80 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (0.880 g, 4.21 mmol), copper(I) iodide (0.053 g, 0.28 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.197 g, 0.280 mmol) in 50 mL tetrahydrofuran was degassed with nitrogen. The mixture was stirred at room temperature for 48 hours and at 50° C. for 8 hours. The mixture was filtered and the filtrate was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica-gel column chromatography eluting with 0-40% ethyl acetate in heptane to afford the title compound. MS (ESI(+)) m/e 438 (M+H)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:7][C:6]1=[O:14])(=O)C.N>CO>[OH:4][C@@H:5]1[C@H:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[NH:7][C:6]1=[O:14]
Reactant: CC(=O)O[C@H]1C(=O)N[C@H]1c1cccs1
Agent: N
Solvent: CO
Product: O=C1N[C@@H](c2cccs2)[C@H]1O
Yield: 72.1 %

Procedure:
Into a solution of 3.88 g of (3R,4R)-3-acetoxy-4-(2-thienyl)-2-azetidinone in 60 cm3 of methanol is injected a stream of anhydrous ammonia gas at a temperature in the region of 5° C. for one hour with stirring. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residual solid is purified by chromatography on 180 g of silica (0.063-0.2 mm) contained in a column of diameter 4 cm [eluent: dichloromethane/methanol (95/5 by volume)], collecting 10 cm3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 2.24 g of (3R,4R)-3-hydroxy-4-(2-thienyl)-2-azetidinone are obtained in the form of white crystals melting at 174° C. and for which the physical characteristics are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:14]OC)=[C:8]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[C:7]([CH3:22])=[CH:6]2.Cl.O1CCOCC1.FC1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:8]1[C:7]([CH3:22])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[O:13][C:14]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1
Reactant: COCOc1c(-c2ccco2)c(C)cc2cc(OC)ccc12
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccco3)c(C)cc2c1
Yield: 36.6 %

Procedure:
2-(6-Methoxy-1-methoxymethoxy-3-methyl-naphthalen-2-yl)-furan (213) (0.54, 1.8 mmol), 4 N HCl/Dioxane (6 mL), 4-fluorobenzaldehyde (0.23 mL, 2.17 mmol), Cs2CO3 (1.47 g, 4.53 mmol) and DMSO (8 mL) were reacted as described above to give 0.236 g (36%) of the title compound (214) as oil. 1H NMR (400 MHz, d-CDCl3): δ 2.48 (s, 3H), 3.93 (s, 3H), 6.34 (s, 2H), 6.84 (d, J=8.6 Hz, 2H), 7.04 (dd, J1=2.4 Hz, J2=9.2 Hz, 1H), 7.11-7.12 (m, 1H), 7.39 (s, 1H), 7.57 (s, 1H), 7.69-7.73 (m, 3H), 9.84 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([O-:13])=O)=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[Na+].[CH3:21][C@@H:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1>>[F:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]([CH2:10][C:11]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:30][C@H:22]2[CH3:21])=[O:13])=[N:4][C:3]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)c(F)c1=O
Reactant: C[C@@H]1Cc2ccccc2N1
Agent: [Na+]
Product: C[C@@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)n1C
Yield: 53.5 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 88 mg of sodium (5-fluoro-1-methyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 8a and 40 mg of (R)-2-methyl-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. (2002), 12(1), 27-28)). After silica column purification: eluent 98/02 dichloromethane/methanol, 62 mg of 5-fluoro-3-methyl-2-[2-((R)-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([O:15]CC)=[O:14])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C(O)C.[O-]CC.[Na+]>O>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([C:13]([OH:15])=[O:14])[CH2:11][CH2:12]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: CCOC(=O)C1CCC(N2CCCC2=O)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCC(N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.7 %

Procedure:
To ethyl 4-(2-pyrrolidon-1-yl)cyclohexylcarboxylate (5.0 g, mixture of cis and trans isomers, cis:trans=61:39) are added ethanol (25.0 mL, 5V/W) and sodium ethoxide (2.0 equiv. 0.0132 mol), and the mixture is stirred at room temperature for 20 hours. After adding water (5.0 mL, 1V/W), the reaction solution is stirred at room temperature for 2 hours, and evaporated to remove ethanol under reduced pressure. The residue is acidified by adding 2 N hydrochloric acid, and thereto is added an excessive amount of crystalline sodium chloride followed by extraction with methylene chloride. The extract is dried, and evaporated to remove the solvent under reduced pressure. The resulting crystals are collected with toluene to give 4-(2-pyrrolidon-1-yl)cyclohexylcarboxylic acid (2.9 g, trans:cis=88:12, yield 58%).