Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@@:23]([OH:49])([CH2:43][N:44]1[CH:48]=[N:47][CH:46]=[N:45]1)[C@H:24]([S:26][C@@H:27]1[CH2:32][O:31][C@@H:30]([C:33]2[CH:42]=[CH:41][C:36]([C:37](OC)=[O:38])=[CH:35][CH:34]=2)[O:29][CH2:28]1)[CH3:25]>>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:37](=[O:38])[C:36]2[CH:41]=[CH:42][C:33]([C@H:30]3[O:29][CH2:28][C@H:27]([S:26][C@H:24]([CH3:25])[C@:23]([C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[F:15])([OH:49])[CH2:43][N:44]4[CH:48]=[N:47][CH:46]=[N:45]4)[CH2:32][O:31]3)=[CH:34][CH:35]=2)=[CH:3][CH:4]=1)(=[O:7])[NH2:8]
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C(N)=O)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available p-aminobenzamide (162 mg, 1.2 mmol), trimethylaluminium (2.2 ml, 1.07M n-hexane solution, 2.4 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (66 mg, yield 37%) as a white solid which was recrystallized from ethyl acetate-hexane to give pale orange powdery crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[CH2:14](SSCC=C)[CH:15]=C.IC1C(C2C=NC=CC=2)=NNC=1>C(OCC)(=O)C>[CH2:1]([S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1)[CH:14]=[CH2:15]
Reactant: C=CCSSCC=C
Reactant: CSc1c[nH]nc1-c1cccnc1
Agent: Ic1c[nH]nc1-c1cccnc1
Solvent: CCOC(C)=O
Product: C=CCSc1c[nH]nc1-c1cccnc1
Yield: 27 %

Procedure:
Compound 21Q was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using 3-allyldisulfanyl-propene as the disulfide and 3-(4-iodo-1H-pyrazol-3-yl)-pyridine (compound 20B). (conditions flash chromatography (ethyl acetate)) Yield: 27%. (oil). 1H-NMR (200 MHz, CDCl3): δ 9.20 (d, J=2 Hz, 1H), 8.60 (dd, J=5 Hz, 2 Hz, 1H), 8.29 (dt, J=8 Hz, 2 Hz, 1H), 7.70 (s, 1H), 7.40-7.36 (m, 1H), 5.77-5.66 (m, 1H), 4.94 (bdd, J=11 Hz, 1 Hz, 1H), 4.83 (bdd, J=17 Hz, 1 Hz, 1H), 3.19 (bd, J=8 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][C:10]([OH:14])=[CH:9]2)([O-:3])=[O:2].Cl[C:16]([F:21])([F:20])C([O-])=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C)C=O>[F:20][CH:16]([F:21])[O:14][C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=[N+]([O-])c1cccc2cc(O)cnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2cc(OC(F)F)cnc12
Temperature: 100 °C
Yield: 15.8 %

Procedure:
A solution of 8-nitro-quinolin-3-ol (CAS25369-37-3) (500 mg, 2.63 mmol) in dimethylformamide (5 ml) was treated with sodium chlorodifluoroacetate (481 mg, 3.15 mmol). The mixture was heated to 100° C. overnight under a nitrogen atmosphere. For the workup, the reaction mixture was cooled to room temperature, then saturated aqueous sodium carbonate solution and dichloromethane were added. The organic layer was separated, dried over sodium sulphate, then evaporated. The crude product was purified by chromatography on silica gel using a gradient of cyclohexane/ethyl acetate=9:1 to 8:1 as the eluent yielding 100 mg (16%) of the 3-difluoromethoxy-8-nitro-quinoline as a yellow solid; (calculated) C10H6F2N2O3 [240.2]; (found) [M+H]+=241.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][Br:34])=[CH:26][CH:25]=1>CC#N>[Br-:34].[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)=[CH:26][CH:25]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: Fc1ccc(OCCCBr)cc1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccc(F)cc3)(CC1)CC2
Product: [Br-]
Yield: 43.7 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0182 g, 0.0621 mmol) and 3-bromopropyl 4-fluorophenyl ether (0.0173 g, 0.0742 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0143 g, 43.7%). EI-MS m/z 446 (M+) Rt (1.96 min).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH:21]=[CH2:22].CN(C)C=O>C(Cl)(Cl)Cl>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH:6]=[CH:5]2)[CH:21]=[CH2:20]
Reactant: Cc1cc(O)cc2ccc(=O)[nH]c12
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C=CCOc1cc(C)c2[nH]c(=O)ccc2c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 54.8 %

Procedure:
A mixture of 6-hydroxy-8-methylcarbostyril (15.0 g, 85.7 mmol), potassium carbonate (23.4 g, 169.5 mmol), allyl iodide (15.6 g, 90.0 mmol), and N,N-dimethylformamide (120 ml) was stirred in a bath of 70° C. for 1.5 hours. The mixture was condensed, and the residue was dissolved in chloroform, followed by washing with water and 2N-NaOH. The washed material was dried and condensed. The resultant residue was recrystallized (chloroform--n-hexane) to obtain 10.11 g of 6-allyloxy-8-methylcarbostyril as pale brown prisms (54.8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:21]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[N:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23])([CH3:27])[CH3:26]
Reactant: Cc1nc(/C=C/c2c(C)nnn2-c2ccc(F)cc2)sc1C(=O)O
Reactant: CC(C)N
Product: Cc1nc(/C=C/c2c(C)nnn2-c2ccc(F)cc2)sc1C(=O)NC(C)C
Yield: 71 %

Procedure:
As described for example 8c, 2-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (72 mg, 0.21 mmol), was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (57 mg, 71%) which was obtained as an off white solid. MS: m/e=386.4 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=O.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:20]([Cl:26])=[CH:21][N:22]=[CH:23][C:24]=3[Cl:25])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)=[O:3])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Reactant: NCc1ccccc1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1ccccc1
Yield: 65 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.10 g) obtained in Example 9 and benzylamine to give Compound 25 (0.08 g, 65%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:11][S:12](C)(=[O:14])=[O:13]>>[CH3:11][S:12]([C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1)(=[O:14])=[O:13]
Reactant: CS(C)(=O)=O
Reactant: CC(=O)c1ccnc(Br)c1
Product: CC(=O)c1ccnc(S(C)(=O)=O)c1

Procedure:
Alternatively, (1-(2-bromopyridin-4-yl)-ethanone) could be converted to the corresponding methyl sulfone via the above procedure to afford 1-(2-methanesulfonyl-pyridin-4-yl)-ethanone. 1-(2-Methanesulfonyl-pyridin-4-yl)-ethanone can be converted to the title compound by methods described in example 14.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14]C2C=CC=C(Cl)C=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (40 mL) was added to crude carbamate 10.5 (18.6 g; 59.7 mmol) cooled in an ice-water bath. After 1 min the reaction was stirred at rt for 15 min, then concentrated on a rotary evaporator. Ether (200 mL) was added and this washed with 3 M NaOH (3×50 mL) and water (50 mL). The product was extracted into 1 M HCl (3×50 mL) and the aq phase was basified with 3 M NaOH (60 mL). The free base was extracted into DCM (1×50 mL then 2×25 mL), dried (MgSO4), filtered and concentrated to an oil. The hydrochloride salt was precipitated from a methanolic (6 mL) solution of the free base by the dropwise addition of HCl in ether (200 mL of HCl-saturated ether plus 150 mL of ether). The salt was collected by filtration and washed with ether (100 mL) giving an off-white solid (7.97 g; 68% from 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester). LC (method B) tR=8.2 min; 1H NMR (200 MHz, DMSO-d6) δ 8.94 (brs, 2H), 7.33 (m, 1H), 7.12 (m, 1H), 7.00 (m, 2H), 4.70 (m, 1H), 3.20 (m, 2H), 3.08 (m, 2H), 2.08 (m, 2H), 1.85 (m, 2H); ESIMS (free base) 212.0/213.9 (100/35) [MH+].
Reaction SMILES: [CH:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH:26]([O:28][CH2:29][CH3:30])=[CH2:27]>CC(OC)(C)C>[CH2:26]([O:28][CH:29]([O:13][CH:1]1[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1)[CH3:30])[CH3:27]
Reactant: C=COCC
Reactant: OC1CCC=CCCC=CCCC1
Agent: CCOC(C)OC1CC/C=C/CC/C=C/CCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: OC1CC/C=C/CC/C=C/CCC1
Solvent: O
Solvent: COC(C)(C)C
Product: CCOC(C)OC1CCC=CCCC=CCCC1
Temperature: 40 °C

Procedure:
To a mechanically stirred mixture of E,E-4,8-cyclododecadien-1-ol (99% (E,E)/1% (E/Z), 2.0 g, 11 mmol), toluene sulphonic acid monohydrate (0.15 g, 2 mmol) and MTBE (methyl terbutyl ether, 20 mL) was added drop wise ethyl vinyl ether (5 g) over 15 minutes. The reaction mixture was heated at reflux at 40° C. for 1 hour, then diluted with MTBE, washed with aqueous NaHCO3, water and brine. The solvent was evaporated and the product (4.5 g) purified by flash distillation (Kugelrohr, 86° C., 0.1 mbar) and liquid chromatography (silica gel 100 g; eluent=heptane/ethyl acetate 95/5).
Reaction SMILES: C(OCC1C2C(=CN=C(C([NH:21][OH:22])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.ClC1C=CC(OCC2C3C=NC(C(OCC)=O)=CC=3N(CC)C=2)=CC=1.[Cl:57][C:58]1[CH:59]=[CH:60][C:61]([OH:81])=[C:62]([CH:80]=1)[CH2:63][C:64]1[C:68]2[CH:69]=[N:70][C:71]([C:73]([O:75]CC)=O)=[CH:72][C:67]=2[N:66]([CH2:78][CH3:79])[CH:65]=1>>[Cl:57][C:58]1[CH:59]=[CH:60][C:61]([OH:81])=[C:62]([CH:80]=1)[CH2:63][C:64]1[C:68]2[CH:69]=[N:70][C:71]([C:73]([NH:21][OH:22])=[O:75])=[CH:72][C:67]=2[N:66]([CH2:78][CH3:79])[CH:65]=1
Reactant: CCOC(=O)c1cc2c(cn1)c(Cc1cc(Cl)ccc1O)cn2CC
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Agent: CCOC(=O)c1cc2c(cn1)c(COc1ccc(Cl)cc1)cn2CC
Product: CCn1cc(Cc2cc(Cl)ccc2O)c2cnc(C(=O)NO)cc21

Procedure:
Ethyl 3-(3-chloro-2-hydroxybenzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate. The title compound can be prepared from ethyl 3-hydroxymethyl-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and 4-chlorophenol using a methods similar to that set forth in Example 55. (b) 3-(5-Chloro-2-hydroxybenzyl)-1-ethyl-N-hydroxy-1H-pyrrolo[3,2-c]pyridine-6-carboxamide. The title compound can be prepared from the mixture of ethyl 3-(4-chloro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(5-chloro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate in a manner similar to step (e) of Example 11. Purification by HPLC can provide the pure title compound.
Reaction SMILES: [NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[CH2:3]1.[C:18]([OH:27])(=[O:26])[C@@H:19]([C@H:21]([C:23]([OH:25])=[O:24])[OH:22])[OH:20].N1CCCCC1.[CH3:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]#C>CO.[Cu]I>[NH2:1][C@:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([C:41]#[C:40][CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH3:34])=[CH:9][CH:8]=2)[CH2:3]1.[C:18]([OH:27])(=[O:26])[C@@H:19]([C@H:21]([C:23]([OH:25])=[O:24])[OH:22])[OH:20]
Reactant: C#CCCCCCOC
Reactant: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(Br)cc2)C1
Agent: [Cu]I
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: C1CCNCC1
Solvent: CO
Product: COCCCCC#Cc1ccc([C@@H]2CC[C@](N)(C(=O)OC)C2)cc1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A round bottomed flask was charged with copper (1) iodide (0.102 g, 0.536 mmol), bis(tripheynlphosphine)palladium(II)dichloride (1.128 g, 1.608 mmol), and (1R,3R)-methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate, 0.5 L-tartaric acid 2 (20 g, 53.6 mmol) (that had been free based by partitioning between EtOAc and saturated NaHCO3. The organic layer was separated, dried (NaSO4), filtered and concentrated) THF (150 mL) was added and the reaction mixture was purged with nitrogen. After 5 min piperidine (23.88 mL, 241 mmol) and 7-methoxyhept-1-yne (6.0 g, 54 mmol) was added. The reaction mixture was heated to about 65° C. After about 8 hours additional 7-methoxyhept-1-yne (3.1 g, 27 mmol) was added. After about 20 hours total the reaction mixture was cooled to about room temperature and partitioned between EtOAc/NaHCO3. The organic layer was separated dried (Na2SO4) filtered and concentrated. The crude mixture was purified by chromatography on silica gel (eluting with EtOAc/MeOH). The fractions containing the desired product were concentrated in vacuo. The dark brown oil was dissolved in MeOH (50 mL) and a solution of (2R,3R)-2,3-dihydroxysuccinic acid (9.65 g, 64.3 mmol) in MeOH (15 mL) was added. The solution was concentrated in vacuo and the resulting solid was slurried in isopropyl alcohol (approx 100 mL), filtered and dried in vacuo to provide (1R,3R)-methyl 1-amino-3-(4-(6-methoxyhex-1-ynyl)phenyl)cyclopentanecarboxylate, L-tartaric acid (25 g, 52.1 mmol, 97% yield) as a colorless solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:10]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+].C(#N)C>O.CCOCC>[O:10]1[C:14]2([CH2:19][CH2:18][N:17]([C:2]3[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=3[C:4]#[N:5])[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccccc1N1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 391.8 %

Procedure:
A mixture of 23 g (0.0163 mol) o-fluorobenzonitrile, 70 g (0.4889 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 34 g (0.246 mol) of K2CO3, and 150 ml of acetonitrile is stirred at reflux for three days. The reaction mixture is allowed to cool to ambient temperature, diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give an oil. Trituration with ether furnishes 15.6 g (39%) of title compound: IR (KBr) 2200, 1590 and 1485 cm-1 ; NMR (CDCl3) δ7.65-6.9 (m, 4H), 4.02 (s, 4H), 3.33 (m, 4H), and 1.94 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11]Br>CC(O)=O>[Br:11][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])cc1Br
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 4-nitroaniline (50 g, 0.36 mol) in AcOH (500 mL) was added liquid Br2 (60 g, 0.38 mol) dropwise at 5° C. The mixture was stirred for 30 min at that temperature. The insoluble solid was collected by filtration and poured into EtOAc (200 mL). The mixture was basified with saturated aqueous NaHCO3 to pH 7. The organic layer was separated. The aqueous phase was extracted with EtOAc (300 mL×3). The combined organic layers were dried and evaporated under reduced pressure to give 2-bromo-4-nitroaniline (56 g, 72%), which was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]=[CH:5][CH:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:7]1.[C:31]([OH:34])(=[S:33])[CH3:32].C(N(CC)CC)C>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([S:33][C:31](=[O:34])[CH3:32])[CH:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([CH3:29])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:7]1
Reactant: COC(=O)C=CC1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Reactant: CC(O)=S
Solvent: CCN(CC)CC
Product: COC(=O)CC(SC(C)=O)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
A suspension of the product from step 11a (1.0 g, 2.5 mmol), thioacetic acid (3.0 mL), and triethylamine (0.25 mL, 1.8 mmol) was stirred for 6 h at room temperature while slowly becoming a clear solution. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate (2×), brine, dried over magnesium sulfate, and concentrated to give the crude product. This was purified by FCC on silica gel eluting ethyl acetate:hexanes (gradient) to give 3-acetylsulfanyl-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester (0.74 g, 63%) as an oil. MS found: (M+H)+=479.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10]Br.[OH-:12].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH:4]([CH3:3])[C:5]([OH:8])=[O:12]
Reactant: COc1ccc(Br)c(CBr)c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COc1ccc(Br)c(CC(C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 168.9 %

Procedure:
To a solution of sodium ethoxide obtained from 15.2 g (0.661 mol) of sodium and 540 ml of dry ethanol 115 g (0.658 mol) of diethyl methylmalonate was added. This mixture was stirred for 15 min; then, 184 g (0.659 mol) of 1-bromo-2-(bromomethyl)-4-methoxybenzene was added with vigorous stirring at such a rate to maintain gentle reflux. This mixture was refluxed for an additional 2 h and then cooled to room temperature. A solution of 130 g of KOH in 400 ml of water was added. The resulting mixture was refluxed for 4 h to saponificate the formed ester. Ethanol and water were distilled off until the vapor temperature reached 95° C. To the residue cooled to room temperature 1500 ml of water and then 12 M HCl (to pH 1) were added. The formed precipitate of (2-bromo-5-methoxybenzyl)(methyl)malonic acid was filtered off, washed with 2×200 ml of cold water, and dried on air. Decarboxylation of the substituted methylmalonic acid at 180° C. gave 152 g (84%) of the title product.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=2[O:27][CH2:28][CH:29]=[CH2:30])(=[O:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH2:28]([O:27][C:20]1[C:21]([Cl:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[S:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=[O:18])=[O:17])[CH:29]=[CH2:30]
Reactant: C=CCOc1c(Cl)cc(Cl)cc1S(=O)(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1c(Cl)cc(Cl)cc1S(=O)(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
The mixture of 2-(2-allyloxy-3,5-dichloro-benzenesulfonylamino)-indan-2-carboxylic acid ethyl ester (33) (143 mg, 0.30 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (5 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until pH˜3. After filtration, the solid is purified by HPLC to give a pure product (34) as white solid (91 mg, 69%).
Reaction SMILES: O.[OH-].[Na+].[CH3:4][C:5]([C:7]1([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8]1)=[O:6].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>C(O)C>[C:11]1([S:10][C:7]2([C:5]([CH:4]=[CH:22][C:21]3[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=3)=[O:6])[CH2:9][CH2:8]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C1(Sc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C1(Sc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98 %

Procedure:
50 ml of water and 8 pellets of solid sodium hydroxide are added at room temperature to a mixture of 75 g (0.39 mol) of 1-phenylmercaptocyclopropyl methyl ketone, 56 g (0.39 mol) of 4-chlorobenzaldehyde and 200 ml of ethanol. The mixture is stirred at room temperature for 14 hours. The precipitated solid is then filtered off. In this manner, 120.3 g (98% of theory) of 4-chlorophenylethenyl 1-phenylmercapto-cyclopropyl ketone are obtained in the form of a solid substance.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:31]([O:33][CH3:34])=[O:32]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:31]([O:33][CH3:34])=[O:32])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC)C3)cc1

Procedure:
Compound em was prepared according to the procedure described in Example 5 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with methyl chloroformate. LC-MS: m/z=+455 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][Br:15]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr

Procedure:
25.55 g (130.9 mmol) of 2-methyl-3-nitrobenzoic acid methyl ester is added to 300 ml of carbon tetrachloride, and mixed with 25.6 g (141.7 mmol) of N-bromosuccinimide and 62.8 mg of benzoyl peroxide. After seven days of refluxing, the succinimide is suctioned off after cooling, and then the filtrate is spun in until a dry state is reached. The desired compound that is incorporated in crude form into the next stage remains.