Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[C:21](Cl)(=[O:33])[O:22][C@@H:23]1[CH2:28][C@H:27]([CH3:29])[CH2:26][CH2:25][C@H:24]1[CH:30]([CH3:32])[CH3:31].O>C(Cl)Cl>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:21]([O:22][C@@H:23]2[CH2:28][C@H:27]([CH3:29])[CH2:26][CH2:25][C@H:24]2[CH:30]([CH3:32])[CH3:31])=[O:33])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
A solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.361 mmol, example 9 (step 3) and (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl carbonochloridate (76.5 μL, 0.361 mmol) in DCM (1 mL) was stirred at RT for 16 h. Then, H2O (2 mL) was added and the mixture was extracted with EtOAc (2×5 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel flash column chromatography (0%-100% EtOAc/hexane) to give the title compound as an off-white oil. MS (ESI, positive ion) m/z: 460 (M+H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@@H:21]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:22]([OH:37])[C:23]([N:25]2[CH2:36][CH2:35][CH2:34][C@H:26]2[C:27]([NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:24])=[O:19])[CH2:14][C:15](=[O:17])[NH2:16])=[O:11])[CH2:4][CH2:3]1.[CH2:45]([O:52][C:53](Cl)=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([O:52][C:53]([N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@@H:21]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@H:22]([OH:37])[C:23]([N:25]2[CH2:36][CH2:35][CH2:34][C@H:26]2[C:27]([NH:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[O:24])=[O:19])[CH2:14][C:15](=[O:17])[NH2:16])=[O:11])[CH2:4][CH2:3]1)=[O:54])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COC1CCNCC1
Agent: Cl
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 78.6 %

Procedure:
Following a procedure similar to that described in Example 30, but using 120 mg (0.19 mmol) of 1-{(2S,3S)-3-[N2 -(4-piperidyloxy)acetyl-L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-N-t-butyl-L-prolinamide hydrochloride (prepared as described in Example 56) and 0.03 ml (0.21 mmol) of benzyloxycarbonyl chloride, 110 mg of the title compound were obtained as a colorless powder, melting at 98°-104° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[O:15]=[C:16]1[CH2:21][CH2:20][C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:22]#[N:23])[CH2:18][CH2:17]1.Cl>C1COCC1>[OH:15][C:16]1([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=2)[CH2:21][CH2:20][C:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:22]#[N:23])[CH2:18][CH2:17]1
Reactant: CSc1ccc(Br)cc1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C2(O)CCC(C#N)(c3ccccc3)CC2)cc1
Temperature: -70 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
5.10 g of 4-bromothioanisole were dissolved in 50 ml of dry THF and 9.29 ml of an n-butyllithium solution (2.7 M in HEP) were added dropwise at a temperature between −65° C. and −70° C. The reaction mixture was stirred for 3 h at −70° C. Subsequently a solution of 5.00 g of 4-oxo-1-phenylcyclohexanecarbonitrile in 30 ml of THF was added dropwise at this temperature and the mixture was stirred for 10 min at −70° C. and 26 h at room temperature. The reaction mixture was then poured onto 400 g of ice, 100 ml of a 1 N hydrochloric acid were added and the mixture was extracted three times with 200 ml each of DCM. The combined extracts were dried over magnesium sulfate and the solvent was removed in vacuo. Chromatography of the residue on silica gel with EA/HEP (1:2) yielded 5.96 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH:11]([CH3:28])[C:12](=[O:27])[N:13]2[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:48]1([CH2:54][CH2:55]O)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>N(C(OCC)=O)=NC(OCC)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH2:55][CH2:54][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH:11]([CH3:28])[C:12](=[O:27])[N:13]2[C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CC1Cc2c(-c3ccccc3Cl)cc(O)cc2N(c2c(Cl)cccc2Cl)C1=O
Reactant: OCCN1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1Cc2c(-c3ccccc3Cl)cc(OCCN3CCCCC3)cc2N(c2c(Cl)cccc2Cl)C1=O

Procedure:
The title compound was prepared from 7 mg of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-hydroxy-3-methyl-3,4-dihydroquinolin-2(1H)-one, 40 mg of Ph3P, 20 μL of 1-piperidine ethanol, and 20 μL of diethyl azodicarboxylate by a procedure analogous to that described in EXAMPLE 2. Mass spectrum (ESI) 545 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[P:13]([O:18]C)([O:16][CH3:17])[O:14][CH3:15]>>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][P:13]([O:16][CH3:17])([O:14][CH3:15])=[O:18])=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COP(OC)OC
Product: COC(=O)c1ccc(CP(=O)(OC)OC)cc1

Procedure:
Methyl 4-(bromomethyl)benzoate (compound 47) (11.2 g, 49 mmol) was dissolved in 25 mL trimethyl phosphite and refluxed under N2 for 5 hrs. Excess trimethyl phosphite was removed by co-distillation with toluene to give crude 4-(Dimethoxy-phosphorylmethyl)-benzoic acid methyl ester (compound 48).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42])[CH3:35]>>[CH2:34]([N:36]1[CH2:41][CH2:40][N:39]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:38][C:37]1=[O:42])[CH3:35]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCN1CCNCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCN1CCN(c2cc(C(=O)Nc3nc4c(OC)ccc(N5CCOCC5)c4s3)ccn2)CC1=O

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 1-ethyl-piperazin-2-one. ES-MS m/e (%):519 (M+Na+, 28), 497 (M+H30 , 100).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH:5]1[CH:6]=[CH:7][C:8]2N[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1.[S:20](=[O:24])(=[O:23])([OH:22])[OH:21]>C(O)(=O)C.O>[CH:5]1[CH:6]=[CH:7][C:8]2[N:1]([C:2]([NH2:4])=[O:3])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:9]=2[CH:10]=1.[S:20](=[O:22])(=[O:21])([OH:24])[OH:23]
Reactant: C1=Cc2ccccc2Nc2ccccc21
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)N1c2ccccc2C=Cc2ccccc21
Temperature: 27.5 °C

Procedure:
To a suspension of urea (400 g, 6.66 mols) in acetic acid (500 ml), sulphuric acid (15 ml) was added, followed by iminostilbene (100 g, 0.518 mols), under stirring at 25-30° C. The resulting reaction mixture was heated to 80-85° C. and maintained for a period of 7-8 hours, and the reaction was monitored by thin layer chromatography (TLC). The reaction mass was diluted with water, and the resulting carbamazepine product (m.p. 188-189° C.) separated by filtration, washed with water until neutral and dried at 90-100° C. until constant weight. The identity of the product was further verified by tlc (toluene/methanol 18/03, uv=254 nm) to be identical to the reference compound and by infra-red spectroscopy (KBr) Vmax=3466, 1677, 1605, 1595 cm−1.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([Cl:21])(C1C=CC(C)=CC=1)(=O)=O>N1C=CC=CC=1>[C:1]1([C:7]#[C:8][CH2:9][Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC#Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: ClCC#Cc1ccccc1
Temperature: 0 °C
Yield: 63 %

Procedure:
1-Phenyl-1-propyn-3-ol (5 g), 5.1 g of tosyl chloride and 20 ml of pyridine were stirred at room temperature for 1 hour. The reaction mixture was poured into 100 ml of ice water and extracted with ethyl acetate. The oil layer was washed with 1N hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give 2.54 g of 3-phenyl-2-propynyl chloride as a pale yellow, oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc(C#N)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cccc(CN)c1
Reaction time: 2 h
Yield: 42.2 %

Procedure:
To a mixture consisting of crude tert-butyl 2-(3-cyanophenylsulfonamido)-ethylcarbamate (Compound 15, 1.52 g) in methanol (46 mL) under a nitrogen atmosphere was added 5% palladium on carbon (1 g). Hydrogen gas was applied via balloon at atmospheric pressure. The reaction mixture was stirred vigorously for two hours and was subsequently filtered over Celite and rinsed with additional methanol. The mixture was concentrated under reduced pressure and purified by silica chromatography (5:95 methanol-dichloromethane) to afford the title intermediate (650 mg, 42% over two steps).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][NH2:20]>>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:20][CH3:19])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CCCCC1
Reactant: CN
Product: CNc1ccc(C(=O)C2CCCCC2)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to Example 7b from 4-(cyclohexylcarbonyl)-2-nitro-chlorobenzene and methylamine solution.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:19])[CH3:18]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:18][C:17](=[O:19])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)C=Cc1ccc(OCc2ccccc2)cc1
Yield: 79.9 %

Procedure:
A solution of 10.0 g of p-benzyloxybenzaldehyde and 15.7 g of acetylmethylenetriphenylphosphorane in 100 ml of toluene was heated under reflux for 2 hours, the solvent was then evaporated and the residual crystals were recrystallized from ether to give 9.5 g of the desired compound melting at 106°-107° C.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)(=O)C(Cl)=O.[CH:21]1[CH:26]=[CH:25][CH:24]=CC=1>>[C:1]([O:14][CH2:24][CH:25]1[CH2:21][CH2:26]1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: CCCCCCCCCCCC(=O)OCC1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3.01 g. of lauric acid in benzene, under nitrogen, is added 5.8 g. of oxalyl chloride. The mixture is stirred at room temperature for 2 hours and then concentrated in vacuo at 40°. To the concentrate is added fresh benzene and 3.25 g. of cyclopropylmethyl alcohol. The solution is stirred overnight at room temperature and then diluted with water. The reaction mixture is worked up by washing with water and brine, drying over calcium sulfate, concentrating the organic phase under reduced pressure and purifying by distillation to yield cyclopropylmethyl laurate (cyclopropanemethyl-n-dodecanoate), b.p. (bath) 90° at 0.005 mm.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[C:57]([O:62][Si](C(C)(C)C)(C)C)[CH:58]=4)[CH:53]=3)[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:61]=[CH:60][C:59]4[C:54](=[CH:55][CH:56]=[C:57]([OH:62])[CH:58]=4)[CH:53]=3)[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc5cc(O[Si](C)(C)C(C)(C)C)ccc5c4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc5cc(O)ccc5c4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 56.2 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-tert-butyldimethylsilyloxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (41.6 mg) in CH2Cl2 (1.5 mL) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL of a 10% w/v solution). The mixture was stirred 1.25 h at 0° C. and then 1.75 h at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted 2× with 2:1 hexanes/acetone) affording 20.8 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(6'"-hydroxynaphth-2-yloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[Cl-].[Li+].[C:25]1([C@H:31]2[CH2:35][O:34][C:33](=[O:36])[NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:1]([N:32]1[C@@H:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:35][O:34][C:33]1=[O:36])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCC(=O)O
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCCCC(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of 69.0 g (615 mmol) of 5-hexynoic acid and 214 mL (1540 mmol) of triethylamine in 1.0 L of anhydrous tetrahydrofuran at −25° C. under an atmosphere of nitrogen was added 83.0 mL (677 mmol) of trimethylacetyl chloride over 20 min. Upon addition a white precipitate formed and the resulting suspension was stirred for 2 h. Next, 28.7 g (677 mmol) of anhydrous lithium chloride and 100.0 g (615.0 mmol) of (4S)-4-phenyl-1,3-oxazolidin-2-one were added sequentially and the mixture was allowed to gradually warm to ambient temperature over 12 h. All volatiles were removed in vacuo and the residue was diluted with water (1 L) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with a 5-50% ethyl acetate in hexanes gradient to afford the title compound as a colorless solid (135 g, 85.4%). 1H NMR (500 MHz, CDCl3): δ 7.40-7.37 (m, 2H), 7.36-7.32 (m, 1H), 7.31-7.28 (m, 2H), 5.42 (dd, J=8.9, 3.7 Hz, 1H), 4.69 (t, J=8.9 Hz, 1H), 4.28 (dd, J=9.2, 3.7 Hz, 1H), 3.13-3.02 (m, 2H), 2.24-2.21 (m, 2H), 1.94 (t, J=2.6 Hz, 1H), 1.84 (quintet, J=7.1 Hz, 2H). LC-MS: m/z (ES) 258.2 (MH)+.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[F:12].Cl.[OH2:15]>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[F:12][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:3]=1[CH:2]=[O:15])[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc(C(Br)Br)c(F)c1
Reactant: O
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: O=Cc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
AgNO3 (0.39 mol) in hot H2O (90 mL) is added dropwise to a solution of crude 4-dibromomethyl-3-fluorobenzoic acid (2, 0.19 mol) in ethanol (EtOH) (480 mL) at 50° C. over 10 min and then the mixture is stirred at the same temperature for 45 min. After cooling to room temperature, the mixture is poured into 1 N HCl (200 mL) and filtered off. The residue is washed with EtOH and the filtrate is concentrated to ca. 300 mL. The mixture is extracted twice with ethylacetate (EtOAc) and the combined organic layers are washed with brine, dried over MgSO4 and evaporated in vacuo. The crystals are collected by filtration and washed with ether/hexane (1:1) to give 3-fluoro-4-formyl benzoic acid (3).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CO.[OH-].[Na+]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)OCO4)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 2-(benzo[d][1,3]dioxol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (150 mg, 0.40 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (79 mg, 1.98 mmol, 4.99 equiv), and water (2 mL). The resulting solution was stirred for 2 h at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. This resulted in 60 mg (40%) of 2-(benzo[d][1,3]dioxol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:23][C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([NH2:33])=[CH:28][CH:27]=2>>[CH3:22][O:21][CH2:20][CH2:19][O:18][C@@H:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:33][C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:23])=[CH:32]4)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: COCCO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Product: COCCO[C@@H]1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)C1

Procedure:
The title compound was prepared from (3R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-[3-(2-methoxy-ethoxy)-pyrrolidin-1-yl]-methanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 451.3 (MH+); HPLC Rf: 4.385 min.; HPLC purity: 97%.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH:14]([OH:16])[CH3:15])=[CH:6][CH:5]=1)([O-])=O.C.O.NN>CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH:14]([OH:16])[CH3:15])=[CH:17][CH:18]=1
Reactant: CC(O)C1CCCN1Cc1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: CO
Solvent: O
Product: CC(O)C1CCCN1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-[1-(4-Nitro-benzyl)-pyrrolidin-2-yl]-ethanol (370 mg, 1.48 mmol) is dissolved in MeOH (15 mL), to this solution is added FeCl3.6H2O (30 mg, 0.11 mmol) and active charcoal (15 mg, 1.2 mmol). The suspension is heated to reflux. Hydrazine hydrate (1.0 mL) is added, and reflux is continued for 3 h. After the mixture is cooled to room temperature, the active charcoal is filtered off through Celite, and the MeOH is removed under reduced pressure. The residue (200 mg, 61%) is directly used in the next step.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[C:21]([CH:22]=O)=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>CO>[Cl:12][C:13]1[C:21]([CH:22]=[N:5][O:4][CH2:2][CH3:3])=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C=O
Reactant: CCON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.5 %

Procedure:
1.63 g (0.017 mol) of O-ethylhydroxylamine hydrochloride and 1.15 g (0.0085 mol) of finely powdered potassium carbonate were stirred for 1 hour in 60 ml of dry methanol. 4.00 g (0.015 mol) of 2-chloro-3-formyl-4-methylsulfonylbenzoic acid in 40 ml of methanol were then added. After stirring for 12 hours at room temperature, the solvent was removed, the residue was taken up in ethyl acetate and the organic phase was washed four times with water. After drying and removal of the solvent by distillation, 3.60 g of 2-chloro-3-ethoxyiminomethyl-4-methylsulfonylbenzoic acid (78% yield) were obtained.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:25]1[CH2:29][CH2:28][CH:27]([NH:30][S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8](=[O:9])[NH:10][C:11]2[S:12][C:13]([CH2:16][N:25]3[CH2:29][CH2:28][CH:27]([NH:30][S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:26]3)=[CH:14][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCS(=O)(=O)NC1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CCS(=O)(=O)NC1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)C1
Yield: 46.9 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol), ethanesulfonic acid pyrrolidin-3-yl amide hydrochloride (41 mg, 0.19 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) to afford 35 mg (47%) of the desired product after purification.