Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[O:5])=[CH2:3].[CH3:12][S:13]([O:16]C)(=[O:15])=[O:14].[C:18]([O-])(=O)C(C)=C.CCOCC>C(#N)C>[CH3:12][S:13]([O-:16])(=[O:15])=[O:14].[C:4]([O:6][CH2:7][CH2:8][N+:9]([CH3:18])([CH3:11])[CH3:10])(=[O:5])[C:2]([CH3:1])=[CH2:3]
Reactant: C=C(C)C(=O)[O-]
Reactant: COS(C)(=O)=O
Reactant: C=C(C)C(=O)OCCN(C)C
Solvent: CC#N
Solvent: CCOCC
Product: C=C(C)C(=O)OCC[N+](C)(C)C
Product: CS(=O)(=O)[O-]
Temperature: 90 °C
Reaction time: 24 h

Procedure:
3.14 g (20 mmol) DMAEMA was dissolved in 30 ml acetonitrile and 1.7 ml (2.203 g, 20 mmol) methyl methanesulfonate was added. The mixture was heated to 90° C. (reflux) with stirring for 24 h. At the end of the reaction period the mixture becomes viscous, indicating probably some polymerization of the methacrylate. The mixture was poured into 400 ml ether, and the precipitate was filtered and washed with ether, then dried in vacuo. The obtained salt is very hygroscopic. It contains a small amount of polymer, so this synthesis will be done again in the presence of inhibitor of polymerization, which can be removed after the reaction. Yield: 3.50 g (65%)
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)OC1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>C1(C)C=CC=CC=1.Cl.CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH:4]2[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]2)[CH2:22][CH2:23]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CCC(N2CCN(c3ccccn3)CC2)CC1
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A solution of 1,4-cyclohexanedione monoethyleneketal (50.0 g), 1-(2-pyridyl)piperazine (52.16 g), and p-toluenesulfonic acid (0.5 g) in 500 ml of toluene is refluxed with a Dean-Stark trap until the theoretical amount of water is collected (about four hours). The solvent is evaporated in vacuo and the residue is dissolved in 750 ml of methanol. This solution is cooled in an ice bath and sodium cyanoborohydride (30.1 g) is added in small portions over a two-minute period. The resulting suspension is stirred mechanically and over the next 30 minutes enough concentrated hydrochloric acid solution is added dropwise to the reaction mixture to maintain a pH of about 4. The solvent is removed in vacuo to leave a semisolid residue which is dissolved in 300 ml of a 10% solution of hydrochloric acid in a well ventilated fume hood. This solution is diluted with an equal volume of acetone and refluxed for two hours. The volatile components of the mixture are removed in vacuo and the residue is cooled in an ice bath and made basic with concentrated ammonium hydroxide. The white solid which forms is recrystallized from ethyl acetate-heptane to give 52.4 g of the title compound; mp 142°-144° C.
Reaction SMILES: [OH:1][CH:2](S(O)(=O)=O)[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[Na].Cl>>[OH2:1].[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3](=[O:19])[CH:2]=[O:1])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(COc2ccc(C(=O)C(O)S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [Na]
Product: Cc1ccc(COc2ccc(C(=O)C=O)cc2)cc1
Product: O

Procedure:
A 2.8 g. portion of α-hydroxy-β-oxo-4-[(4-methylphenyl)methoxy]-benzeneethanesulfonic acid, sodium salt was combined with 25 ml. of 0.5N hydrochloric acid, heated on a steam bath for 5 minutes and then allowed to stand for several hours. The solid was collected, slurried with 50 ml. of acetone, 25 ml. of 0.5N hydrochloric acid were added and the mixture was refluxed for 2 hours. The solid was collected, again refluxed with acid and the solid collected, washed free of acid and dried, giving the desired product as a white solid, m.p. 125°-130° C.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:24]([OH:26])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:73][C@@H:74]([NH2:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>C(#N)C.C(Cl)Cl>[C:1]([NH:8][C@@H:9]([C:24]([NH:81][C@@H:74]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:73])=[O:26])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Prepared according to the method described in Example 1(a) above from Nα -Boc-Nδ -Cbz-(R)-ornithine (5.0 g; 13 mmol), BOP reagent (6.0 g; 13 mmol), HOBT (1.8 g; 13 mmol) and DiPEA (7.1 mL; 40.0 mmol) 100 mL of acetonitrile:CH2Cl2 (1:1), followed by 1.8 mL (13 mmol) of (R)-α-methylbenzylamine, then stirred overnight. After work up, the crude product was purified by passing it through a plug of silica gel with EtOAc to give 5.9 g (92%) of the sub-title compound as a light yellow solid.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C2C(=CC=CC=2)C=CC=1S(Cl)(=O)=O>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415 mmol), 1-naphthalenesulfonyl chloride (15 mg, 0.072 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT. The two enantiomers were separated by Chiral chromatography (Chiracel OD). 3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole (17.5 mg, 97.7%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415 mmol), 2-naphthalenesulfonyl chloride (15 mg, 0.072 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5mL) at RT.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][C:37]3[NH:38][CH:39]=[N:40][C:36]=3[CH:35]=2)O1>>[ClH:1].[ClH:1].[ClH:1].[NH:38]1[C:37]2[CH:41]=[CH:42][C:34]([C:2]3[N:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]4[NH:15][C@H:16]3[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]([CH3:24])[CH3:25])[CH2:20][CH2:21]3)=[CH:35][C:36]=2[N:40]=[CH:39]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2ccc3[nH]cnc3c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3ccc4[nH]cnc4c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Product: Cl

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclo-hexylamino}-1,5-naphthyridin-3-yl)ethanone (68 mg, 0.188 mmol) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (69 mg, 0.282 mmol) followed by formation of the trihydrochloride salt to afford the desired product (76 mg, 73%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.49 (s, 1H), 9.19 (s, 1H), 8.63 (d, J=8.9 Hz, 1H), 8.56 (s, 1H), 8.46 (d, J=8.9 Hz, 1H), 8.37 (d, J=8.5 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 5.65-5.55 (m, 1H), 3.15 (d, J=6.9 Hz, 2H), 2.93 (s, 6H), 2.78 (s, 3H), 2.52-2.48 (m, 2H), 2.07-1.95 (m, 3H), 1.76-1.64 (m, 2H), 1.43-1.31 (m, 2H); ESI MS m/z 443 [M+H]+; HPLC 97.7% (AUC), tR=8.20 min.
Reaction SMILES: [CH3:1][S:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13]([OH:15])=[O:14].[CH:20]1[CH:25]=CC=C[CH:21]=1.C(Cl)(=O)C(Cl)=O.C(=O)(O)[O-].[Na+]>CCOCC.C(O)(C)C>[CH3:1][S:2][C:3]([CH3:18])([CH3:19])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13]([O:15][CH:20]([CH3:25])[CH3:21])=[O:14]
Reactant: c1ccccc1
Reactant: CSC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: CSC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C
Reaction time: 2 h

Procedure:
To 0.6 g. of 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoic acid in 10 ml. of dry benzene is added 0.23 ml. of oxalyl chloride at room temperature with stirring. After 2 hours, isopropanol (2ml.) is added and the mixture allowed to stand at room temperature for about 2 hours. Ether and saturated sodium bicarbonate is added and the organic phase separated. The organic phase is washed with aqueous sodium bicarbonate, saturated sodium chloride, dried over calcium sulfate and evaporated to yield isopropyl 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][C:13]=1[Cl:20].N>>[Cl:20][C:13]1[CH:14]=[C:15]([C:18]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=2)[CH:16]=[CH:17][C:12]=1[Cl:11]
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1ccc(Cl)c(Cl)c1
Agent: N
Product: Clc1ccc(-c2cc(-c3cccnc3)no2)cc1Cl

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1,2-dichloro-4-ethynylbenzene (Aldrich, 86 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (dd, J=8.1, 5.0 Hz, 1H), 7.82-8.00 (m, 3H), 8.21 (d, J=2.0 Hz, 1H), 8.38 (dt, J=7.9, 1.8 Hz, 1H), 8.78 (dd, J=4.8, 1.6 Hz, 1H), 9.14 (d, J=1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z 293 (M+H)+, 291 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[CH2:9][C:8]3([CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][NH:45][CH:46]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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>[F:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([N:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:42]5[CH:43]=[N:44][NH:45][CH:46]=5)[CH:3]=4)[C:8]4([CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:9]3)=[C:12]([CH3:28])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ncc(-c3cn[nH]c3)cc21
Temperature: 140 °C

Procedure:
A stirred solution of 6′-bromo-1′-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (25 mg, 0.049 mmol), 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (9.60 mg, 0.049 mmol), PdCl2(PPh3)2 (3.5 mg, 4.95 μmol) and Na2CO3 (10.5 mg, 0.099 mmol) in toluene:water (2 mL:1 mL) was heated in the microwave for 2 h at 120° C. After this time PdCl2(PPh3)2 (5.0 mg) and 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (9.60 mg, 0.049 mmol) was added and the reaction was heated in the microwave for 1 h at 140° C. After this time the reaction was partitioned between EtOAc (50 mL) and water (20 mL). The separated organic layer was dried with MgSO4, filtered and evaporated in vacuo. Reverse phase HPLC (10 to 60% acetonitrile:water) gave 1′-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(1H-pyrazol-4-yl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. Mass Spectrum (ESI) m/e=493.0 (M+1).
Reaction SMILES: [Li][CH2:2]CCC.[CH2:6]([C:13]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1CCl.Cl>C1COCC1>[CH3:24][O:23][C:21]1[CH:22]=[C:13]2[C:14](=[CH:19][CH:20]=1)[C:15](=[O:16])[N:17]([CH3:2])[C:18]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1)=[C:6]2[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CNC(=O)c1ccc(OC)cc1Cc1ccccc1
Reactant: [Li]CCCC
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(C)c(-c3ccccn3)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (1.6 M in hexanes, 17.6 mL, 28 mmol) was added to a solution of amide 9 (3 g, 12 mmol) in THF (70 mL) at −78 C. After stirring for 30 min, 2-picolyl chloride.HCl (3.1 g, 8.8 mmol) was added. After stirring for 30 min the reaction mixture was quenched with water then warmed to room temperature. The reaction mixture was concentrated and the residue partitioned between water and EtOAc. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography.
Reaction SMILES: [CH2:1]([C:4]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[C:12]=2[F:14])[NH:7][C:6](=[O:16])[N:5]1[CH2:17][C:18]([F:21])([F:20])[F:19])[CH:2]=C.[O:29]=[O+][O-].CSC>CO.CCOC(C)=O>[F:14][C:12]1[C:11]([F:15])=[CH:10][CH:9]=[C:8]2[C:13]=1[C:4]([CH2:1][CH:2]=[O:29])([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[N:5]([CH2:17][C:18]([F:21])([F:19])[F:20])[C:6](=[O:16])[NH:7]2
Reactant: O=[O+][O-]
Reactant: C=CCC1(c2ccc(F)cc2)c2c(ccc(F)c2F)NC(=O)N1CC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CSC
Product: O=CCC1(c2ccc(F)cc2)c2c(ccc(F)c2F)NC(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of 2.6 g (6.495 mmol) 4-allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 25 ml MeOH was bubbled ozone. After 15 mins at −78° C., the ozone was removed and the reaction mixture was quenched with 4.8 mL (64.946 mmol) dimethyl sulfide. After stirring at room temperature overnight, the reaction mixture was diluted with EtOAc and washed three times with water and brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Afforded [5,6-difluoro-4-(4-fluorophenyl)-2-oxo-3-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]acetaldehyde. 1H NMR (CDCl3, 400 MHz) δ 9.79 (s, 1H, O═CH); 8.61 (br s, 1H, ArNHC═O); 7.38-7.27 (m, 2H, ArH); 7.15-7.03 (m, 3H, ArH); 6.57-6.53 (m, 1H, ArH); 4.08 (m, 1H, C); 3.72 (dd, 1H, J=17.4 Hz, CH2C═O); 3.50 (dd, 1H J=1.28 Hz, 17.58 Hz, CH2C═O); 3.32 (m, 1H, CH2C═O). ES MS+1=403.1.
Reaction SMILES: OO.[N:3]1([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:22]=[C:21]4[O:23][CH2:24][CH2:25][C:20]4=[CH:19][C:17]=3[N:18]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(O)(C(F)(F)F)=[O:28]>C(Cl)Cl.N>[N:3]1([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:22]=[C:21]4[O:23][CH2:24][CH2:25][C:20]4=[CH:19][C:17]=3[N+:18]=2[O-:28])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: O=C(O)C(F)(F)F
Reactant: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)OCC3
Agent: N
Agent: OO
Solvent: ClCCl
Product: [O-][n+]1nc(NCCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)OCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
H2O2 (70%, 1.6 mL, ca. 32 mmol) was added dropwise to a stirred solution of TFM (4.5 mL, 32 mmol) in DCM (40 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 199 (1.06 g, 3.2 mmol) and TFA (1.25 mL, 16 mmol) in DCM (40 mL) at 0° C. The solution was stirred at 20° C. for 4.5 h, diluted with dilute aqueous NH3 solution (50 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM to give 1,4-dioxide 200 (150 mg, 14%) as a red solid: mp 145-148° C.; 1H NMR δ 8.26 (br s, 1H, NH), 8.14 (s, 1H, H-9), 7.53 (s, 1H, H-5), 4.74 (t, J=8.3 Hz, 2H, H-7), 3.83 (t, J=4.6 Hz, 4H, 2×CH2O), 3.65 (br q, J=5.9 Hz, 2H, CH2N), 3.43 (dt, J=8.3, 1.2 Hz, 2H, H-6), 2.58 (br t, J=6.1 Hz, 2H, CH2), 2.53 (br s, 4H, 2×CH2N), 1.88 (p, J=6.2 Hz, 2H, CH2); 13C NMR δ 159.8, 149.0, 141.5, 135.2, 130.8, 113.1, 97.4, 72.4, 66.8 (2), 57.7, 53.8 (2), 41.6, 29.7, 24.5; MS (APCI) m/z 348 (MH+, 100%); HRMS (FAB+) calcd for C16H22N5O4 (MH+) m/z 348.1672, found 348.1666. Anal. calcd for C16H21N5O4.0.4CH2Cl2: C, 51.7; H, 5.8; N, 18.4. Found: C, 51.7; H, 5.4; N, 18.1%.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[S:7]([OH:17])(=[O:16])([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)=[O:8].[N:18]([O-])=O.[Na+].[ClH:22]>O>[Cl-:22].[S:7]([C:9]1[CH:10]=[CH:11][C:12]([N+:15]#[N:18])=[CH:13][CH:14]=1)([OH:17])(=[O:16])=[O:8]
Reactant: O=N[O-]
Reactant: Cl
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(S(=O)(=O)O)cc1
Product: [Cl-]

Procedure:
A solution of 0.78 g of sodium carbonate and 2.55 g of sulfanilic acid in 55 ml of water was cooled to 0° C., and 6 ml of an aqueous solution containing 1.11 g of sodium nitrite was added. Further, 15 ml of cold 2N-HCl was added while maintaining the temperature in the range of 0° to 5° C., to form p-sulfophenyldiazonium chloride. Starch iodide paper was used in recognizing the end of reaction.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH3:25].O.O>C1COCC1>[C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:16])[NH2:25]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: N
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(N)=O)C1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A 1-L 3-necked round-bottomed flask was charged with a solution of 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (10 g, 42.79 mmol, 1.00 equiv, 98%), TEA (5.2 g, 50.46 mmol, 1.18 equiv, 98%) in THF (100 mL). To this mixture was added isobutyl carbonochloridate (6.8 g, 49.00 mmol, 1.15 equiv, 98%) drop wise at 10° C. The resulting solution was stirred for 15 minutes at 10° C. in a water/ice bath. Then, to the mixture was added NH3.H2O (25%, 60 mL) and allowed to stir for 10 minutes at 10° C. Then, it was treated with water (40 mL) to afford off-white solids after filtration. The solid was dried in an oven under reduced pressure affording tert-butyl 3-carbamoylpiperidine-1-carboxylate as white solid (7 g, 72%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32](O)=[O:33])[CH2:29][N:30]=1)=[CH:9]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:57][NH:58][CH2:59][CH2:60][OH:61]>O.CN(C)C=O>[OH:61][CH2:60][CH2:59][N:58]([CH3:57])[C:32](=[O:33])[CH2:31][CH:28]1[S:27][C:26]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=3[N:15]([CH3:25])[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:18])=[N:30][CH2:29]1
Reactant: CNCCO
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)N(C)CCO)S3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.3 %

Procedure:
A mixture of (2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (250 mg), 1H-1,2,3-benzotriazol-1-ol (100 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (140 mg), 2-(methylamino)ethanol (60 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-95:5, volume ratio) to give colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (140 mg, yield 50%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4](=[O:16])[CH:3]=1.[S-:17][C:18]#[N:19].[K+].N1C=CC=CC=1.BrBr>CN(C)C=O.O>[NH2:1][C:2]1[NH:7][C:6]([S:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:5][C:4](=[O:16])[C:3]=1[S:17][C:18]#[N:19]
Reactant: Nc1cc(=O)nc(SCc2ccccc2)[nH]1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: N#CSc1c(N)[nH]c(SCc2ccccc2)nc1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
6-Amino-2-[(phenylmethyl)thio]-4-(1H)-pyrimidinone (10.5 g) (prepared as described in WO 96/35678) and potassium thiocyanate (25 g) in dimethylformamide (200 mL) were heated together at 65° C. Pyridine (6.3 mL) was added and the solution cooled to 5° C. Bromine (2.2 mL) was added slowly and the reaction mixture stirred for 2 hours at 5-10° C. The reaction mixture was poured onto ice and water, stirred for 1 hour and the solid was filtered off. After washing with water and ether a pure sample was obtained after tituration with hot methanol.
Reaction SMILES: CN1CCC([NH:8][C:9]2C=[C:11]([NH:19][C:20](=[O:28])[O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:12]=[C:13]([C:15]([F:18])([F:17])F)[CH:14]=2)CC1.N1C=CC=C[CH:30]=1.ClC(OC1C=CC=CC=1)=O>C(Cl)Cl>[F:18][C:15]([C:13]1[CH:14]=[CH:9][N:8]=[C:11]([NH:19][C:20](=[O:28])[O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=1)([F:17])[CH3:30]
Reactant: CN1CCC(Nc2cc(NC(=O)Oc3ccccc3)cc(C(F)(F)F)c2)CC1
Reactant: c1ccncc1
Agent: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: CC(F)(F)c1ccnc(NC(=O)Oc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Add the amine obtained in Step 3 (624 mg, 3.95 mmol), pyridine (780 mg, 9.85 mmol) in DCM (15 mL), cool to 0° C. on ice bath. Add slowly a solution of phenyl chloroformate (678 mg, 4.34 mmol) in DCM. After addition, stir on ice bath for 1 hr. Concentrate the mixture to get a crude residue. Purification by chromatography (silica gel, EtOAc:PE=1:3) affords the target compound (780 mg, 71%). MS: (M+1): 279.1.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])([OH:17])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8]1)[CH3:5].[CH3:25][S:26]([OH:29])(=[O:28])=[O:27]>O1CCCC1.O>[CH3:25][S:26]([OH:29])(=[O:28])=[O:27].[CH3:5][N:4]([CH2:6][CH:7]1[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])([OH:17])[CH2:15][CH2:14][C:9](=[O:10])[CH2:8]1)[CH3:3]
Reactant: Cc1ccccc1C1(O)CCC2(CC1CN(C)C)OCCO2
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C1(O)CCC(=O)CC1CN(C)C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
178 ml of hydrochloric acid (32%, excess) were added rapidly at 0° C. to a solution of 7-dimethylaminomethyl-8-(2-methyl-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol hydrochloride (73.5 g, 215 mmol) in tetrahydrofuran/water mixture, and stirring was then carried out for 16 hours at RT. The mixture was adjusted to pH 12 with 32% sodium hydroxide solution, and extraction was carried out with ether. After evaporation of the solvent in vacuo, the residue was taken up in diisopropyl ether and EE, and the corresponding salt was precipitated by addition of methanesulfonic acid (13 ml, 200 mmol). 64.3 g (84%) of the product were obtained in the form of a colorless solid.