Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][O:44][CH2:45][CH3:46])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:45]([O:44][CH2:43][CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:36][CH:37]=1)[CH3:46]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCCc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOCCCc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 4-(3-ethoxypropyl)phenyl borate (0.18 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol to give 7-[4-(3-ethoxypropyl)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 123) (0.25 g) as colorless crystals.
Reaction SMILES: C([O:4][C:5]1[C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=[C:7]2[S:8][C:9]([C:11](=[O:13])[CH3:12])=[CH:10][C:6]=12)(=O)C.CC([OH:23])C.C(Cl)(Cl)Cl>CC(O)=O>[C:11]([C:9]1[S:8][C:7]2[C:14](=[O:23])[C:15]3[CH:19]=[CH:18][S:17][C:16]=3[C:5](=[O:4])[C:6]=2[CH:10]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Oc1c2cc(C(C)=O)sc2cc2ccsc12
Reactant: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)c1cc2c(s1)C(=O)c1ccsc1C2=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a suspension of crude 8 (7.5 g) in HOAc (30 mL) was added CrO3 (5.7 g, 57 mmol). After stirring for 1 h, i-PrOH (20 mL) and CHCl3 (300 mL) were added and stirred for 30 min. The resulting solution was poured into ice water, and the aqueous layer was extracted with CHCl3 three times. The combined extracts were dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, CHCl3) to give 9 (mp 223-225° C.) in a 45% yield. IR (KBr) 1650, 1670 (C═O) cm−1; 1H NMR (CDCl3) δ 2.67 (s, 3H, CH3), 7.68 (d, J=5.1 Hz, 1H, H-7), 7.74 (d, J=5.1 Hz, 1H, H-6), 8.12 (s, 1H, H-3); 13C NMR (CDCl3): δ 26.9 (C-2-CH3), 126.9 (C-7), 129.4 (C-3), 134.3 (C-6), 170.0 (C-4), 174.4 (C-8), 190.7 (C-2-C═O); MS m/z 262 (M+); Anal. (C12H6O3S2) C, H.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:17]([C:16]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:15]=1[Cl:14])=[O:18])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2,4-dichlorobenzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.90 (t, 3 H) 1.30-1.40 (m, 2 H) 1.58-1.65 (m, 2 H) 2.21 (s, 3 H) 2.23 (s, 3 H) 3.94-3.99 (m, 2 H) 6.11 (s, 1 H) 7.46 (dd, 1 H) 7.52-7.57 (m, 1 H) 7.62 (d, 1 H); MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[S:17])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>O>[CH2:1]([NH:8][C:9]1[S:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=C(NCc1ccccc1)Nc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: c1ccc(CNc2nc3ccccc3s2)cc1

Procedure:
240.0 Parts of N'-benzyl-N-phenylthiourea are added, while stirring, over a period of 90 minutes to 334.6 parts of thionyl chloride of approximately 65° C. The reaction mixture is then refluxed (65° to 70° C.) for 5 hours while stirring. The cyclization melt obtained is hydrolyzed with 3,200 parts of water analogously to Example 53 and further treated as described in said Example. 221.5 Parts (92.3% of the theory) of 2-benzylamino-benzthiazole melting at 159° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.[S:35]([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)C>[C:1]([O:5][C:6](=[O:29])[C:7]1[CH:12]=[CH:11][C:10]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][SH:35])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(N=Nc2ccc(OCCCCCCBr)cc2)cc1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(N=Nc2ccc(OCCCCCCS)cc2)cc1
Temperature: 25 °C

Procedure:
4-[4-(6-Mercapto-hexyloxy)-phenylazo]-benzoic acid t-butyl ester was synthesized by modifying a literature procedure [Material Science and Engineering, 1999, 8-9, 385-389; J. Phys. Chem., 1995, 99, 7102]. 0.41 g (0.9 mmol) of 4-[4-(6-bromo-hexyloxy)-phenyazo]-benzoic acid t-butyl ester and 0.25 mg (1.1 mmol) of sodium thiosulfate pentahydrate in 5 mL of water was dissolved in 18 mL of ethanol and refluxed for 3 hours. The mixture was stirred at room temperature for an additional hour. After cooling, the precipitate was filtered off using a fritted funnel. A fine orange solid (bunte salt) was obtained and was used without purification. 10 ml of chloroform and 10 mL of 1M HCl were added to the bunte salt. The reaction mixture was refluxed for 2 hours at 70° C. after which the orange organic phase was extracted from the colorless aqueous layer. The organic layers were further extracted with 10 mL of chloroform (3 times) and combined, washed with saturated NaHCO3 solution, distilled water, and then dried over MgSO4. The solvent was removed by roto-evaporation and the product (compound 1, FIG. 11) was further purified by recrystallization from an ethanol-water mixture. Drying under vacuum produced a fine orange powder (0.22 g, 60% yield) with the following characteristics: 1H NMR (CDCl3) δ 8.11 (d, J=9 Hz, 2H), 7.91 (dd, J=9 Hz, 4H), 7.14 (d, J=9 Hz, 2H), 4.08 (t, J=6 Hz, 2H), 2.48 (m, 2H), 1.85-1.41 (m, 17H), 1.32 (t, 1H). High-resolution mass spectroscopy (HR-MS) yielded a mass of 414.1988 compared to the value 414.1628 calculated for C23H30O3N2S.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:24][N:23]([C:25]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[CH:28]=[CH:27][C:26]=3[CH3:34])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([C:8]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:20])=[N:11][N:12]3C=O)[N:7]=1.[F:35][CH2:36][CH2:37][OH:38].[H-].[Na+]>C1COCC1>[CH3:20][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:17])[C:8]=2[C:6]2[N:7]=[C:2]([O:38][CH2:37][CH2:36][F:35])[C:3]3[CH2:24][N:23]([C:25]4[CH:30]=[C:29]([CH:31]([CH3:32])[CH3:33])[CH:28]=[CH:27][C:26]=4[CH3:34])[CH2:22][CH2:21][C:4]=3[N:5]=2)[NH:12][N:11]=1
Reactant: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)ccc4c3c(C)nn4C=O)nc(Cl)c2C1
Reactant: OCCF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)ccc4[nH]nc(C)c34)nc(OCCF)c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-chloro-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-3,5-dimethyl-1H-indazole-1-carbaldehyde (30 mg, 0.063 mmol) in THF (3 mL) was added 2-fluoroethanol (16.2 mg, 0.25 mmol) and NaH (15.1 mg, 0.63 mmol, 60% in mineral oil). The mixture was stirred at room temperature for 4 h. LC-MS showed reaction complete. The reaction mixture was concentrated and the residue was partitioned between saturated aqueous NH4Cl solution and DCM. The layers were separated and the aqueous layer was extracted further with DCM. The organics were combined and concentrated. The residue was purified by FCC (0-100% EtOAc/heptane) to provide 2-(3,5-dimethyl-1H-indazol-4-yl)-4-(2-fluoroethoxy)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.47 (d, J=8.59 Hz, 1H), 7.34 (s, 1H), 7.15 (d, J=7.71 Hz, 1H), 7.06 (d, J=1.39 Hz, 1H), 6.92 (dd, J=1.52, 7.71 Hz, 1H), 4.71-4.81 (m, 2H), 4.67 (s, 2H), 4.13 (s, 2H), 3.33-3.39 (m, 2H), 3.05 (t, J=5.56 Hz, 2H), 2.88 (td, J=6.93, 13.80 Hz, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 1.98 (s, 3H), 1.25 (d, J=6.82 Hz, 6H); MS (ESE) m/z 474.4 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=2[O:27][CH2:28][O:29][CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:22][C:21]=2[O:27][CH2:28][O:29][CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCOc1cc(O)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reactant: BrCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc(OCc2ccccn2)ccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Methyl 3-cyclohexyl-2-[4-hydroxy-2-(methoxymethoxy)phenyl]-1H-indole-6-carboxylate was dissolved in DMF (0.17 M) and Cs2CO3 (1.05 eq) was added. The mixture was stirred for 20 min, then 2-bromomethylpyridine (1.05 eq) was added and the suspension was stirred at RT. After 4 h Cs2CO3 (0.3 eq) was added and the mixture was stirred overnight. Since the reaction was incomplete the mixture was warmed for 30 min to 35° C. The mixture was diluted with EtOAc and extracted with 1N aqueous HCl, sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The product was obtained as a beige amorphous solid (89%). (ES+) m/z 501 (M+H)+.
Reaction SMILES: [C:1]([NH2:7])([NH2:6])=[N:2][C:3]([NH2:5])=[S:4].Br[CH:9]1[CH2:14][CH:13]([CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][C:10]1=O.C(OCC)(=O)C>C(O)C>[CH:15]([CH:13]1[CH2:14][CH2:9][C:10]2[N:5]=[C:3]([NH:2][C:1]([NH2:7])=[NH:6])[S:4][C:11]=2[CH2:12]1)([CH3:17])[CH3:16]
Reactant: NC(=S)N=C(N)N
Reactant: CC(C)C1CCC(=O)C(Br)C1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)C1CCc2nc(NC(=N)N)sc2C1

Procedure:
2-imino-4-thiobiuret (5 mmol) is added accompanied by stirring to a solution of 2-bromo-4-isopropyl-cyclohexanone (5 mmol) in ethanol (10 ml) and the reaction mixture is then refluxed for 16 hours. After evaporating-off of the solvent ethyl acetate is added to the residue and the precipitated-out product is isolated by filtering off: tR 2.75 min (LC-1, one peak); ESI-MS (+/−): m/z 239.25 [M+H]+/237.24 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Br:13])[CH:7]=1)[CH3:2].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[C:8]([Br:13])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Reactant: BrCC1CC1
Product: CCOC(=O)Cc1ccc(OCC2CC2)c(Br)c1

Procedure:
Prepared according to the procedure described in Example 123, Step 1, using the following starting materials: (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester and (bromomethyl)cyclopropane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (808 mg), 1N aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (8 ml), and ethanol (8 ml) was stirred at room temperature for 3 hours, diluted with 1 N hydrochloric acid (4 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (709 mg, yield: 93%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-methanol (5:1, volume ratio).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[CH2:21][OH:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]1([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OCc1oc2ccccc2c1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1oc2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
Methanesulfonyl chloride (160 μL, 2.05 mmol) was added dropwise to a solution of (3-phenylbenzofuran-2-yl)methanol (367 mg, 1.64 mmol) and DIPEA (343 μL, 1.97 mmol) in anhydrous DCM (10 mL) at 0° C. Stirring at 0° C. was continued for 15 min, then the mixture slowly warmed to RT. After 2 h at RT, additional amounts of methanesulfonyl chloride (80 μL, 1.03 mmol) and DIPEA (172 μL, 0.99 mmol) were added and stirring continued for 1.5 h. The reaction mixture was diluted with DCM and the organic fraction washed with water, dried (Na2SO4) and concentrated in vacuo affording the title compound as an oil (443 mg, 89%). 1H NMR (DMSO-d6, 400 MHz): δ 7.71-7.64 (2H, m), 7.62-7.56 (4H, m), 7.52-7.41 (2H, m), 7.37-7.32 (1H, m), 4.98 (2H, s), 3.89 (3H, s)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([Cl:15])[CH:8]=[CH:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].[N+:16]([O-])([O-:18])=[O:17].[Na+]>S(=O)(=O)(O)O>[C:12]([NH:11][C:10]1[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]([Cl:15])=[C:8]([N+:16]([O-:18])=[O:17])[CH:9]=1)(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)Nc1ccc(Cl)cc1NC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A solution of 5 g (22 mmol) of 3,4-diacetamido-1-chlorobenzene in 50 ml of concentrated sulfuric acid was cooled to 0° C., and 1.9 g (8.5 mmol) of sodium nitrate were added a little at a time, and the mixture was stirred at room temperature for 15 minutes. It was then poured into ice-water, and the crude product was filtered off with suction and washed with water. A yield of 63% of the product was obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([S:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[CH3:22][C:23](N(C)C)=[O:24]>O1CCCC1>[C:23]([C:12]1[S:11][C:10]([S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)=[CH:14][CH:13]=1)(=[O:24])[CH3:22]
Reactant: FC(F)(F)c1cccc(Sc2cccs2)c1
Reactant: CC(=O)N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Sc2cccc(C(F)(F)F)c2)s1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(3-trifluoromethylphenylthio)thiophene (4.0 g) in dry tetrahydrofuran (30 ml) at -30° C. under nitrogen, was added dropwise n-butyllithium (9.2 ml, 2.5M) and the solution left to stir at -30° C. for 2 hours. Dimethylacetamide (2.8 ml) was then added dropwise and the reaction mixture stirred at -30° C. for a further hour, allowed to warm to room temperature and stirred over night. The reaction mixture was quenched with 2N HCl (100 ml), extracted with ether (2×100 ml), dried over MgSO4 and evaporated to give a brown oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using 30% ether-hexane to give a colourless oil which crystallised on standing.
Reaction SMILES: [CH2:1]([C:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2].C(=O)=O.CO.C(#N)C>>[CH2:1]([C@:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2]
Reactant: CCC1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Agent: O=C=O
Solvent: CC#N
Solvent: CO
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Yield: 29 %

Procedure:
3-Ethyl-1-(2-((4-(morpholin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Example 2 was resolved by SFC (column: CHIRALCEL OJH, 20 mmID×250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide/methanol/acetonitrile=660/170/170), and the compound having a longer retention time was recrystallized (hexane/ethyl acetate) to give the title compound (58 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[N:33](COCC[Si](C)(C)C)[CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:7][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][C@H:17]([CH:19]3[CH2:21][CH2:20]3)[CH3:18])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].C(O)(C(F)(F)F)=O>>[C:1]([CH2:3][C:4]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:33][CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][C@H:17]([CH:19]3[CH2:20][CH2:21]3)[CH3:18])=[O:15])=[N:12][CH:13]=2)[CH2:7]1)#[N:2]
Reactant: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1)C1CC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-{3-(Cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropylethyl]pyridine-2-carboxamide (0.350 g, 0.75 mmol) was dissolved in dichloromethylene (3 mL). To the solution was added TFA (1.5 mL). The mixture was stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure. The residue was dissolved in methanol (5 mL), and ethylenediamine (1.0 mL) was added. The mixture was stirred at room temperature overnight, and was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=467.3.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.[ClH:37].CCOCC>O1CCOCC1>[ClH:37].[NH:27]1[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:14]4=[CH:15][C:16]5[O:20][CH2:19][O:18][C:17]=5[CH:21]=[C:13]4[O:12][CH2:11]3)[C:2]2=[O:1])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C1N(CCC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate (0.94 g, 1.91 mmol) in dioxane (5.00 mL) was added 4.0 M HCl in dioxane (2.00 mL, 8.00 mmol). The mixture was stirred at ambient temperature for 30 min followed by the addition of anhydrous ether (40.0 mL). The precipitated white solid was filtered, washed with ether and dried to give the title compound (0.75 g, 91%): 1H NMR (300 MHz, CD3OD) δ 7.37 (t, 1H), 7.20-7.07 (m, 3H), 6.52 (s, 1H), 6.10 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.67 (d, 1H), 3.97-3.75 (m, 2H), 3.45-3.33 (m, 2H), 3.01-2.85 (m, 2H), 2.15-2.01 (m, 2H), 1.82-1.37 (m, 5H); 13C NMR (75 MHz, CD3OD) δ 179.8, 157.6, 150.4, 143.7, 143.4, 133.6, 130.3, 124.9, 124.8, 120.8, 110.3, 103.7, 102.9, 94.3, 81.4, 59.8, 45.2, 38.5, 34.4, 32.6, 29.8, 29.7; MS (ES+) m/z 393 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:30][CH2:31][CH:32]3[CH2:36][CH2:35][CH2:34][N:33]3[CH3:37])=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(O)cc1
Reactant: CN1CCCC1CCCl
Agent: Cl
Product: COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCN2C)cc1
Yield: 44.5 %

Procedure:
The title compound was prepared as described in Example 3.D, using 2-(4-fluorophenyl)-1-(4-hydroxybenzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (0.13 g, 0.36 mmol) and 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (0.079 g, 0.429 mmol) to provide the title compound (0.076 g, 45% yield): ES-MS (m/z) 475 [M+H]+.