Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[CH2:4]1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:20][C:18]([C@H:4]1[C@H:3]([CH2:2][F:1])[CH2:7][N:6]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5]1=[O:16])=[O:19])[CH3:22]
Reactant: C[C@H](c1ccccc1)N1C[C@@H](CF)CC1=O
Reactant: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C(=O)N([C@H](C)c2ccccc2)C[C@H]1CF
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
To a solution of (4S)-4-fluoromethyl-1-[(1R)-1-phenylethyl]-2-pyrrolidone (7.59 g, 34.3 mmol) and ethyl chloroformate (3.92 mL, 41.2 mmol) in tetrahydrofuran (150 mL), lithium bistrimethylsilyl amide (75.5 mL, 75.5 mmol, 1.0M solution in tetrahydrofuran) was added at 0° C., and the mixture was stirred the same temperature for 20 minutes. Saturated aqueous solution of ammonium chloride (200 mL) was added to the reaction mixture at the same temperature, and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 5:1→2:3) to obtain 8.50 g (85%) of the title compound as a pale yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][CH2:31][C:32]([O:34]CC)=[O:33])=[CH:17][CH:18]=2)[C:13]1=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:17][CH:18]=2)[C:13]1=[O:37])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CNc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCn1c2c(c3ccc(NCC(=O)O)cc3c1=O)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 785.3 %

Procedure:
The ester 39 (0.1 g, 0.02 mmol) was dissolved in MeOH-THE (10+10 mL) and aq NaOH (4 N, 5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 4 h. The solvent was removed on a rotary evaporator and the residue washed with 1 N HCl (30 mL) and extracted with CHCl3 (2×50 mL). The extract was dried over Na2SO4 and concentrated to afford pure 42 (0.075 g, 80%) which was obtained as a brown solid: mp 190-192° C. IR (KBr) 3350, 2973, 1692, 1645, 1619, 1578, 1520, 1364, 1164, 666 cm−1; 1H NMR (DMSO-d6, 300 MHz) δ 8.30 (d, J=8.7 Hz, 1H), 7.59 (m, 1H), 7.45 (m, 2H), 7.39 (m, 1H), 7.21 (dd, J=2.4, J=8.7 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.07 (m, 1H), 4.40 (m, 2H), 3.90 (s, 2H), 3.09 (m, 2H), 1.86 (m, 2H), 1.33 (s, 9H); ESIMS (m/z, relative intensity) 500 (MNa+, 100); HRESIMS calcd for C26H27N3O6Na, 500.1798 (MNa+). found 500.1806 (MNa+); HPLC purity: 95.5% (MeOH—H2O, 75:25).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([F:39])=[C:14]([C@:16]([NH:31]S(C(C)(C)C)(=O)=O)([CH3:30])[C:17]([F:29])([F:28])[C:18]([CH3:27])([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:19])[CH:15]=1.CCOC(C)=O>ClCCl.CCCCCCC>[NH2:31][C@@:16]([C:14]1[CH:15]=[C:10]([Br:9])[CH:11]=[CH:12][C:13]=1[F:39])([CH3:30])[C:17]([F:28])([F:29])[C:18]([CH3:27])([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:19]
Reactant: CCOC(=O)COC(C)(C)C(F)(F)[C@](C)(NS(=O)(=O)C(C)(C)C)c1cc(Br)ccc1F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)COC(C)(C)C(F)(F)[C@](C)(N)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
Dropwise addition of TRIFLUOROMETHANESULFONIC ACID in CH2Cl2 0.25 M (225 ml, 56.3 mmol, Eq: 3) to a solution of (R)-ethyl 2-(4-(5-bromo-2-fluorophenyl)-4-(1,1-dimethylethylsulfonamido)-3,3-difluoro-2-methylpentan-2-yloxy)acetate (RO5545483-000-005) (10 g, 18.8 mmol, Eq: 1.00) in Dichloromethane (188 ml) at 0° C. this reaction mixture was stirred at room temperature for 30 minutes Extracted with sat NaHCO3, CH2Cl2, dried over Na2SO4, filtered off, evaporated, dried in HV to give a brown oil (8.8 g; 114%) The residue was chromatographed, 50 g SiO2 (Flashmaster) with EtOAc 0%-50% in heptane to give (R)-ethyl 2-(4-amino-4-(5-bromo-2-fluorophenyl)-3,3-difluoro-2-methylpentan-2-yloxy)acetate (6.85 g, 16.6 mmol, 88.5% yield) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1>C(O)(=O)C.O=[Pt]=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]([NH2:10])=[O:9]
Reactant: Cc1cccnc1C(N)=O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: C[C@H]1CCCN[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
A mixture of 3-methylpicolinamide (2.23 g, 16.4 mmol) and PtO2 (0.18 g, 0.8 mmol) in acetic acid (55 mL) was placed in a Parr shaker type hydrogenation apparatus, pressurized to 4.70 bar with H2 and maintained at rt for 7 h. The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to a solid. A mixture of this crude solid and DCM and solid Na2CO3, were stirred at rt overnight. The resulting suspension was filtered and the filtrate was concentrated in vacuo to provide rac-cis-3-methylpiperidine-2-carboxamide as a white solid (2.0 g, 86% yield). 1H NMR (CDCl3, 400 MHz) δ 6.51 (brs, 1H), 5.32 (brs, 1H), 3.37 (d, 1H), 3.14-3.10 (m, 1H), 2.70-2.63 (m, 1H), 2.33-2.28 (m, 1H), 1.73-1.58 (m, 4H), 1.42-1.39 (m, 1H), 1.00 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.ClCCOC1C=CC(C=O)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)[C:9]2=[O:13])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCCCCl)cc1
Reactant: O=C1NCCN1c1ccc(Cl)cc1
Agent: O=Cc1ccc(OCCCl)cc1
Product: O=Cc1ccc(OCCCN2CCN(c3ccc(Cl)cc3)C2=O)cc1
Yield: 34 %

Procedure:
A reaction was conducted in a manner similar to Referential Example 13 by using 1-(4-chlorophenyl)-2-imidazolidinone (Compound No. 2) in place of 1-(4-ethylphenyl)-2-imidazolidinone (Compound No. 1) and 4-(3-chloropropoxy)benzaldehyde in lieu of 4-(2-chloroethoxy)benzaldehyde, whereby the title compound was obtained in a yield of 34%.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][CH2:26][OH:27])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:25][CH2:26][OH:27])[CH:13]=[N:12]2)[C:8]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C@@H:32]3[CH2:31][O:30][C:29]([CH3:41])([CH3:28])[O:33]3)[N:36]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2CCO)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4ccccc4CCO)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-{4-[2-(2-hydroxy-ethyl)-phenoxy]-6-oxo-6H-pyridazin-1-yl}-propionic acid (Intermediate 79) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded impure 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-{4-[2-(2-hydroxy-ethyl)-phenoxy]-6-oxo-6H-pyridazin-1-yl}-propionamide as a white foam as a mixture of diastereomers (0.70 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]#[C:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: [H][H]
Reactant: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(C(F)(F)F)cc2)C3=O)CC1
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CCN(CCCc2cc(Cl)c3c(c2)CN(Cc2ccc(C(F)(F)F)cc2)C3=O)CC1
Yield: 27 %

Procedure:
A mixture of 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.125 g, 0.27 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.034 g, 30%). 1H NMR (300 MHz, CDCl3): 5 (ppm) 1.79 (m, 2H), 2.23-2.60 (m, 13H), 2.64 (t, 2H), 4.18 (s, 2H), 4.80 (s, 2H), 7.08 (s, 1H), 7.24 (s, 1H), 7.42 (d, 2H), 7.59 (d, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH:8]2[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([O-:3])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:25](=[O:27])[CH3:26])[CH:8]2[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2Nc3ccccc3-c3c([N+](=O)[O-])cnn32)cc1
Product: COc1ccc(C2N(C(C)=O)c3ccccc3-c3c([N+](=O)[O-])cnn32)cc1
Yield: 99 %

Procedure:
1-Nitro-5-(p-methoxyphenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline is reacted with acetic anhydride as described in Example 27 to give 1-nitro-5-(p-methoxyphenyl)-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline with a yield of 99%. M.p.: 153°-154° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:35]=[N:36][C:37]([NH:40][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nn2)CC1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nn3)nc2n1C1CCCC1
Yield: 41.2 %

Procedure:
Following General Procedure D, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.68 mmol) and 4-(6-amino-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (210 mg, 0.75 mmol) to give 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (150 mg, 46%). MS (ESI) m/z 536.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:46]1([NH:51][C:52]2[CH:57]=[CH:56][C:55]([S:58]([O:61][C:62]3[CH:71]=[CH:70][C:65]4[NH:66][C:67]([NH2:69])=[N:68][C:64]=4[CH:63]=3)(=[O:60])=[O:59])=[CH:54][CH:53]=2)[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C)C=O>[CH:46]1([NH:51][C:52]2[CH:57]=[CH:56][C:55]([S:58]([O:61][C:62]3[CH:71]=[CH:70][C:65]4[NH:66][C:67]([NH:69][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:68][C:64]=4[CH:63]=3)(=[O:59])=[O:60])=[CH:54][CH:53]=2)[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: Nc1nc2cc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(NC4CCCC4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.3 mg of N-(tert-butoxycarbonyl)glycine, 25 mg HBTU and 12 μl diisopropylethylamine were taken up in 0.4 ml dimethylformamide. Reaction mixture was stirred at room temperature for one hour and 5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-ylamine was added in 0.2 ml dimethylformamide. Reaction mixture was then stirred at room temperature for 24 hours. Solvent was evaporated in a Jouan model RC 10.10 centrifuge evaporator and title compound was solubilised in 0.5 ml dimethylsulfoxide for LCMS trigged purification yielding 2.4 mg of N-[5-(4-cyclopentylaminophenylsulfonyloxy)-1H-benzimidazole-2-yl]-tert-butoxycarbonylglycineamid. (LC/MS analysis: retention time=3.87 min., mass spectrum: 530.38, [M+H]+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.Cl.[CH3:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][N:48]=1)[C:43](Cl)=[O:44]>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][N:19]([C:43]([C:42]5[CH:46]=[CH:47][N:48]=[C:40]([CH3:39])[CH:41]=5)=[O:44])[CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:6][CH:5]=1
Reactant: Cc1cc(C(=O)Cl)ccn1
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccnc(C)c3)CC4)nc12
Yield: 5007.6 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.5 ml tetrahydrofurane were added at 0–4° C. 0.37 ml N-ethyldiisopropylamine and 0.19 mg 2-methyl-isonicotinoyl chloride hydrochloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with ethylacetate/methanol 9:1 to yield 0.025 g (50%) [2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-(2-methyl-pyridin-4-yl)-methanone as yellow solid; MS (ISP): m/e=505 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][CH2:30][N:46]3[CH2:45][CH2:44][C:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CN2CC(CCCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(CN2CC(CCCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the method of example 3.3 using 3--[3-(3,4-dichloro-phenyl)-1(3,4,5-trimethoxy-benzyl)-5-oxo -pyrrolidin-3-yl]-propyl-methanesulfonate (5 mmol) and 4-phenyl -piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:27])=[O:26])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N)c2c(-c3ccccc3)c(C)sc2n1
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2c(-c3ccccc3)c(C)sc2n1
Yield: 19.1 %

Procedure:
Following the general method as outlined in Example 28, starting from 2,6-dimethyl-3-phenylthieno[2,3-b]pyridin-4-amine (97 mg, 0.381 mmol) (Description 10) and benzenesulfonyl chloride (135 mg, 0.763 mmol), the title compound (28.7 mg) was isolated. LCMS (A) m/z: 395 [M+1]+, Rt 0.96 min (basic), Rt 1.39 min (acidic).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].C[S+](C)(C)=[O:10].C(C1(C2C=C(F)C=C[C:19]=2[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[C:34]2([C:37]#[N:38])[CH2:36][CH2:35]2)=O)CC1)#N>O>[C:37]([C:34]1([C:28]2([C:27]3[CH:25]=[CH:19][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:29][O:10]2)[CH2:35][CH2:36]1)#[N:38]
Reactant: C[S+](C)(C)=O
Reactant: N#CC1(c2cc(F)ccc2C(=O)c2ccc(F)cc2C2(C#N)CC2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(C2(c3ccc(F)cc3)CO2)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
130 ml of abs. DMSO are slowly added dropwise at 10° C. to 6.6 g (0.22 mol) of sodium hydride (80% in oil) and 34.2 g (0.16 mol) of trimethylsulphoxonium iodide. The mixture is stirred for one hour at 20° C. and then 26.3 g (0.14 mol) of 1-cyanocyclopropyl-4-fluorophenyl ketone (compound II-2, Example 19, dissolved in 65 ml of abs. DMSO) are added dropwise. The mixture is stirred for 14 h at 20° C. The solution is poured into water and the mixture is extracted with ethyl acetate. The combined organic phases are washed with H2O and dried over Na2SO4, and the solvent is evaporated in vacuo. The residue is chromatographed on silica gel and 15 g (54% of theory) of 2-(1-cyanocyclopropyl)-2-(4-fluorophenyl)oxirane are obtained in the form of a colorless oil after evaporating the solvent, 1H--NMR (CDCl3):
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:22]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C:23]([CH2:25][CH2:26][C:27]([NH:29][CH2:30][CH2:31][NH:32][C:33](=[S:50])[NH:34][CH2:35][CH2:36][NH:37][C:38](=[S:49])[NH:39][CH2:40][CH2:41][NH:42][C:43](=[S:48])[NH:44][CH2:45][CH2:46][NH2:47])=[O:28])=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[CH3:65][N:66]=[C:67]=[S:68]>C(Cl)Cl>[CH2:51]([N:22]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:23]([CH2:25][CH2:26][C:27]([NH:29][CH2:30][CH2:31][NH:32][C:33](=[S:50])[NH:34][CH2:35][CH2:36][NH:37][C:38](=[S:49])[NH:39][CH2:40][CH2:41][NH:42][C:43](=[S:48])[NH:44][CH2:45][CH2:46][NH:47][C:67](=[S:68])[NH:66][CH3:65])=[O:28])=[O:24])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCC(=O)NCCNC(=S)NCCNC(=S)NCCNC(=S)NCCN
Reactant: CN=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCC(=O)NCCNC(=S)NCCNC(=S)NCCNC(=S)NCCNC(=S)NC
Reaction time: 0.25 h
Yield: 51 %

Procedure:
Triethylamine (1.38 mmol, 0.19 ml) was directly added to the amine (14) (0.23 mmol, 0.224 g) obtained in the preceding stage and the reaction mixture was kept under stirring for 15 minutes. Then, CH2Cl2 (2.3 ml) and methylisothiocyanate (0.46 mmol, 0.034 g) were added and the reaction mixture was left at room temperature under stirring for 12 hours. The mixture was then evaporated and purified by flash chromatography (100% ethyl acetate followed by ethyl acetate/methanol 95:5). 109 mg of DT-4TU were thus obtained (yield: 51%).
Reaction SMILES: [OH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH:20]1[CH2:19][CH2:18][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([C:4]3[N:3]=[C:2]([OH:1])[N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH:5]=3)=[CH:16][CH:15]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cc4nccn4c(O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1nc(-c2ccc(C3CCNCC3)cc2)cc2nccn12
Yield: 78.8 %

Procedure:
To a flask charged with tert-butyl 4-(4-(5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)phenyl)piperidine-1-carboxylate (1.75 g, 4.44 mmol) in 40 mL of dichloromethane was added 2,2,2-trifluoroacetic acid (15 mL, 195 mmol) at ambient temperature for 3 hours. The solvent was concentrated under reduced pressure and the resulting crude was taken up in methanol (10 mL) and to it was added aqueous saturated sodium bicarbonate slowly. The resulting solid was collected by means of vacuum filtration and was dried overnight on high vacuum. This solid was triturated with water (50 mL) and solids were collected by means of vacuum filtration and dried on high vacuum to afford 7-(4-(piperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidin-5-ol (1.03 g, 3.50 mmol, 78.9% yield). MS (apci) m/z=295.1 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][S:29]([C:32]1[S:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[CH:33]=1)(=[O:31])=[O:30].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([S:17](=[O:19])(=[O:18])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][S:29]([C:32]3[S:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[CH:33]=3)(=[O:31])=[O:30])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(S(=O)(=O)Cl)cc2C1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2sc(S(=O)(=O)Nc3ccccc3NS(=O)(=O)c3cc4ccccc4s3)cc2C1
Yield: 312.3 %

Procedure:
2-[2-(Benzo[b]thiophene-2-sulfonylamino) -phenylsulfamoyl]-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (280 mg) was prepared by using 2-chlorosulfonyl-6,7-dihydro-4H-thieno[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.049 g, 0.148 mmol) and benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide (0.045 g, 0.148 mmol, prepared as in Example 1) using pyridine in DCM following procedure as in Example 2.
Reaction SMILES: CN(C)CCN(C)C.[CH2:9]([Li:13])[CH2:10][CH2:11][CH3:12].[F:14][C:15]1([F:24])[O:19][C:18]2C=CC=C[C:17]=2[O:16]1>C1(C)C=CC=CC=1.CCCC>[F:14][C:15]1([F:24])[O:19][C:18]2[CH:12]=[CH:11][CH:10]=[C:9]([Li:13])[C:17]=2[O:16]1
Reactant: [Li]CCCC
Reactant: FC1(F)Oc2ccccc2O1
Agent: CN(C)CCN(C)C
Solvent: Cc1ccccc1
Solvent: CCCC
Product: [Li]c1cccc2c1OC(F)(F)O2

Procedure:
39.3 g (339 mmol) of N,N,N',N'-tetramethylethylenediamine are added dropwise under a nitrogen atmosphere at from -15° to -10° C. to 137.8 g (409 mmol) of n-butyllithium solution (19.0% in toluene). The resulting reaction mixture is added dropwise at from -15° to -10° C. under a nitrogen atmosphere to a solution of 53.3 g (337 mmol) of 2,2-difluoro-1,3-benzodioxole in 46 ml of toluene, n-butane being formed in addition to the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][Br:10])=[C:2]([I:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)cc1I
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(I)c1
Yield: 78.8 %

Procedure:
A solution of 23.6 g of 2-iodo-4-fluorotoluene in 50 ml of tetrachloromethane was treated with 0.2 g of dibenzoyl peroxide and 19.6 g of N-bromosuccinimide. The mixture was then refluxed for 6 hours and illuminated by a 200 W bulb. After cooling, the spearated succinimide was filtered off and washed with 15 ml tetrachloromethane. The filtrate was evaporated and the residue distilled. There was obtained 24.8 g of 4-fluoro-2-iodobenzyl bromide with a b.p. of 130°-140° C./20 Torr. The product crystallized on standing and a sample recrystallized from petroleum ether; m.p. 71°-73° C.