Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=5)[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCOC(C)=O.CO.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:23][C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2cccc(CC3CCC=C3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(-c2cccc(CC3CCCC3c3nc(-c4ccccc4)c(-c4ccccc4)o3)c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84 %

Procedure:
A mixture of methyl 3′-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclopenten-1-yl]methyl}biphenyl-3-carboxylate (204 mg) and 10% Pd/C (wet) (50 mg) in EtOAc (3 ml) and MeOH (3 ml) was stirred under hydrogen atmosphere at room temperature for 14 hours. The catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc 12:1 to 6:1) to give methyl 3′-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}biphenyl-3-carboxylate (172.1 mg) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+].O.CCOC(C)=O>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][N:23]=[N+:24]=[N-:25])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(c2ccc(C(=O)CBr)cc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)CC1CCC(c2ccc(C(=O)CN=[N+]=[N-])cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
To a solution of {4-[4-(2-bromoacetyl)-phenyl]-cyclohexyl}-acetic acid ethyl ester (166 mg, 0.451 mmol) in acetone/water (4:1, v/v, 5 mL) is added NaN3 (44 mg, 0.676 mmol) and the mixture is stirred at ambient temperature for 2 h. Water (10 mL) is added and EtOAc is used to extract. The organic phase is dried with MgSO4, concentrated, and dried under high vacuum to give the title compound (154 mg): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05-1.16 (m, 2H) 1.20 (t, J=7.07 Hz, 3H) 1.40-1.49 (m, 2H) 1.84 (d, J=10.11 Hz, 4H) 1.76-1.87 (m, 1H) 2.17 (d, J=6.82 Hz, 2H) 2.48 (tt, J=112.25, 3.03 Hz, 1H) 4.08 (q, J=7.16 Hz, 2H) 4.45 (s, 2H) 7.25 (d, J=8.34 Hz, 2H) 7.76 (d, J=8.34 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:55][C:56]1[C:57]([C:62](O)=[O:63])=[N:58][CH:59]=[CH:60][CH:61]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH3:55][C:56]1[C:57]([C:62]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:13][CH2:14]2)=[O:63])=[N:58][CH:59]=[CH:60][CH:61]=1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: Cc1cccnc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccnc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (100 mg, 0.340 mmol) in DMF (5 ml) was added HOBT.H2O (52.0 mg, 0.340 mmol), HBTU (129 mg, 0.340 mmol), 3-methyl-2-pyridinecarboxylic acid (46.6 mg, 0.340 mmol) and DIPEA (0.178 ml, 1.019 mmol). The reaction mixture was stirred for 2 hours at room temperature. Reaction mixture was transferred to a 100 ml round bottom flask and was reduced to dryness in vacuo. The residue was dissolved in DCM (50 ml) and transferred to a separating funnel then was washed with saturated aq. NaHCO3 solution (5 ml), twice. The organic layer was collected and dried with dried magnesium sulphate. The solid was removed by filtration and the filtrate collected in a 250 ml round bottom flask and reduced to dryness in vacuo. The residue was then dissolved in 1.8 ml 1:1 MeCN/DMSO and purified by MDAP in 2 batches. The fractions containing desired product were combined in a 250 ml round bottom flask and reduced in vacuo to yield the title compound (91 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:31][CH3:32])=[CH:7][CH:6]=2.Br[CH2:34][CH2:35][O:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1[F:44].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:20][CH2:19][N:18]([CH2:34][CH2:35][O:36][C:37]3[C:38]([F:44])=[CH:39][CH:40]=[CH:41][C:42]=3[F:43])[CH2:17][CH2:16]1)=[CH:9][C:8]([O:31][CH3:32])=[CH:7][CH:6]=2
Reactant: Fc1cccc(F)c1OCCBr
Reactant: COc1ccc2ncc(Cl)c(CCCC3(C(=O)OCc4ccccc4)CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2ncc(Cl)c(CCCC3(C(=O)OCc4ccccc4)CCN(CCOc4c(F)cccc4F)CC3)c2c1
Temperature: 75 °C
Yield: 87.6 %

Procedure:
A mixture of 1.4 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]piperidine-4-carboxylate, 0.82 g of 1-(2-bromoethoxy)-2,6-difluorobenzene, 0.6 g of potassium iodide and 2 g of potassium carbonate in 100 cm3 of acetonitrile was heated for 18 hours at a temperature in the region of 75° C., with stirring and under an inert atmosphere. After cooling to a temperature in the region of 20° C., the reaction mixture was filtered and washed with three times 30 cm3 of acetonitrile. The filtrate was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height: 27 cm), eluting with ethyl acetate and collecting 50-cm3 fractions. Fractions 7 to 17 were combined and then concentrated to dryness under the above conditions. 1.65 g of benzyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,6-difluorophenoxy)ethyl]piperidine-4-carboxylate were obtained in the form of a thick yellow oil.
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([NH:10][C:11]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([CH3:19])[CH:14]=2)=[O:12])[CH:4]=1.[OH-].[Na+].Cl>CO>[F:9][C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][C:5]=1[NH:10][C:11]([C:13]1[N:17]([CH3:18])[N:16]=[C:15]([CH3:19])[CH:14]=1)=[O:12]
Reactant: COC(=O)Oc1ccc(F)c(NC(=O)c2cc(C)nn2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)Nc2cc(O)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83.8 %

Procedure:
To a solution of 3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-fluorophenyl methyl carbonate (448 mg, 1.46 mmol) in methanol (10 mL) was added 1N aqueous sodium hydroxide solution (2 mL, 2 mmol) under ice-cooling, and the mixture was stirred at room temperature for 40 min. Under ice-cooling, 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was recrystallized from diethyl ether/hexane to give the title compound (305 mg, 84%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.C([Li])CCC.CCCCCC.ClCC[I:37]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:37])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: ClCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1nc(N2CCOCC2)c2nc(I)n(C3CCCCO3)c2n1
Reaction time: 1.5 h

Procedure:
To a solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1.0 g, 3.1 mmol) and N,N,N′,N′-tetramethylenediamine (0.7 mL, 4.6 mmol) in anhydrous THF (23 mL) at −42° C. was added 2.5 M n-butyllithium solution in hexane (4.3 mL, 11.0 mmol) dropwise down the side of the reaction flask. The reaction was stirred at cold temperature and maintained for 1 h before 1-chloro-2-iodoethane (1.4 mL, 15 mmol) was introduced. Stirring was continued for 1.5 h period. LC-MS indicated the reaction had reached complete conversion to the desired product. The reaction mixture was subsequently quenched and worked up with sat. NH4Cl aqueous solution which was extracted with EtOAc (3 times), dried over MgSO4, filtered and concentrated in vacuo to give 4-(2-chloro-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1.4 g, 84% yield) determined by LC-MS to be >90% purity. MS (ESI+): m/z 450.1 (M+H+)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]([O:26]CC)=[O:25])=[CH:14]3)=[CH:6][CH:5]=1.[OH-].[Na+].O1CCCC1.Cl>O.C(O)C>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24]([OH:26])=[O:25])=[CH:14]3)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(COC)nc3)cc(OC(C)C)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C(=O)O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.5 %

Procedure:
A mixture of ethyl 5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indole-2-carboxylate (1.65 g), 1M aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at room temperature for 15 h. Water and 1M hydrochloric acid (10 mL) were added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (1.43 g, 93%) as a brown amorphous solid. MS 357 (MH+).
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Temperature: 0 °C
Yield: 386.9 %

Procedure:
The starting amine (5) (0.15 g, 0.12 mmol) and fluorescein isothiocyanate (FLITC) (0.056 g, 0.14 mmol) were dissolved in a mixture of DMF and CH2Cl2 (6 mL, 1:5 ratio) at room temperature. The reaction was cooled to 0° C., and then an excess amount of Et3N (66 μL, 0.48 mmol) was added dropwise. An orange colored precipitate was immediately formed and remained during the entire period of the reaction. After completion of the reaction, the insoluble precipitate was filtered off; and the solvent was removed under reduced pressure. The residue was diluted with CH2Cl2 (15 mL), washed with 1N HCl (2×15 mL) and H2O (2×15 mL). The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford 0.18 g (92%) of fluorescein-labeled guanidine (17) as an orange colored foam-shaped solid. 1H NMR (CD3OD): δ 8.20 (s, 1H, ArH), 7.86 (m, 1H, ArH), 7.22 (m, 2H, ArH), 6.64 (m, 3H, ArH), 6.56 (m, 2H, ArH), 3.86 (m, 2H, CH2NHCS), 3.66 (m, 12H, CH2O), 3.46 (m, 6H, CH2NHCO), 3.38 (m, 6H, CH2NH), 2.58 (m, 2H, CH2CO), 2.42 (m, 6H, CH2CO), 1.48 (s, 27H, t-Bu), 1.46 (s, 27H, t-Bu).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([C:18](O)=[O:19])[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:30].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:18]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17][CH2:16]2)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c2C1
Reactant: Nc1nc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)Nc3nc4ccccc4s3)c2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid (6.8 g) and benzo[d]thiazol-2-amine (5.52 g) in dichloromethane (80 mL) was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (9.4 g) and 4-dimethylaminopyridine (6 g). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (400 mL), washed with 5% aqueous HCl, water, and brine, and dried over Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22](O)[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[CH:11]=[N:10]1.[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([SH:38])[CH:33]=1.CCCCP(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:29][O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38][CH:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]3[N:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[N:10]=[CH:11][C:12]=3[CH:26]([CH3:27])[CH3:28])=[CH:17][C:18]=2[CH3:25])[CH3:23])[CH:33]=1
Reactant: COC(=O)c1cccc(S)c1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C(C)O
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(SC(C)c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)c1
Temperature: 0 °C
Yield: 53.4 %

Procedure:
To an ambient temperature solution of 1-{4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-ethanol (75 mg, 1.78 mmol) in toluene (20 mL) are added 3-Mercapto-benzoic acid methyl ester (299 mg, 1.78 mmol) and tri-N-butylphosphine (668 μL, 2.68 mmol). The reaction mixture is cooled to 0° C. 1,1′-(Azocarbonyl)-dipiperidine (676 mg, 2.68 mmol) is added and the reaction mixture is warmed to room temperature overnight. The reaction mixture is concentrated and the residue is chromatographed (40 g SiO2, 0% to 30% EtOAc/Hexanes) to yield the title compound (541 mg, 54%). 1H NMR (400 MHz, CDCl3) δ 8.00-7.98 (m, 1H), 7.99 (t, 1H, J=1.8 Hz), 7.87 (dt, 1H, J=4.6, 2.5 Hz), 7.70 (s, 1H), 7.43-7.39 (m, 3H), 7.32-7.22 (m, 3H), 6.61-6.54 (m, 2H), 4.79 (s, 2H), 4.53 (q, 1H, J=7.0 Hz), 3.90 (s, 3H), 2.99 (sept, 1H, J=6.6 Hz), 2.32 (s, 3H), 1.56 (d, 3H, J=6.9 Hz), 1.30 (d, 6H, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:22](=[O:23])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(CC(=O)Nc2ccc3sc(C)nc3c2Cl)c1
Yield: 44 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 3-methoxyphenylacetyl chloride (47 μL, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave N-(4-chloro-2-methyl-benzothiazol-5-yl)-2-(3-methoxy-phenyl)-acetamide (40 mg, 0.11 mmol, 48% yield) as a white powder after crystallisation in hexane/DCM.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH3:25][NH2:26].Cl>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:26][CH3:25])[S:7]1(=[O:24])=[O:23]
Reactant: O=S1(=O)N(CCCCBr)Cc2ccccc2N1c1ccccc1F
Reactant: CN
Agent: Cl
Product: CNCCCCN1Cc2ccccc2N(c2ccccc2F)S1(=O)=O
Yield: 82 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(4-bromobutyl)-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.11 g, 0.26 mmol) was reacted to methylamine and then treated with HCl to provide 4-[1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine (0.078 g, 82%) as a white solid:
Reaction SMILES: [F:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]([F:6])([CH3:5])[CH3:4].Cl>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[F:1][CH:2]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([CH:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[OH:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]([F:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)C(Cc1cccc(C(F)C(C)(C)F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(C(F)C(C)(C)F)c1)C(O)c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
While stirring zinc chloride (2.37 g, 17.4 mmol) in diethyl ether (50 ml), sodium borohydride (1.32 g, 34.8 mmol) was added at room temperature, and the mixture was stirred as it was for 2 hrs. The insoluble material in the mixture was removed by filtration and washed with diethyl ether to give a solution of zinc borohydride in diethyl ether. A solution of ethyl 2-[3-(1,2-difluoro-2-methylpropyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate(3.412 g, 8.695 mmol) in diethyl ether (20 ml) was added to the obtained solution under ice-cooling, and the mixture was stirred as it was for 20 min. To the reaction solution was added dilute hydrochloric acid by small portions to decompose excess zinc borohydride, and the mixture was extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give the objective substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCC
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 55 °C
Reaction time: 6 h
Yield: 109.1 %

Procedure:
To a solution of 3-bromobenzaldehyde (30.3 g) and 1-undecyne (29.5 g) in triethylamine (120 ml) was added bis(triphenylphosphine)palladium(II)chloride (1.9 g) followed by copper(I) iodide (0.25 g). The mixture was stirred in the dark at 55° C. for 6 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to yield 45.8 g of 3-(1-undecynyl)benzaldehyde, as an oil.
Reaction SMILES: [CH2:1]([N:5]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:11]=1[O:19][CH3:20])[C:6]([CH2:8][NH2:9])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:21][O:22][C:23]([CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35](O)=[O:36])=[O:24]>>[CH2:1]([N:5]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([CH3:18])=[CH:12][C:11]=1[O:19][CH3:20])[C:6]([CH2:8][NH:9][C:35]([C:27]1[N:26]([CH2:25][C:23]([O:22][CH3:21])=[O:24])[C:34]2[C:29]([CH:28]=1)=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:36])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)Cn1c(C(=O)O)cc2ccccc21
Reactant: CCCCN(C(=O)CN)c1c(OC)cc(C)cc1OC
Product: CCCCN(C(=O)CNC(=O)c1cc2ccccc2n1CC(=O)OC)c1c(OC)cc(C)cc1OC
Yield: 90 %

Procedure:
This product is prepared according to the process described in EXAMPLE 1 from [butyl(2,6-dimethoxy-4-methylphenyl)carbamoyl]methylamine and 1-(methoxycarbonylmethyl)-2-indolecarboxylic acid; M.p.=139° C.; Yield: 90%.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[CH2:28][N:14]3[C:15](=[O:27])[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:13]3[CH2:12]2)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CO>CO>[OH:10][C@@H:11]1[CH2:28][N:14]2[C:15](=[O:27])[CH2:16][CH2:17][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:19][C@@H:13]2[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](O)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To tert-butyl (8S,9aS)-8-[(4-nitrobenzoyl)oxy]-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (495 mg, 0.291 mmol, Part A) in methanol (8 ml) was added potassium carbonate (98 mg, 0.708 mmol). The mixture was stirred at room temperature for one hour, and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then ethyl acetate/methanol=10:1) to give 280 mg (88% yield) of the title compound as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (s, 9H), 1.61 (m, 1H), 2.24 (m, 1H), 2.38 (m, 1H), 2.58 (m, 1H), 2.80-3.15 (m, 2H), 3.23 (dd, J=13, 4 Hz, 1H), 3.42 (dd, J=13, 4 Hz, 1H), 3.81 (m, 1H), 3.98 (m, 2H), 4.18 (m, 1H), 5.02 (t, J=4 Hz, 1H); MS (ESI) m/z 271.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH3:11].[N-:13]=[N+:14]=[N-:15].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]([CH3:11])=[N:15][N:14]=[N:13]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(I)cc1F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: Cc1nnnn1-c1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A suspension of N-(2-fluoro-4-iodo-phenyl)-acetamide (5 g, 18.24 mmol) in acetonitrile (100 mL) was cooled to 0° C. and then treated with sodium azide (3.56 g, 54.7 mmol). The reaction mixture was then treated with trifluoromethanesulfonic anhydride (13.6 g, 48 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (100 mL) and water (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (3.45 g, 62%) as a white solid: mp 122-124° C.; EI-HRMS m/e calcd for C8H6FIN4 (M+) 303.9621, found 303.9615.