Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:24]Br.O>CO>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH2:13][Br:24])[CH2:3]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrBr
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12

Procedure:
To a flask containing a solution of 3α-hydroxy-5β-pregnan-20-one (5.15 g, 16.5 mmol) in methanol (100 mL) was added a solution of bromine (1.1 mL) in methanol (30 mL) dropwise in such a rate to maintain the brown color of the bromine until this color was persistent. Then water (200 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined extracts were dried over Na2SO4. Removal of the solvent resulted in the product as a foamy white solid (6.63 g). Other 21-bromo-pregnan-20-ones (3β-ethynyl-3α-hydroxy-21-bromo-5β-pregnan-20-one, 3β-methyl-3α-hydroxy-21-bromo-5α-pregnan-20-one and 3α-hydroxy-3β-trifluoromethyl-12-bromo-5β-19-norpregnan-20-one) were synthesized using the same method.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([CH:8]1[NH:12][CH:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C:10]2([CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[S:9]1)[C:5]([OH:7])=[O:6].[C:34](Cl)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.P(=O)(O)(O)O>ClCCl>[CH2:16]([O:15][C:13]([CH:11]1[C:10]2([CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)[S:9][CH:8]([CH:4]([NH:3][C:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:5]([OH:7])=[O:6])[NH:12]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(C(=O)O)C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1
Agent: Cl
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)C1NC(C(=O)OCc2ccccc2)C2(CCN(c3ccccc3)CC2)S1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
9.1 g (0.0177 mole) of alpha-amino-4-benzyloxycarbonyl-8-phenyl-1-thia-3,8-diazaspiro[4.5]decane-2-acetic acid dihydrochloride (obtained in 5.3) are suspended in 150 ml of dichloromethane. After cooling to -20° C., 18,6 g (0.0668 mole) of trityl chloride are added all at once. While maintaining the temperature at about -20° C., the suspension is slowly treated over the course of 1 hour with 17.6 g (0.17 mole) of triethylamine in 100 ml of dichloromethane. The reaction mixture is stirred for 1 hour at a temperature of from -10 to -20° C. and then left to stand overnight in a refrigerator, whereafter it is poured onto an ice-water mixture (pH about 11) and neutralized to about pH 6 by the addition of 85% phosphoric acid. The aqueous phase is extracted three times with 100 ml of dichloromethane. The combined extracts are washed with water and dried over anhydrous sodium sulfate, followed by evaporation to dryness under high vacuum on a waterbath at a temperature of from 20° to 25° C. The 4-benzyloxycarbonyl-8-phenyl-alpha-tritylamino-1-thia-3,8-diazaspiro[4.5]-decane-2-acetic acid thus obtained is used, without further purification, in step 7.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH:23]=[CH:22][C:21]=1[NH:34][C:35](=[O:44])[NH:36][CH2:37][C:38]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:19][C:20]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)[CH2:30][CH2:29]2)=[O:27])[CH:23]=[CH:22][C:21]=1[NH:34][C:35](=[O:44])[NH:36][CH2:37][C:38]1([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39]1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: NC(=O)C1(CNC(=O)Nc2ccc(C(=O)N3CCNCC3)cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C1(CNC(=O)Nc2ccc(C(=O)N3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2F)CC1
Yield: 9.6 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.303 mmol, 102 mg), 1-((3-(2-fluoro-4-(piperazine-1-carbonyl)phenyl)ureido)methyl)cyclopropanecarboxamide (0.303 mmol, 110 mg) and potassium carbonate (0.303 mmol, 42 mg) were stirred in acetonitrile (2 ml) at room temperature for 4 hours. The reaction was concentrated under reduced pressure and the residue obtained was purified by silica chromatography eluting with dichloromethane increasing to dichloromethane:methanol (10%). Further purification by HPLC and SCX chromatography yielded the title compound (18 mg). MS (ESI) m/z 620.7 [M+H]+
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:42][CH3:43])=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([O:42][CH3:43])=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: COc1ccc(N)c2c1CN(C)C2=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(OC)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-4-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 205A). MS (ES+): m/z 610.25 (100) [MH+]; HPLC: tR=1.10 min (UPLC, purity).
Reaction SMILES: C1N(S(F)(F)[F:8])CCOC1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH2:26][CH:27](O)[CH2:28][N:29]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44]C)[CH:38]=3)[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[C:17]3[C:22]([C:23]=2[CH:24]=1)=[CH:21][C:20]([Br:25])=[CH:19][CH:18]=3.C(=O)(O)[O-]>C(Cl)Cl>[Br:25][C:20]1[CH:19]=[CH:18][C:17]2[N:16]([CH2:26][CH:27]([F:8])[CH2:28][N:29]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=3)[S:30]([C:33]([F:34])([F:35])[F:36])(=[O:32])=[O:31])[C:15]3[C:23]([C:22]=2[CH:21]=1)=[CH:24][C:12]([Br:11])=[CH:13][CH:14]=3
Reactant: CCOc1cccc(N(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)C(F)(F)F)c1
Reactant: FS(F)(F)N1CCOCC1
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1cccc(N(CC(F)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)S(=O)(=O)C(F)(F)F)c1
Reaction time: 8 h
Yield: 104 %

Procedure:
Morpho-Dast (14.0 ml, 115 mmol) was added to a solution of N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-1,1,1-trifluoro-N-(3-ethoxyphenyl)methanesulfonamide (20.6 g, 32.4 mmol) in anhydrous methylene chloride (315 ml) and stirred overnight. The solution, in a water bath at ambient temperature, was neutralized by dropwise addition of 375 ml saturated bicarbonate solution. The biphasic mixture was extracted with methylene chloride twice. The combined organics were dried over MgSO4, filtered and condensed to give 21.5 g of off-white foam in quantitative yield.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].I[CH2:12][CH2:13][OH:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH:1]([N:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:12][CH2:13][OH:14])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccccc1
Reactant: OCCI
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)N(CCO)c1ccccc1
Yield: 58.7 %

Procedure:
Compound 4a (617 mg, 4.6 mmol) was reacted with 2-Iodoethanol (0.54 mls, 6.9 mmol) and diisopropylethylamine (1.2 mls, 6.9 mmol) in ACN (20 mls) at 30° C. for 48 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane and EtOAc to provide the intermediate 4b (483 mg, 2.7 mmol, 59% yield) as a light brown oil. HRMS (ESI, positive) m/z calcd. for C11H18N1O1 [M+H]+: 180.13829, found: 180.13829. 1H NMR (400 MHz, CDCl3) δ 7.28-7.19 (t, J=8.0 Hz, 2H), 6.92-6.85 (d, J=8.2 Hz, 2H), 6.83-6.75 (t, J=7.3 Hz, 1H), 4.03-3.88 (hept, J=6.6 Hz, 1H), 3.70-3.62 (t, J=6.2 Hz, 2H), 3.34-3.24 (m, 2H), 1.19-1.12 (d, J=6.6 Hz, 6H).
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cccc1-c1ccccc1
Product: Clc1ncccc1-c1ccccc1
Yield: 17 %

Procedure:
Using the procedure given above in Example 1, 3-methyl-2(1H)-pyridone (VIII) was refluxed in phosphorus oxychloride followed by work-up to give a 17% yield of 2-chloro-3-methylpyridine (VI).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:31])[C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)=[C:4]([OH:32])[CH:3]=1.Br[CH:34]([CH3:37])[C:35]#[N:36]>>[C:35]([CH:34]([CH3:37])[O:32][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH3:31])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)#[N:36]
Reactant: CC(Br)C#N
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccc(F)cc1O
Product: CC(C#N)Oc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 49, from N-[4-(4-fluoro-2-hydroxy-phenyl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 48) and 2-bromopropionitrile (CAS RN 19481-82-4). Off-white solid (74%). MS (ESI): m/z =512.0 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.N1C=CC=CC=1>ClCCl>[CH2:19]([N:16]1[CH2:15][CH2:14][N:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][CH2:17]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
Methanesulfonyl chloride (0.91 mL, 11.7 mmol) was added to a cooled (0° C.) solution of 1-(2-aminophenyl)-4-benzylpiperazine (2.61 g, 9.8 mmol) and pyridine (0.95 mL, 11.7 mmol) in dichloromethane (30 mL) and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure and triethylamine (1.4 mL) was added. The mixture was azeotroped with xylene, diluted with ethyl acetate and washed with aqueous potassium carbonate (saturated, 3×). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (99:1) to give the title compound as yellow oil (2.83 g, 84%). δH (250 MHz, CDCl3) 7.88-7.80 (1H, br s), 7.51 (1H, dd, J 1.6, 8.0 Hz), 7.34-7.27 (5H, m), 7.25 (1H, dd, J 1.6, 7.5 Hz), 7.16 (1H, dt, J 1.6, 7.5 Hz), 7.07 (1H, dt, J 1.7, 7.6 Hz), 3.59 (2H, s), 3.04 (3H, s), 2.90-2.85 (4H, m), and 2.66-2.60 (4H, br s).
Reaction SMILES: [O-:1][N+:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[N:12]3[C@@H:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17][O:16][CH2:15][C:13]3=[N:14][C:4]=2[CH:3]=1.[NH4+:30].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH4+:2].[OH-:1].[NH2:30][C:3]1[C:4]2[N:14]=[C:13]3[CH2:15][O:16][CH2:17][C@H:18]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:12]3[C:5]=2[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H]1COCc2nc3c[n+]([O-])c4ccccc4c3n21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reaction time: 2 h

Procedure:
tert-Butyl 3-[(11S)-5-oxido-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (850 mg, 2.15 mmol) was dissolved in 25 mL of CH2Cl2 and treated with 3 mL of concentrated NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (451 mg, 2.37 mmol) was carefully added. Rapid stirring was continued for 2 hours. The reaction mixture was treated with 25 mL of CH2Cl2 and 25 mL of H2O. The layers were separated and the organic portion was washed with 2% Na2CO3 solution (3×25 mL), H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 4% methanol/CHCl3 with 0.4% concentrated NH4OH) gave tert-butyl 3-[(11S)-6-amino-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (734 mg) as an off-white foam.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][C:12]4[NH:13][C:14]5[C:19]([C:20]=4[CH:21]=3)=[CH:18][CH:17]=[CH:16][CH:15]=5)[O:6][N:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CN(C=O)C>[Cl:28][CH2:27][CH2:26][CH2:25][N:13]1[C:12]2[CH:11]=[N:10][C:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]=3)=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2
Reactant: c1ccc2c(c1)[nH]c1cnc(-c3nc(C4CC4)no3)cc12
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCCn1c2ccccc2c2cc(-c3nc(C4CC4)no3)ncc21
Yield: 63 %

Procedure:
The compound was synthesized by mixing (Compound 5) (1.0 g, 3.6 mmol), NaH (0.22 g, 4.3 mmol) and 1-bromo-3-chloropropane (0.68 g, 4.3 mmol)in DMF, in the same manner as illustrated in example 3, to give the title compound (0.76 g, 63%) as a white solid. M.p. 165°-169° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[N:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[N:23]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[C:30](Cl)(=[O:32])[CH3:31]>N1C=CC=CC=1.ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][C:22]2[N:23]=[C:24]([CH3:29])[CH:25]=[C:26]([CH3:28])[N:27]=2)=[CH:14][CH:13]=1)[C:30](=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NCc3nc4ccccc4[nH]3)cc2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(Cc1nc2ccccc2[nH]1)c1ccc(S(=O)(=O)Nc2nc(C)cc(C)n2)cc1
Yield: 30 %

Procedure:
18 mg (0.044 mmol) 4-[(1H-benzimidazol-2-ylmethyl)-amino]-N-(4,6-dimethylpyrimidin-2-yl)-benzenesulfonamide was dissolved in 2 ml of 15% pyridine in dichloromethane. Acetyl chloride (31 μl, 0.44 mmol) was diluted with 1 ml dichloromethane and solution was added to the reaction mixture. After three hours reaction mixture was washed with acidic water and organic layer was evaporated to dryness. Crystals were purified on silica using gradient elution (chloroform to 5% methanol in chloroform) to obtain white crystals with 30% yield. 1H NMR (DMSO-d6, 500 MHz): 7.97 (2H, m), 7.60 (2H, m), 7.48 (2H, m), 7.14 (2H, m), 6.68 (1H, s), 5.08 (2H, s), 2.18 (6H, s), 1.93 (3H, s); MS (ESI+): m/z 473 (M+Na)+, 451 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[CH:9]=[CH:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.[OH-:22].[Na+].OO.Cl>C(O)C>[NH2:1][C:2]1[C:3]2[N:4]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[CH:9]1[O:22][CH:10]1[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1
Reactant: [OH-]
Reactant: Cc1nc2c(N)c(C(=O)C=Cc3ccsc3)ccn2c1C
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2c(N)c(C(=O)C3OC3c3ccsc3)ccn2c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of 2.6 9 of 8-amino-2,3-dimethyl-7-[3-(3-thienyl)-1-oxo-2-propenyl]imidazo[1,2-a]pyridine in 80 ml of ethanol is treated successively with 5.2 ml of 6 N aqueous sodium hydroxide solution and 5 ml of 30% strength aqueous hydrogen peroxide solution, stirred at room temperature for 48 hours, poured onto 200 ml of ice water and adjusted to pH 7–8 with semisatd. aqueous hydrochloric acid. The mixture is then extracted three times with 100 ml of dichloromethane each time, the combined organic phases are washed once with saturated sodium thiosulfate solution and once with 100 ml of distilled water, the solvent is stripped off in vacuo and the residue is purified on silica gel (eluent:methylene chloride/methanol=100/3). 1.2 g of the title compound of m.p. 186–89° C. (diethyl ether) are obtained.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]=[N:22][N:23]=2)=[CH:15][CH:14]=1.C(N(CC)CC)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.CN(C)C=O>[O:20]1[CH:21]=[N:22][N:23]=[C:19]1[C:16]1[CH:17]=[CH:18][C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:14][CH:15]=1
Reactant: Brc1ccc(-c2nnco2)cc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1(C#Cc2ccc(-c3nnco3)cc2)CN2CCC1CC2
Temperature: 65 °C
Yield: 39.2 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (1.06 g), 2-(4-bromopbenyl)-1,3,4-oxadiazole (1.58 g), bis(triphenylphosphine)palladium (II) chloride (245 mg), copper (I) iodide (123 mg), triethylamine (7 ml) and dimethylformamide (14 ml) were heated at 65° C. under an atmosphere of argon for 4 hours. The triethylamine and DHF were removed by evaporation. An aqueous solution of sodium hydroxide (2M, 20 ml) was added to the residue and the mixture extracted with dichloromethane (3×30 ml). The organic extracts were combined, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in dichloromethane containing 1% ammonia (density 0.88 g/cm3) to give 3-[2-(4-[1,3,4-oxadiazol-2-yl]phenyl)ethynyl]-3-hydroxyquinuclidine (811 mg) as a solid, m.p. 229-230%; microanalysis, found: C, 67.9; H, 5.8; N, 14.2%; C17H17N3O3. 0.4 H2O requires: C, 67.5; H, 5.9; N, 13.9; NMR: 1.20-1.44(1H,m), 1.50-1.71(1H,m), 1.77-2.04(3H,m), 2.69(4H,t), 2.79-2.94(1H,d), 3.04-3.20(1H,d), 5.69(1H,s), 7.63(2H,d), 8.03(2H,d), 9.35(1H,s); m/z 296(M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:30]>>[C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([NH:18][CH:19]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[NH:21][C:20]2=[O:30])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCCC1
Reactant: NC1CCc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2CCc3ccccc3NC2=O)CCCCC1

Procedure:
Prepared from 1(t-butoxycarbonylamino)cyclohexanecarboxylic acid and 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step A) by the procedure described in Example 25, Step A. 1H NMR (200 MHz, CDCl3): 1.1-2.2 (m,19 H), 2.00 (m,2 H), 2.50 (m,2 H), 4.55 (m,1 H), 6.9-7.2 (m,4 H). FAB-MS: calculated for C22H31N3O4 401; found 402 (M+H,40%).
Reaction SMILES: [C:1]12([CH2:15][C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.Cl.O([NH2:20])C.N1C=CC=CC=1>CO.Cl>[C:1]12([CH2:15][CH:14]([NH2:20])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CC2(CCCCC2)Oc2ccccc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: NC1CC2(CCCCC2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 1A (3.022 g, 13.99 mmol) in methanol (50 mL) was added methoxylamine hydrochloride (1.17 g, 14.0 mmol) and pyridine (5.7 mL, 70.5 mmol). The mixture was stirred overnight at room temperature and was then evaporated in vacuo. The residue was partitioned between ethyl acetate and H2O, and the organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue thus obtained was dissolved in methanol (50 mL) and was hydrogenated (balloon) over 10% Pd-on-carbon in the presence of 4 drops of conc. HCl overnight at room temperature. After this time, the catalyst was filtered off (Celite), and the filtrate was evaporated in vacuo. The residue was taken up in ether (50 mL) and was extracted with 1N HCl (3×20 mL). These acidic extracts were then basified to pH 10 with 2N NaOH and were extracted with ethyl acetate (3×20 mL). The organic extracts were dried over Na2SO4, filtered and evaporated in vacuo to yield the title compound as a yellow oil, 880 mg (29%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.52 (m, 1H), 7.06 (m, 1H), 6.82 (td; J=7.4, 1.3 Hz; 1H), 6.69 (dd; J=8.1, 1.3 Hz; 1H), 3.83 (dd; J=11.1, 6.3 Hz; 1H), 2.08 (dd; J=13.5, 6.3 Hz; 1H), 1.90 (m, 1H), 1.74 (m, 2H), 1.31-1.57 (m, 8H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[Li]CCCC.[C:12]1([C:18]([CH2:20][CH2:21][C:22]#[CH:23])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1.CCCCCC>[OH:19][C:18]([CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:20][CH2:21][C:22]#[CH:23]
Reactant: C1CSCSC1
Reactant: C#CCCC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCCC(O)(c1ccccc1)C1SCCCS1
Reaction time: 1.25 h
Yield: 75 %

Procedure:
1,3-Dithiane (3.8 g, 31.6 mmol) was stirred in 120 mL of tetrahydrofuran at -40° C. under argon and 13.2 g (33 mmol) of 2.5M n-BuLi in hexane was added. After 10 minutes the temperature was adjusted to -20° C. and 1.25 hours later 2.27 g (14.36 mmol) of but-3-ynyl phenyl ketone was added as a solid. Stirring was continued for 20 minutes before placing in a freezer at -20° C. for 20 hours. The mixture was then poured onto water, the layers were separated, and the aqueous portion extracted with methylene chloride (3×30 mL). The combined organics were washed with brine, dried (MgSO4) and solvents evaporated at reduced pressure. The residue was chromatographed on 75 g silica (98:2, hexane:EtAc, then 4%, 10%, and 20% EtAc) to give 3.0 g (75%) of product.