Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH2:3][OH:4].[C:18](OC(=O)C)(=[O:20])[CH3:19].ClC1C=CC=C(C(OO)=[O:33])C=1>CO>[C:18]([O:4][CH2:3][CH:2]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:33])=[CH:9][C:8]=2[N:7]=[CH:6]1)[CH3:1])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CO)n1cnc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: CC(=O)OCC(C)n1cnc2c[n+]([O-])c3ccccc3c21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 13.1 g (0.058 mole) of beta-methyl-1H-imidazo[4,5-c]quinoline-1-ethanol and 35 mL of acetic anhydride was heated at about 100° C. for two hours. To this solution was added 350 mL of methanol and the solution was stirred for about 0.5 hour. The solution was evaporated in vacuo and the residue was added to a saturated sodium bicarbonate solution. The mixture was extracted with chloroform, the extracts were dried over magnesium sulfate and concentrated to a volume of about 150 mL. To this solution was added 15 g (0.07 mole) of meta-chloroperbenzoic acid. The mixture was stirred for one hour, then washed with chloroform, saturated sodium bicarbonate solution and water. The organic layer was then dried over magnesium sulfate and concentrated by evaporation in vacuo to provide 1-(2-acetoxy-1-methylethyl)-1H-imidazo[4,5-c]-quinolin5-oxide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.[N:52]1([CH2:56][CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:55][CH2:54][CH2:53]1>CN(C)C=O>[N:52]1([CH2:56][CH:57]2[CH2:62][CH2:61][N:60]([C:13]([NH:12][C:8]3[CH:7]=[C:6]([O:5][C:4]4[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]5([C:40]([NH:41][C:42]6[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=6)=[O:49])[CH2:39][CH2:38]5)=[O:36])=[C:2]([F:1])[CH:3]=4)[CH:11]=[CH:10][N:9]=3)=[O:14])[CH2:59][CH2:58]2)[CH2:55][CH2:54][CH2:53]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: C1CN(CC2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC(CN2CCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) was added 4-(azetidin-1-ylmethyl)piperidine dihydrochloride (85.2 mg), followed by stirring at room temperature for 16 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (21.9 mg, 48.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]([C:32]([NH2:34])=[O:33])=[N:18][CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[N:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.[N:35]1C=CC=C[CH:36]=1.N.C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl>[C:36]([C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:17]([C:32]([NH2:34])=[O:33])=[N:18][CH:19]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[N:21]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1)#[N:35]
Reactant: c1ccncc1
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2Br)CC1
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc([N+](=O)[O-])c4)cnc3C(N)=O)cc2C#N)CC1

Procedure:
To a mixture of 3-{[3-bromo-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (645 mg) and pyridine (3.87 mL) was added cuprous cyanide (219 mg), followed by heating and refluxing for 5 hours. Cuprous cyanide (328 mg) was further added thereto, followed by heating and refluxing for 15 hours. The reaction mixture was left to be cooled, and then a mixed solvent (10:1:0.1) of chloroform:methanol:28% aqueous ammonia was added thereto. A saturated aqueous sodium hydrogen carbonate solution was further added thereto, followed by stirring, and then the insoluble matter was separated by filtration. The filtrate was subjected to liquid separation, and then the organic phase was dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=1:0:0-20:1:0.1) to obtain 3-{[3-cyano-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (68 mg) as a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]3[C:24](=[O:40])[N:25]([CH2:27][C:28]4[C:29]([CH2:38][OH:39])=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=4)[N:26]=[C:20]3[C:19]=2[C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][N:21]3[C:24](=[O:40])[N:25]([CH2:27][C:28]4[C:29]([CH:38]=[O:39])=[N:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=4)[N:26]=[C:20]3[C:19]=2[C:41]2[CH:42]=[CH:43][N:44]=[CH:45][CH:46]=2)=[CH:16][CH:17]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2CO)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a stirring solution of oxalyl chloride (12 μL, 0.134 mmol) in CH2Cl2 (0.5 mL) cooled at −30° C. under argon was added anhydrous DMSO (19 μL, 0.268 mmol) over 5 min. After stirring at −30° C. for 15 min, the reaction mixture was cooled at −60° C., then a solution of 7-(4-chlorophenyl)-2-((2-(hydroxymethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (36 mg, 0.07 mmol) in CH2Cl2 (1.0 mL) was added over 5 min. After stirring at −60° C. for 30 min, triethylamine (72 μL, 0.54 mmol) was added, the reaction mixture was stirred at −60° C. for 30 min before warming up to room temperature. The mixture was partitioned between water and CH2Cl2. The aqueous layer was extracted with CH2Cl2 (10 mL×2), and the combined CH2Cl2 layers were washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (4 g) eluted with a gradient of ethyl acetate (50-100%) in hexanes to afford 25 mg of the title compound as a yellow foam. The product was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 80% B over 8 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 15 mg of the title compound as a yellow powder. HPLC/MS: retention time=2.76 min, [M+H]+=510.6.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][CH:4]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)[NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=2.Cl.[CH3:28][O:29][C:30](=[O:34])[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCOC(C)=O>[CH3:28][O:29][C:30](=[O:34])[CH2:31][CH2:32][NH:33][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([CH:4]([NH:5][C:6]2[CH:7]=[N:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[C:11]([CH3:16])[CH:10]=3)[CH2:3][CH:2]([CH3:26])[CH3:1])=[CH:25][CH:24]=1
Reactant: Cc1ccc2cc(NC(CC(C)C)c3ccc(C(=O)O)cc3)cnc2c1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2cnc3cc(C)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a solution of 4-[3-Methyl-1-(7-methyl-quinolin-3-ylamino)-butyl]-benzoic acid (44 mg, 0.13 mM) in DCM (1 mL) was added TEA (63.6 mg, 0.629 mM) and followed by 3-amino-propionic acid methyl ester hydrochloric acid (6) (26.4 mg, 0.189 mM) and then HBTU (57.3 mg, 0.151 mM). The reaction was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (2×2 mL). The organic layer was separated, dried over Na2SO4 and concentrated. The crude material was separated by a 12 g silica gel column with 10-100% EtOAc in heptane to afford desired product (49 mg, 90%). 1H NMR (500 MHz, CDCl3) 6 ppm 0.98 (d, J=6.10 Hz, 3H) 1.04 (d, J=6.34 Hz, 3H) 1.61-1.70 (m, 1H) 1.71-1.86 (m, 2H) 2.66 (t, 2H) 2.82 (s, 3H) 3.68-3.76 (m, 5H) 4.36 (d, J=4.88 Hz, 1H) 4.44-4.54 (m, 1H) 6.73 (d, J=2.20 Hz, 1H) 6.80 (t, J=5.49 Hz, 1H) 7.20 (d, J=8.29 Hz, 1H) 7.35 (d, J=8.54 Hz, 1H) 7.45 (d, J=8.29 Hz, 2H) 7.67 (s, 1H) 7.75 (d, 2H) 8.45 (d, J=2.44 Hz, 1H). LC-MS: 434.2 (M+1).
Reaction SMILES: C(OCC)(=O)C.Cl.[NH2:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([O:28][C:29]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1COc2ccccc2NC1=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1COc2ccccc2NC1=O)OCc1ccccc1

Procedure:
To a mixture of 100 ml of ethyl acetate and 50 ml of water is added 1.5 g of 3(S)-amino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride, and 1.5 ml of benzyloxycarbonyl chloride is added dropwise to the mixture at ice bath temperature with stirring. After stirring for 1 hour, the ethyl acetate layer separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue is added ethyl ether and the deposited crystals are collected by filtration to give 2 g of 3(S)-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one. This product is recrystallized from a mixture of ethyl acetate and ether to give colorless needles melting at 157°-159° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][NH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:3]1.[CH3:26][N:27]=[C:28]=[O:29]>N1C=CC=CC=1>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][C@@H:4]([CH2:18][N:19]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:28](=[O:29])[NH:27][CH3:26])[CH2:3]1
Reactant: COC(=O)CCNC[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: CN=C=O
Solvent: c1ccncc1
Product: CNC(=O)N(CCC(=O)OC)C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 60 °C

Procedure:
A mixture of 8.5 g of 6-methyl-8β-[N-(2-methoxycarbonylethyl)-aminomethyl]-ergoline (prepared as described in Example 1) and 2.95 ml of methyl isocyanate in 100 ml of pyridine was heated at 60° C. for one hour. After evaporating off the solvent, the residue was crystallized from methanol to give 8.5 of the title compound, m.p. 140°-142° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:29])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCN=C=O
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: CCCCNC(=O)NCCCn1c(CCOC)nc2c(N)nc3ccccc3c21

Procedure:
Using the general method of Example 149, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin4-amine (1.50 g, 5.01 mmol) was reacted with butyl isocyanate to provide 1.13 g of N- (3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl)-N′-butylurea as an off-white powder, m.p. 159-160° C. Analysis: Calculated for C21H30N6O2. 0.29H2O: %C, 62.47; %H, 7.63; %N, 20.82; Found: %C, 62.64; %H %N, 21.17.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:22]2C(=O)C3C(=CC=CC=3)C2=O)[C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.O.NN>CO>[NH2:22][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[C@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(c2ccc(F)c(Cl)c2)N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](C(N)c2ccc(F)c(Cl)c2)C1
Temperature: 60 °C
Yield: 72.3 %

Procedure:
A solution of 71a/71b (212.3 mg, 0.4626 mmol) in 1:1 THF:MeOH (2.3 mL, 0.2 M) was treated with hydrazine monohydrate (224.4 μL, 4.626 mmol) and heated to 60° C. overnight. The reaction was cooled to RT, and the solids were filtered off. The filtrate was concentrated to dryness and taken up in EtOAc (30 mL). The EtOAc solution was washed with saturated NaHCO3 (2×30 mL) and brine (1×30 mL). The organics were isolated, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with a 1-25% gradient of MeOH/3% NH4OH in DCM to afford 110 mg (72%) of 73a/73b as a clear oil containing approximately a 1:1 mixture of diastereomers.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25](O)([CH3:27])[CH3:26])[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[F:29][C:30]([F:41])([F:40])C1(COS(C)(=O)=O)CC1.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN1CCCC1=O.O.C(OCC)(=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3([C:30]([F:41])([F:40])[F:29])[CH2:27][CH2:26]3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: CC(C)(O)CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(CC2(C(F)(F)F)CC2)CC1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of N-cyclopropyl-N-[1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-4-oxazol-5-yl-benzamide (80 mg), methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester (269 mg), K2CO3 (81 mg), and potassium iodide (38 mg) in N-methyl-2-pyrrolidone (3 mL) is stirred at 100° C. for two days. After cooling to room temperature, ethyl acetate and water are added to the mixture. The organic phase is separated, dried over MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel [dichloromethane/7 M ammonia in methanol 9:1→7:3] and the crude product is purified by preparative HPLC to give the title compound. LC (method 3): tR=1.22 min; Mass spectrum (ESI+): m/z=434 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11]C)=[O:10])=[C:4]([F:14])[CH:3]=1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH:15]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])=[C:4]([F:14])[CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)C(C)c1ccc(N)cc1F
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C(=O)O)c1ccc(NC2CCCCC2)cc1F
Yield: 67.9 %

Procedure:
A solution of compound (7) (1.50 g, 7.6 mmol), cyclohexanone (1.57 mL, 15.2 mmol), and NaBH3CN (0.96 g, 15.2 mmol) in methanol (10 mL) and acetic acid (0.2 mL) was allowed to undergo conventional reactions, followed by the same reactions and treatments as those in Example 3. The obtained crude product was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (4:1) solution followed by conventional hydrolysis to give 1.37 g (65%) of compound (11b) of interest as brown powder.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[Cl-:1].[CH2:2]([N+:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: c1ccncc1
Reactant: O=C(CCl)c1ccccc1
Solvent: CC#N
Product: O=C(C[n+]1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 70 °C

Procedure:
Phenacylpyridinium chloride was prepared by reacting 424 grams chloroacetophenone with 322 ml pyridine by dropwise adding the pyridine to the former in 1400 ml acetonitrile at 65° C. A crystalline mass was obtained which was heated to 70° C. and allowed to cool to 10° C., then filtered and washed with 500 ml acetonitrile. The dried product (626.5g) had a melting point of 203-206° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].[CH3:19][C:20](C)([O-:22])[CH3:21].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:19][CH:20]1[CH2:21][O:22]1
Reactant: CC(C)(C)[O-]
Reactant: CC(CCc1ccccc1O)Cc1ccccc1
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(CCc1ccccc1OCC1CO1)Cc1ccccc1
Yield: 83 %

Procedure:
Following a procedure similar to that described in Example 1(a), 0.98 g of 2-(3-methyl-4-phenylbutyl)phenol (prepared as described in Preparation 13), 0.46 of potassium t-butoxide and 0.56 g of epibromohydrin were reacted in 10 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 1.0 g (yield 83%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:12]([O:26][S:27]([CH:30]([CH3:32])[CH3:31])(=[O:29])=[O:28])[CH:11]=2)=[CH:4][N:3]=1.[CH3:33][C:34]([O-:37])(C)C.[K+].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CN(C)C=O>[C:34]([O:25][C:22]1[CH:21]=[CH:20][C:19]([C:13]2[C:14]([O:16][CH2:17][CH3:18])=[CH:15][C:10]([CH2:9][C:5]3[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[CH:11][C:12]=2[O:26][S:27]([CH:30]([CH3:31])[CH3:32])(=[O:29])=[O:28])=[CH:24][CH:23]=1)(=[O:37])[CH3:33]
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)C)c1-c1ccc(O)cc1
Reactant: CC(C)(C)[O-]
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)C(C)C)c1-c1ccc(OC(C)=O)cc1
Yield: 26 %

Procedure:
Starting from propane-2-sulphonic acid 4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-4′-hydroxy-biphenyl-2-yl ester (example 15c) (137 mg; 0.30 mmol), potassium tert-butylate (42 mg; 0.37 mmol) and acetic anhydiide (0.028 ml; 0.30 mmol) in dimethylformamide (3.5 ml) at 0-5° C. (15 minutes) and then room temperature (3 hours), 39 mg (27%) 4′-(2,4-diamino-pyrimidin-5-ylmethyl)-6′-ethoxy-2′-(propane-2-sulphonyloxy)-biphenyl-4-yl acetate are obtained as a colourless powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](O)[CH:9]=[CH2:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=O)=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([S:18]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:10][CH:9]=[CH2:8])=[O:6])(=[O:20])=[O:21])=[CH:16][CH:17]=1
Reactant: NCCCC(=O)O
Reactant: C=CCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CCOC(=O)CCCNS(=O)(=O)c1ccc(C)cc1
Yield: 104.7 %

Procedure:
γ-Aminobutyric acid (25.8 g, 250 mmol), allyl alcohol (100 mL, 1.50 mol) and p-toluenesulfonic acid (48.5 g, 255 mmol) were suspended in 100 mL of toluene and the suspension was refluxed for 16 h under a water separator. Subsequently, the orange solution was concentrated under reduced pressure. Following complete crystallization of the residue, it was thoroughly washed with diethyl ether (4×300 ml). The product was obtained as a colorless solid (77.8 g, 99%).
Reaction SMILES: [C-]#[C-].[Na+].[Na+].COC1C=CC([C:13]2C=CS[C:14]=2[C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=O)=CC=1.CS(C)=[O:35]>>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]([C:20]2[S:21][CH:13]=[CH:14][CH:18]=2)([OH:35])[C:23]#[CH:22])=[CH:30][CH:29]=1
Reactant: CS(C)=O
Reactant: COc1ccc(-c2ccsc2C(=O)c2sccc2-c2ccc(OC)cc2)cc1
Agent: [C-]#[C-]
Agent: [Na+]
Product: C#CC(O)(c1ccc(OC)cc1)c1cccs1

Procedure:
Sodium acetylide (1.37 g, 33.5 mmol) suspended in dry DMSO (25 ml) was added to p-methoxyphenyl-thiophene-2-yl-ketone (4.8 g, 22 mmol) in portions with stirring under water bath cooling while bubbling acetylene gas. After addition, the reaction mixture was stirred at room temperature for 2 hours, poured onto crushed ice, acidified with 4 M hydrochloric acid until the pH was approximately 6. After extraction with methylene chloride (20 ml, then 2×10 ml), the mixture was dried over anhydrous sodium sulfate and filtered. Evaporation of the solvent gave an oil that was purified by flush chromatography on neutral alumina (activity III) using hexane/methylene chloride (2:1) as eluent. De-coloration with a small amount of charcoal followed by removal of solvent afforded the relatively clean 1-(4-methoxyphenyl)-1-(thiophene-2-yl)prop-2-yn-1-ol as yellow-brown oil.
Reaction SMILES: N1C=CC=CC=1.[C:7]([Cl:10])(Cl)=[O:8].ClCCCl.[CH:15]([NH:18][S:19]([Cl:22])(=[O:21])=[O:20])([CH3:17])[CH3:16]>O>[Cl:10][C:7]([N:18]([CH:15]([CH3:17])[CH3:16])[S:19]([Cl:22])(=[O:21])=[O:20])=[O:8]
Reactant: O=C(Cl)Cl
Reactant: CC(C)NS(=O)(=O)Cl
Solvent: O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)N(C(=O)Cl)S(=O)(=O)Cl
Temperature: 22 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
316.4 parts of pyridine are introduced at -10° C., whilst stirring, into a solution of 400 parts of phosgene in 2,500 parts of 1,2-dichloroethane. 630.4 parts of isopropylsulfamic acid chloride are then added at the same temperature and the reaction mixture is stirred for one hour at 22° C. Thereafter, the mixture is stirred for 8 minutes with 700 parts of water at 6° C. and pH 1. The organic phase is then separated off from the 2-phase mixture formed, and is filtered and subjected to fractional distillation. 763 parts (87% of theory) of N-chlorocarbonyl-N-isopropylsulfamic acid chloride, of boiling point 57°-62° C./0.11 mbar and nD25 =1.4749, are obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[N:6]([C:20](I)=[CH:21][N:22]=3)[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>>[CH:1]1([C:4]2[C:5]3[N:6]([C:20]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:21][N:22]=3)[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(-c2cc(C3CC3)c3ncc(I)n3c2)cc1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1cnc2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)cn12

Procedure:
Prepared from 8-cyclopropyl-3-iodo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (example C.25 step 5) (3.1 g, 7 mmol) and trimethylsilylacetylene (2.00 mL, 14 mmol) as described in example C.20 step 4. Obtained the title compound as an amorphous brown material (2.3 g, 79%). MS (ISP) 399.2 [(M+H)+].