Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9])[CH3:2].[C:51]([O:54][CH2:55]Cl)(=[O:53])[CH3:52].C(N(CC)CC)C>C1COCC1>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH2:55][O:54][C:51](=[O:53])[CH3:52])=[O:9])[CH3:2]
Reactant: CCCc1nc(CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)OCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1nc(CC)c(C(=O)OCOC(C)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 45.2 %

Procedure:
0.37 g of 4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylic acid was dissolved in 5 mL THF and 0.5 g chloromethyl acetate and 0.5 mL triethylamine were added. The resulting solution was stirred overnight. The solvent was evaporated and the residue dissolved in methanol with 0.25 mL acetic acid and stirred 8 hours with 10 g silica gel. The mixture was evaporated and the residue on the gel was flash chromatographed with MeOH/CH2Cl2 (1:9) to provide 0.124 g of the title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[O:12]1[CH2:14][CH2:13]1>C1COCC1.C(Cl)Cl>[CH3:6][N:7]1[C:11]([CH2:14][CH2:13][OH:12])=[CH:10][CH:9]=[N:8]1
Reactant: C1CO1
Reactant: Cn1cccn1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1nccc1CCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
n-Butyl lithium (1.6M in hexanes) (1226 mL, 1961.78 mmol) was added dropwise to 1-methyl-1H-pyrazole (153.4 g, 1868.37 mmol) in THF (3000 mL) cooled to −78° C. over a period of 1 hour under nitrogen. The resulting solution was stirred at −60° C. for 30 minutes, then warmed to −10° C. and stirred for a further 40 minutes. A solution of oxirane (210 mL, 4203.82 mmol) in THF (600 mL) was added slowly at −10° C. followed by further THF (1000 mL) and the resulting slurry was stirred at −10° C. for 30 minutes, then at 0° C. for 30 minutes. The mixture was then allowed to gradually warm to room temp under nitrogen and stirred for 16 hours. The reaction mixture was quenched with saturated NH4Cl solution (2000 ml), the layers separated and the aqueous phase extracted with n-butanol (3×1000 ml). The combined organics were washed with saturated brine (1500 ml), dried over MgSO4, filtered and evaporated to give an oil, which was azeotroped with toluene (1000 ml) to leave an oil with some solid. The oil was dissolved in DCM and the insoluble solid was filtered off and washed with DCM. The filtrate was purified by chromatography using a silica Novasep prep HPLC column, eluting with a gradient of 5-10% methanol in DCM. Pure fractions were evaporated to dryness to afford 2-(1-methyl-1H-pyrazol-5-yl)ethanol (195 g, 83%) as an oil.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:27][C:28]1[CH:29]=[C:30]([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)O)[CH:31]=[CH:32][C:33]=1[F:34].C(N(CC)CC)C>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:35]([C:30]1[CH:31]=[CH:32][C:33]([F:34])=[C:28]([F:27])[CH:29]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:11])[CH2:3]2
Reactant: OC(c1ccccc1)c1ccc(F)c(F)c1
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(OC(c1ccccc1)c1ccc(F)c(F)c1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (80 mg, 0.42 mmol), EDC (120 mg, 0.62 mmol), and HOBT (96 mg, 0.62 mmol) were dissolved in dry THF (3 ml). (3,4-Difluorophenyl)(phenyl)methanol (101 mg, 0.46 mmol) was dissolved in dry THF (2 ml) and then added to the reaction mixture. Triethylamine (203 μl, 1.46 mmol) was finally added, and the resulting reaction was stirred at room temperature overnight. The volatiles were evaporated, and the crude was taken up with EtOAc and washed with water and then with sat. NaHCO3. The organic phase was dried over sodium sulfate, filtered, and evaporated under vacuum. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (3,4-difluorophenyl)(phenyl)-methyl quinuclidine-3-carboxylate (65 mg, mixture of diastereoisomers).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[C:3]=1[C:4]#[N:5].Cl.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>O.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[C:9]([CH2:10][Br:16])=[CH:8][CH:7]=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1ccc(C)c(C)c1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1ccc(CBr)c(C)c1C#N
Reaction time: 1 h
Yield: 42.3 %

Procedure:
In a carefully dried Pyrex reaction vessel were combined 10 g of 2,3-dimethyl-6-acetamidobenzonitrile, 300 ml of CCl4, and 200 ml of HCl-free CHCl3 under argon. To this solution was added 10.8 g of N-bromosuccinimide (recrystallized from H2O) and 0.5 g of azo bisisobutyronitrile (AIBN). The reaction was heated to reflux and irradiated with an external General Electric sunlamp. The initially yellow reaction turned red-brown after 1 h when an additional 0.5 g of AIBN was added. After another 2 h, the reaction mixture was poured into H2O, separated, and the aqueous layer reextracted with CHCl3. The combined CHCl3 layers were washed with H2O, saturated NaHCO3 solution, and brine. The dried organic solution was evaporated at reduced pressure and the residue was crystallized from ethyl acetate to yield 6 g (42%) of the title compound, m.p. 152°-153° C. NMR (CDCl3) 2.30 (3H, s, CH3CON), 2.60 (3H, s, CH3), 4.50 (2H, s, --CH2Br), 7.40 (1H, d, ArH), 8.10 (1H, d, ArH), Anal. Calc'd for C11H11BrN2O: C, 49.5; H, 4.15; N, 10.5. Found: C, 50.3, H, 4.31; N, 10.6.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][C@@H:4]1[O:17][CH3:18].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:16])[CH2:5][C@@H:4]1[O:17][CH3:18])(=[O:22])=[O:21]
Reactant: CO[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CC[C@@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CC[C@@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of tert-butyl [(1S,3S,4R)-4-(hydroxymethyl)-3-methoxycyclohexyl]carbamate (racemic) (720 mg, 2.8 mmol) in dichloromethane (9 mL) was added methanesulfonyl chloride (0.430 mL, 5.56 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic phase was concentrated and purified by flash chromatography (eluting with a gradient of 50% ethyl acetate in hexanes) to give the desired product (0.859 g, 92%). LCMS calculated for C9H20NO4S (M+H-Boc)+: m/z=238.1. Found: 238.0.
Reaction SMILES: ClC1C=CC(C2N=C(N3C=CN=C3C)OC=2CCCCO[C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=CC=1.O1CCCC1.[OH-].[Na+]>C(O)C>[C:22]([OH:24])(=[O:23])[C:21]1[CH:26]=[CH:27][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCCCCc2oc(-n3ccnc3C)nc2-c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccccc1
Temperature: 62.5 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl 4-[4-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]butoxy]benzoate (1.86 g), tetrahydrofuran (20 ml) and ethanol (10 ml) was added 15 ml of a 1 N aqueous solution of sodium hydroxide, and the resulting mixture was stirred at 60-65° C. for 3 hours. The reaction mixture was concentrated and then diluted with a 10% aqueous solution of citric acid, and the resulting precipitate was filtered, washed with water and air-dried to give crystals of 4-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]butoxy]benzoic acid. Recrystallization from tetrahydrofuran-isopropyl ether gave colorless prisms (1.15 g, 51%). Melting point 214-216° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][SH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:16]1[CH:17]=[C:18]([CH:22]2[C:31]3[C:26](=[C:27]([Cl:33])[CH:28]=[C:29]([Cl:32])[CH:30]=3)[CH2:25][N:24]([CH3:34])[CH2:23]2)[CH:19]=[CH:20][CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:13]([S:14][C:20]1[CH:19]=[C:18]([CH:22]2[C:31]3[C:26](=[C:27]([Cl:33])[CH:28]=[C:29]([Cl:32])[CH:30]=3)[CH2:25][N:24]([CH3:34])[CH2:23]2)[CH:17]=[CH:16][CH:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(Br)c2)C1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(SCc3ccccc3)c2)C1
Temperature: 0 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of potassium carbonate (930 mg, 0.50 equiv) in xylene (50 mL). This was followed by the addition of phenylmethanethiol (2.5 g, 1.50 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at 25° C. Into another 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was added a solution of 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (5.0 g, 1 equiv) in xylene (50 mL), Pd2(dba)3 (300 mg), Xantphos (300 mg). The resulting solution was stirred for 30 min at 25° C. and then added to the above reaction solution. The mixture was stirred overnight at 140° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100˜1:50). This resulted in 2.5 g (45%) of 4-(3-(benzylthio)phenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO.C(OCC)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1c[nH]cc1-c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)c1c[nH]cc1-c1ccc(N)cc1
Yield: 44.6 %

Procedure:
0.2 g (0.769 mmol) of ethyl 4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate is added at a temperature in the region of 20° C. to a suspension of 0.02 g (0.188 mmol) of 10% palladium on carbon in 15 cm3 of methanol. After hydrogenating for 20 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with three times 5 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 10 cm3 of diethyl ether and then filtered and dried under reduced pressure (2.7 kPa) to give 0.079 g of ethyl 4-(4-aminophenyl)-1H-pyrrole-3-carboxylate, in the form of a brown solid; EI: m/z=230 (M+) base peak, m/z=202 (M-C2H4+), m/z=157 (M-C2H5O+).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[F:5][C:6]1[C:11]2[NH:12][C:13](=[O:15])[O:14][C:10]=2[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[F:5][C:6]1[C:11]2[N:12]([CH:2]([CH3:4])[CH3:3])[C:13](=[O:15])[O:14][C:10]=2[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1
Reactant: CC(C)I
Reactant: O=c1[nH]c2c(F)cc([N+](=O)[O-])cc2o1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)n1c(=O)oc2cc([N+](=O)[O-])cc(F)c21

Procedure:
Prepared from 2-iodopropane (0.76 ml, 7.57 mmol), 4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (EXAMPLE 86, Step 5, 1.2 g, 6.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.13 ml, 7.57 mmol) in DMF (10 ml) according to the method of EXAMPLE 86, Step 6 (0.87 g, 60%); mp 122-3° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:24]=[C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[N:22]=[C:21]([NH2:31])[N:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[CH:17][C:10]=12.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(O)C>[C:32]([N:27]1[CH2:28][CH2:29][CH2:30][CH:25]([C:23]2[N:22]=[C:21]([NH2:31])[N:20]=[C:19]([NH:18][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][N:12]=[C:11]5[NH:15][CH:16]=[CH:17][C:10]=45)=[C:2]([F:1])[CH:3]=3)[CH:24]=2)[CH2:26]1)(=[O:34])[CH3:33]
Reactant: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(C2CCCNC2)n1
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)N1CCCC(c2cc(Nc3ccc(Oc4ccnc5[nH]ccc45)c(F)c3)nc(N)n2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
50 mg (0.119 mmol) of N4-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-6-piperidin-3-ylpyrimidine-2,4-diamine (from example 134) are suspended in ethanol. 0.013 ml (0.146 mmol) of acetic anhydride are added, and the mixture is stirred at room temperature for 18 hours. The mixture is then concentrated. The residue is purified by preparative HPLC.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].C(N(CC)CC)C.[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)(C)C=O
Reactant: NCC(=O)N1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)CNCC(=O)N1CCOCC1
Reaction time: 6 h
Yield: 64.6 %

Procedure:
To a stirred solution of the above 2-amino-1-morpholin-4-yl-ethanone hydrochloride (0.23 g, 1.3 mmol) in methylene chloride (4.0 mL) and triethylamine (0.19 mL, 1.4 mmol), 4 angstrom sieves (10 beads, pulverized to a powder) were added, followed by trimethylacetaldehyde (0.35 mL, 3.3 mmol) at room temperature, under argon. The resulting mixture was stirred at room temperature overnight after which time sodium triacetoxyborohydride (0.54 g, 2.6 mmol) was added. After 6 h, the solids were removed via filtration and washed with methylene chloride. The combined filtrates were concentrated and the remaining residue was diluted with EtOAc and water. The aqueous phase was lyophilized to give a white solid that was diluted with EtOAc. The solids were removed via filtration and washed with EtOAc. The combined organics were concentrated to give the crude product which was purified via silica gel flash chromatography eluting with 100% EtOAc, then 0.5% NH4OH/10% MeOH/EtOAc, flow rate 30 mL/min. The product-containing fractions were concentrated to give 0.18 g (67%) of 2-(2,2-dimethyl-propylamino)-1-morpholin-4yl-ethanone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([CH2:18][CH:19]=[CH2:20])[CH:8]=1)[CH3:2].[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:37][CH2:38]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:38][CH2:37][C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:30][C:26]=2[CH3:25])=[C:9]([CH2:18][CH:19]=[CH2:20])[CH:8]=1)[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: C=CCc1cc(CC(OCC)C(=O)OCC)c2ccccc2c1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCc1cc(CC(OCC)C(=O)OCC)c2ccccc2c1OCCc1nc(-c2ccccc2)oc1C

Procedure:
In analogy to the procedure described in example 17 a], [rac]-3-(3-allyl-4-hydroxy-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester was reacted with 2-(5-methyl-2-phenyl-oxazole-4yl)-ethanol in tetrahydrofuran in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [rac]-3-{3-allyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-3-{3-allyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [F:1][C:2]([F:15])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)[C:3]([NH2:5])=[O:4].C([SiH](CC)CC)C>CO.[Pd]>[NH2:12][C:8]1[CH:7]=[C:6]([C:2]([F:1])([F:15])[C:3]([NH2:5])=[O:4])[CH:11]=[CH:10][CH:9]=1
Reactant: NC(=O)C(F)(F)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: NC(=O)C(F)(F)c1cccc(N)c1
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a stirred solution of 2,2-difluoro-2-(3-nitrophenyl)acetamide (0.5 g, 2.313 mmol) in methanol (20 ml) was added Pd—C (100 mg) followed by slow addition of triethylsilane (3.7 ml, 23.13 mmol) at RT. The reaction was stirred at same temperature for 30 min. The reaction mixture was filtered through celite bed and washed with methanol (50 ml). Filtrate was collected and concentrated under vacuum to get 2-(3-aminophenyl)-2,2-difluoroacetamide (0.301 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:7](=[O:22])[NH:6]1.[H-].[Na+].[Cl-].CN([CH:30]=[O:31])C>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)[C:7](=[O:22])[N:6]1[CH2:11][C:12]1[CH:21]=[CH:20][C:19]([O:31][CH3:30])=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: COC(=O)CC1NC(=O)N(Cc2ccc3ccccc3c2)C1=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC1C(=O)N(Cc2ccc3ccccc3c2)C(=O)N1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95 %

Procedure:
A 0° C. solution of compound (1-naphthalen-2-ylmethyl-2,5-dioxo-imidazolidin-4-yl)-acetic acid methyl ester (6.29 g, 20.1 mmol) in DMF (60 mL) is treated with sodium hydride (60% dispersion, 0.97 g, 24.3 mmol) and warmed to room temperature and stirred under N2 for 20 minutes. The resultant mixture is cooled to 0° C. and then treated with 4-methoxybenzyl, chloride (6.35 g, 40.6 mmol) and then warmed to room temperature and stirred for 16 hours. The reaction is quenched with aqueous 1 N HCl (100 mL) and then worked up extractively with Et2O and water. The organic layer is dried and the solvent removed to give crude product that is purified by flash chromatography using a gradient of 4:1 hexanes:acetone to afford 8.31 g (95%) [3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester. Rf=0.44 (1:1 hexanes:acetone). 1H NMR.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19]([CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:21])=[O:20])[CH:12]=2)=[O:7])CCC.[NH2:30][CH2:31][C:32]1([C:36]([OH:38])=[O:37])[CH2:35][CH2:34][CH2:33]1.C[O-].[Na+].[OH-].[Na+].Cl>C(O)C.O>[C:28]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:20])=[O:21])[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:30][CH2:31][C:32]2([C:36]([OH:38])=[O:37])[CH2:35][CH2:34][CH2:33]2)=[O:7])[N:9]=1)#[N:29]
Reactant: NCC1(C(=O)O)CCC1
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(S(=O)(=O)C3CCCCC3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1nc(C(=O)NCC2(C(=O)O)CCC2)c(O)c2ccc(S(=O)(=O)C3CCCCC3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.4 %

Procedure:
To a mixture of 1-cyano-7-cyclohexanesulfonyl-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (30 mg, 0.072 mmol) and 1-aminomethyl-cyclobutanecarboxylic acid (48 mg, 0.29 mmol) (available from Ukrorgsyntez Ltd) in ethanol (0.7 mL) was added NaOMe solid (16 mg, 0.29 mmol). The resultant mixture was microwaved at 140° C. for 1 h. The reaction mixture was then treated with 1 mL of 3 N NaOH aqueous solution and stirred at room temperature for 3 h. Reaction mixture was diluted with water (60 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected and purified by silica gel chromatography, eluting with 0-10% MeOH/CH2Cl2 to provide the title compound 6.4 mg (0.014 mmol) in 19% yield. LC-MS ESI−: 470.12 (M−1)−.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:10][S:11](O)(=[O:13])=[O:12]>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCC2
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(c1)CCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of indane (50 mmol, 6.11 mL) in dichloromethane (50 ml) at 0° C. is added dropwise chlorosulfonic acid (200 mmol, 13.3 ml). The resulting solution is allowed to return to room temperature and is stirred for 2 hr. The solution is then poured slowly onto a mixture of ice (200 g) and dichloromethane (50 ml). The organic layer is separated, washed with brine (50 mL), dried over sodium sulfate, filtered and evaporated to produce indan-5-sulfonic acid chloride.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10]([NH2:12])=[O:11])[CH:5]=[CH:4][CH:3]=1.[CH2:13](C(CC)(CC)C([O-])([O-])[O-])[CH3:14]>>[F:1][C:2]1[N:7]=[C:6]([N:8]2[C:13]([CH3:14])=[N:12][C:10]([OH:11])=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: NC(=O)NNc1cccc(F)n1
Product: Cc1nc(O)nn1-c1cccc(F)n1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
A solution was prepared by admixing 17.02 g (0.10 m) of 2-(6-fluoro-2-pyridinyl)hydrazinecarboxamide with 100 ml of triethylorthoacetate. The mixture was refluxed overnight and the reaction mixture cooled to room temperature and poured over ice water. The solids which precipitated out were recovered by filtration. The solids were washed with methylene chloride and dried under vacuum to yield 11.4 g (58.7 percent of theoretical) of the desired 1-(6-fluoro-2-pyridinyl)-5-methyl-1H-1,2,4-triazol-3-ol. The product melted at 272°-274° C. and upon analysis was found to have carbon, hydrogen and nitrogen contents of 49.58, 3.83 and 28.88 percent, respectively, as compared with the theoretical contents of 49.48, 3.63 and 28.85 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])=[N:5][CH2:6][CH2:7][CH2:8]C#C)#[N:2].C(NC(NCCSCC1NC=NC=1C)=NC(C)(C#C)C)#N>>[C:1]([NH:3][C:4]([NH:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])=[N:5][CH2:6][C:7]#[CH:8])#[N:2]
Reactant: C#CCCCN=C(NC#N)NCCSCc1[nH]cnc1C
Agent: C#CC(C)(C)N=C(NC#N)NCCSCc1[nH]cnc1C
Product: C#CCN=C(NC#N)NCCSCc1[nH]cnc1C

Procedure:
N-Cyano-N'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(4-pentyn-1-yl)guanidine or a nontoxic pharmaceutically acceptable acid addition salt thereof. ⟦11. N-Cyano-N-'-{2-[(4-methyl-5-imidazolyl)methylthio]ethyl}-N"-(2-methyl-3-butyn-2-yl)guanidine or a nontoxic pharmaceutically acceptable acid addition