Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[NH2:14][C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][C:17]([OH:25])([CH2:18]3)[CH2:16]1)[CH2:22]2>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:14][C:15]23[CH2:24][C@H:19]4[CH2:20][C@H:21]([CH2:23][C:17]([OH:25])([CH2:18]4)[CH2:16]2)[CH2:22]3)[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: NC12CC3CC(C1)CC(O)(C3)C2
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC12C[C@@H]3C[C@@H](CC(O)(C3)C1)C2
Reaction time: 48 h

Procedure:
To a stirred solution of Example 8D (0.06 g, 0.305 mmol) in acetonitrile (3 mL) at room temperature under nitrogen, was added 3-amino-1-adamantanol (0.1 g, 0.61 mmol). The reaction mixture was stirred for two days and then concentrated under reduced pressure. The residue was flash chromatographed with 5-7% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 328 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.5-2 (14H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH2:19][O:20]C)[N:17]=[CH:18][C:13]=3[CH2:12][CH:11](C)[C:10]2=[O:23])=[CH:4][CH:3]=1.N1C=CC=C[CH:25]=1.I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([CH2:19][OH:20])[N:17]=[C:18]([CH3:25])[C:13]=3[CH2:12][CH2:11][C:10]2=[O:23])=[CH:4][CH:3]=1
Reactant: COCc1ncc2c(n1)N(Cc1ccc(Br)cc1)C(=O)C(C)C2
Reactant: c1ccncc1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc(CO)nc2c1CCC(=O)N2Cc1ccc(Br)cc1

Procedure:
To a solution of 8-[(4-bromophenyl)methyl]-6-methyl-2-methoxymethyl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 2.70 mmol) and pyridine (0.11 g, 1.30 mmol) in CHCl3 (9 mL) was added iodotrimethylsilane (0.77 g, 3.80 mmol). The mixture was heated under reflux for 30 h and MeOH (0.5 mL) was added. The mixture was concentrated, taken up in CH2Cl2, washed with aqueous Na2SO3 and brine, dried (MgSO4), and concentrated. Purification by flash chromatography (5% MeOH/CH2Cl2) gave o.54 g (56%) of product as a colorless foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:24])=[C:18]([CH2:20][C:21]([OH:23])=O)[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH:29]1[CH:30]=C[C:32]2N(O)N=[N:35][C:33]=2[CH:34]=1.Cl.C[C@@H]1CCCN1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]([CH3:24])=[C:18]([CH2:20][C:21]([N:35]3[CH2:30][CH2:29][CH2:34][C@H:33]3[CH3:32])=[O:23])[N:19]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CC(=O)O
Reactant: On1nnc2ccccc21
Agent: C[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CC(=O)N1CCC[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a mixture of [2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-acetic acid [CAS 403611-89-2] (2.2 g, 6.8 mmol) in CH2Cl2 (40 mL) is added EDC (1.57 g, 8.2 mmol) and HOBT (1.11 g, 8.2 mmol). After a few minutes, (R)-2-methylpyrrolidine hydrochloride [CAS 41720-98-3] (1.0 g, 8.2 mmol) and DIPEA (2.5 mL, 13.6 mmol) are added. The mixture is stirred at room temperature overnight. The mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc (2×), and the combined organic phase is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by flash chromatography [120 g SiO2, elute gradient 30% EtOAc/hexane to 80% EtOAc/hexane) to yield 1.25 g of the title compound as a yellow oil. MS (m/e): 391.2 (M+1)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH3:34][C:35]1([O:38][CH2:37]1)[CH3:36]>CO>[OH:38][C:35]([CH3:37])([CH3:36])[CH2:34][N:23]1[CH2:22][CH2:21][C:20]2([CH2:26][C:18]3([O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:27]3)[CH2:19]2)[CH2:25][CH2:24]1
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)cc1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(O)CN1CCC2(CC1)CC1(Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 5-(4-methylsulfonyl-phenyl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt; 50 mg) and K2CO3 (17 mg) in methanol (4 mL) is stirred at room temperature for 15 min prior to the addition of isobutylene oxide (20 μL). The reaction vessel is sealed and the mixture is stirred at 60° C. overnight. After cooling to room temperature, the mixture is concentrated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate/methanol 5:4:1→0:9:1) to give the title compound. LC (method 1): tR=0.71 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:13]=[C:14]([CH2:15][OH:16])[C:7]=2[N:6]=1>[O-2].[Mn+4].[O-2].O1CCCC1>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([CH3:27])[C:3]=1[O:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:12][CH:13]=[C:14]([CH:15]=[O:16])[C:7]=2[N:6]=1
Reactant: CCC(CC)c1ccc(CO)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCC(CC)c1ccc(C=O)c2nc(Oc3c(C)cc(Cl)cc3Cl)n(C)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A mixture of [2-(2,4-dichloro-6-methylphenoxy)-7-(1-ethylpropyl)-1-methyl-1H-benzimidazol-4-yl]methanol (100 mg, 0.25 mmol), manganese(IV) oxide (428 mg, 4.92 mmol) and tetrahydrofuran (5 ml) was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on alumina with a 50% ethyl acetate/n-hexane to give 93 mg (0.23 mmol, 93%) of the title compound as a white powder.
Reaction SMILES: CN(C)C=O.CS([C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]([O:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:18])=[CH:12][N:11]=1)(=O)=O.[CH2:27]([NH:31][CH3:32])[CH2:28][CH2:29][CH3:30]>O>[CH2:27]([N:31]([C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]([O:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:18])=[CH:12][N:11]=1)[CH3:32])[CH2:28][CH2:29][CH3:30]
Reactant: CC(CCOC(=O)c1cnc(S(C)(=O)=O)nc1C)=C(F)F
Reactant: CCCCNC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(C)c1ncc(C(=O)OCCC(C)=C(F)F)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To 3 ml of N,N-dimethylformamide were dissolved 0.50 g (1.6 mmol) of 4,4-difluoro-3-methyl-3-butenyl 2-methanesulfonyl-4-methylpyrimidine-5-carboxylate, followed by the addition of 0.28 g (3.2 mmol) of N-butyl-N-methylamine and stirring at room temperature for 30 minutes. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate ether:hexane=1:7) to obtain 0.41 g (yield: 80%) of 4,4-difluoro-3-methyl-3-butenyl 2-(N-butyl-N-methylamino)-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])[N:5]=[C:4]([C:24]#[N:25])[N:3]=1.C([O-])([O-])=[O:27].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9]([F:16])=[CH:10][C:11]([F:15])=[CH:12][C:13]=2[F:14])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:20])([F:21])[F:22])[N:5]=[C:4]([C:24]([NH2:25])=[O:27])[N:3]=1
Reactant: C[C@H](Nc1nc(C#N)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](Nc1nc(C(N)=O)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
5.0 g of 4-chloro-6-((S)-2,2,2-trifluoro-1-methylethylamino)-5-(2,4,6-trifluorophenyl)-pyrimidine-2-carbonitrile (see WO 03/04993, pages 28 and 29) were initially charged in 5 ml of DMSO, 344 mg of K2CO3 were added and the mixture was cooled to 10° C. 1.4 ml of 30% strength H2O2 were then added. The mixture was stirred in an ice bath for 5 min and then at room temperature for another 30 min. The reaction mixture was introduced into 150 ml of water. During the addition, the amide precipitated out. The amide was filtered off, washed and dried under high vacuum. This gave 4.7 g of the beige title compound of m.p. 157-162° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:11]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1ccccc1
Temperature: -10 °C
Yield: 84.9 %

Procedure:
A solution of 11.0 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 14.1 g (0.1 mole) benzoyl chloride in 200 ml xylene was heated at reflux for 20 hours. Upon cooling to -10° C., 13.7 g (85% yield) of pure product precipitated from the reaction mixture and was isolated by filtration; m.p. 190° C.
Reaction SMILES: [CH3:1][SH:2].Cl[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:1][S:2][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:18]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1CCl
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CSCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Yield: 49 %

Procedure:
Methyl mercaptan (1.9 g) is slowly introduced to a refluxing mixture composed of 4-chloromethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (4.48 g), potassium carbonate (3.3 g) and methyl ethyl ketone (30 ml). The reaction mixture is refluxed for 5 hours, made free from methyl ethyl ketone by evaporation in vacuo, and the resultant residue is extracted with ethyl acetate. The extract is washed with saturated sodium carbonate aqueous solution and with water, dried over sodium sulfate, and condensed to ensure crystallization. The collected solid is washed with a small amount of ether to obtain 4-methylthiomethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (2.3 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].S(=O)(=O)(O)O>C1C=CC=CC=1.C(OCC)C>[OH:16][C:15]1([C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)[N:11]([CH3:10])[C:12](=[O:17])[CH2:13][CH2:14]1
Reactant: Cc1cccc(Br)c1
Reactant: CN1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: Cc1cccc(C2(O)CCC(=O)N2C)c1
Reaction time: 8 h

Procedure:
To a Grignard prepared from 27.3g (0.16 mole) of 3-bromotoluene and 3.7 g. (0.16 mole) of magnesium turnings in 100 ml. of dry diethylether, there is added dropwise over a period of about 10 minutes 12.2 g. (0.11 mole) of N-methylsuccinimide in 100 ml. of dry benzene. The resulting mixture is stirred and refluxed for about 4 hours and then allowed to stand overnight at room temperature. Stirring is resumed and 40 ml. of 50% sulfuric acid is added dropwise at such a rate to maintain a gentle reflux. After an additional 0.5 hours, the water layer is separated and washed twice with 50 ml. of benzene. The organic layers are combined and washed with 50 ml. of sodium carbonate and then twice more with 50 ml. of water. The resulting layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting residue is crystallized from methylene chloride/hexane to give 5-hydroxy-1-methyl-5-(m-tolyl) pyrrolidone; m.p. 128°-130°C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[CH3:7].Br[CH2:19][CH:20]=[CH:21][CH3:22]>>[CH2:19]([N:3]1[C:4]([C:8](=[O:17])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]([CH3:7])=[C:2]1[CH3:1])[CH:20]=[CH:21][CH3:22]
Reactant: Cc1cc(C(=O)CCc2ccccc2)[nH]c1C
Reactant: CC=CCBr
Product: CC=CCn1c(C(=O)CCc2ccccc2)cc(C)c1C
Yield: 75.7 %

Procedure:
The title compound (cis/trans=23/77) was prepared as a yellow oil in 75.7% yield in a similar procedure to that described in Referential Example 97 by using 2,3-dimethyl-5-(3-phenylpropionyl)pyrrole and 1-bromo-2-butene.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8](#[N:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13]>ClCCl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][C:8]#[N:14])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCCCC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCCC#Cc1cccnc1
Yield: 79 %

Procedure:
Argon was passed through a solution of 45 ml of 3-bromopyridine and 49.61 g of 5-hexynenitrile in 500 ml of dichloromethane and 150 ml of dry triethylamine for 15 minutes and 3.0 g of bis(triphenylphosphine)palladium dichloride and 0.45 g of cuprous iodide were added. The reaction flask was evacuated and refilled with argon and was heated to reflux for 12 hours. The resulting mixture was diluted with 1 L of dichloromethane and washed with 2×300 ml of water, 1×300 ml brine, dried over potassium carbonate and concentrated. The residue was distilled to afford 62.82 g (79%) of 6-(3-pyridinyl)-5-hexynenitrile as a yellow oil, bp 140°-170° C./0.2 mm., suitable for use in the next step. A portion was purified by chromatography over silica gel eluting with 1:1 ethyl acetate-hexane containing 1% triethylamine and was redistilled to give an analytical sample of 6-(3-pyridinyl)-5-hexynenitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.C([O:56][C:57]([CH2:59][CH2:60][CH:61]([NH2:72])[C:62]1[NH:66][C:65]2[CH:67]=[CH:68][C:69]([Cl:71])=[CH:70][C:64]=2[N:63]=1)=[O:58])C1C=CC=CC=1.ClCl>CS(C)=O.[OH-].[Na+].C(OCC)(=O)C.C(O)(=O)C>[Cl:71][C:69]1[CH:68]=[CH:67][C:65]2[NH:66][C:62]([CH:61]([NH:72][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:60][CH2:59][C:57]([OH:58])=[O:56])=[N:63][C:64]=2[CH:70]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: NC(CCC(=O)OCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1cc(C(=O)NC(CCC(=O)O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 53 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, 3-benzyloxycarbonyl-1-(5-chloro-1H-benzimidazol-2-yl)propylamine in dimethylsulfoxide and sodium hydroxide solution. Yield: 53%; Rf value: 0.16 (silica gel; ethyl acetate/acetic acid=95:5); C24H25ClN4O4 (468.94); mass spectrum: (M+H)+=469/471 (chlorine isotope).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][NH2:12])[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.C(N(CC)CC)C>C(O)(C)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][N:25]4[CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][O:31]3)[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]=2[CH:19]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: NCc1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Fc1ccc2nc(CNc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c2c1
Yield: 70.5 %

Procedure:
(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)methylamine hydrochloride (0.113 g, 0.4 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.19 g, 0.8 mmol), triethylamine (0.28 mL, 2 mmol) in isopropanol (2 mL) was heated to 80° C. in a sealed tube for 6 h. The reaction mixture was partitioned between DCM and water and the organic layer was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-3.5% MeOH in DCM) to afford the title compound as a colourless gum, (0.125 g, 70%). LCMS (Method B): RT 2.99 min [M+H]+ 444.19.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27](I)[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:27][CH3:28])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCI
Agent: [Na+]
Product: CCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12

Procedure:
In the same manner as in Example 81, 143 mg of the title compound was prepared from 265 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 0.063 ml of ethyl iodide.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:20]([O:22][CH3:23])=[O:21].C(OCC)(=O)C.CCCCCC>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cl
Reactant: Brc1ccc2c(c1)CNCC2
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)N1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a mixture of 7-bromo-1,2,3,4-tetrahydroisoquinoline (19.33 g, 0.091 mol) and triethylamine (16.6 ml, 0.119 mol) in dichloromethane (300 ml) was added a solution of methyl chloroformate (8.5 ml; 0.109 mol) in dichloromethane (30 ml), dropwise with ice cooling. Mixture was stirred for 3 h at room temperature then partitioned between saturated aqueous NaHCO3 (100 ml) and dichloromethane (100 ml). Organic phase was dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica with 30% ethyl acetate-hexane as eluant gave the title compound as an oil (15.25 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[N:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=1.[OH-].[K+]>CN(C)C=O>[Cl:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[O:25][CH2:24][C:21]1[CH:22]=[N:23][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(OCc2ccc(Cl)nc2)cnn1-c1ccc(Cl)cc1
Yield: 61.2 %

Procedure:
The procedures in Synthesis Example 2 were repeated by using 2.0 g (7.2 m mol) of 2-(4-chlorophenyl)-4,5-dichloro-3(2H)-pyridazinone, 1.1 g (7.7 m mol) of 6-chloro-3-pyridine methanol, 0.4 g of potassium hydroxide and 80 ml of N,N-dimethylformamide to give 1.7 g of the intended product (recrystallized from benzene/n-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([CH3:13])=O)=[C:4]([CH3:15])[CH:3]=1>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH3:15])[CH:3]=1)[NH:8][C:9](=[O:14])[CH:10]=[C:11]2[CH3:13]
Reactant: CC(=O)CC(=O)Nc1ccc(Br)cc1C
Agent: O=S(=O)(O)O
Product: Cc1cc(=O)[nH]c2c(C)cc(Br)cc12

Procedure:
N-[4-Bromo-2-methylphenyl]-acetoacetamide (18 g) was heated for 5 hours with stirring in 98% sulphuric acid (50 cm3) at 100°. The cooled mixture was then poured onto ice (200 g), the solid was filtered off and dried in vacuo at 100° for 2 hours to give the crude product (15.0 g). A small portion (1.5 g) of this material was recrystallised from ethyl acetate/methanol to afford 6-bromo-4,8-dimethyl-2-(1H)-quinolone, m.p. >300° (1.1 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18](Cl)[N:17]=1>CN1C=CC=CC1=O>[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][NH:22]2)=[C:18]([O:11][C:7]2[C:6]([CH3:12])=[CH:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:8]=2[CH3:10])[N:17]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1cc(C2CC2)cc(C)c1O
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 4-cyclopropyl-2,6-dimethylphenol (263 mg, 1.62 mmol) in 1-methyl-2-pyridone (3 mL) at 0° C. was added NaH (65 mg, 1.62 mmol). The reaction mixture was stirred at room temperature for 30 min and a solution of 2,6-dichloropurine (102 mg, 0.54 mmol) in 1-methyl-2-pyridone (2 mL) was added to the mixture. The mixture was heated at 100° C. for 16 h and then cooled to room temperature. The reaction was poured into ice water and extracted with CHCl3 (3×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (MeOH:CHCl3=5:95) yielded 114 mg (67%) of 2-chloro-6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purine.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O1CCCC1.O>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccc(F)cc2F)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccc(F)cc2F)=CC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
A mixture of (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.53 g, 1.58 mmol) in tetrahydrofuran (12 mL) and water (4 mL) was treated with lithium hydroxide monohydrate (80 mg, 1.89 mmol). The reaction was stirred at 25° C. for 4 h. At this time, the reaction was diluted with water (75 mL), acidified with a 2N aqueous hydrochloric acid solution and then extracted with 10% methanol/dichloromethane (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.50 g, 97%) as a light yellow solid: HR-ES-MS m/z calculated for C16H17NO4F2 [M+Na]+ 348.1018, observed 348.1018; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (d, J=6.4 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H), 1.36-1.52 (m, 1H), 1.53-1.68 (m, 1H), 1.75-1.86 (m, 1H), 4.15 (d, J=18.4 Hz, 1H), 4.26 (d, J=18.4 Hz, 1H), 4.62 (dd, J=11.5, 4.2 Hz, 1H), 4.93 (s, 1H), 7.14-7.25 (m, 1H), 7.49-7.64 (m, 2H), 12.91 (br. s., 1H).