Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.[Li]CCCC.B(OCCCC)(OCCCC)[O:28]CCCC.OO.Cl>C(OCC)C>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([OH:28])=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: CCCCOB(OCCCC)OCCCC
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: OO
Solvent: CCOCC
Product: Oc1cccc2c1oc1ccccc12
Temperature: 0 °C

Procedure:
To a solution of dibenzofuran (50 g, 0.29 mol) in 1000 ml dry diethyl ether and N,N,N′,N′-tetramethylethane-1,2-diamine (70 ml, 0.43 mol) (TMEDA), 1.6M BuLi (235 ml, 0.32 mol) in hexanes was added with stirring under Nitrogen. The mixture was refluxed for 1 hour (yellow precipitate) and then cooled to 0° C. Tributyl borate (120 ml, 0.43 mol) was added until the precipitate disappeared. The reaction mixture is allowed to reach room temperature. After cooling again to 0° C., 125 ml of 30% hydrogen peroxide (H2O2) solution was added drop wise with vigorous stirring (light yellow precipitate). This mixture was refluxed for 1.5 hours, then cooled to 0° C. and acidified with 5M HCl. The organic phase was washed with cold 10% sodium sulphite solution and extracted with 2M sodium hydroxide. The combined aqueous extract was acidified, extracted with ethyl acetate and dried on sodium sulfate. Evaporation gave an orange oil which was filtered and isolated by column chromatography eluting with 15% ethyl acetate/hexane, yielding the product dibenzofuran-4-ol as an off-white solid. Yield 44 g (81%) 1H-NMR (300 MHz, CDCl3) 7.95 (d, J=7.5, 1H); 7.60 (d, J=8.4, 1H); 7.53 (dd, J=7.8, 1H); 7.48 (t, J=8.4, 1.2, 1H); 7.36 (t, J=7.5, 1.2, 1H); 7.23 (t, J=7.8, 1H); 7.03 (dd, J=8.1, 1.0, 1H); 5.50 (s, OH)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)N.[S:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.N(OCCC(C)C)=O>>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccsc1
Reactant: Cc1c(N)cccc1Cl
Agent: CC(C)CCON=O
Product: Cc1c(Cl)cccc1-c1cccs1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 12.5 %

Procedure:
To a stirred solution of 50.0 g (0.353 mol) of 3-chloro-2-methylaniline in 100 g (1.19 mol) of thiophene was added dropwise 82.7 g (0.706 mol) of isoamyl nitrite during 0.5 hour. Upon complete addition, the reaction mixture was heated to reflux temperature, and stirred for 0.75 hour. The reaction mixture was then allowed to cool to ambient temperature, and stirring was continued for 16 hours. The reaction mixture was concentrated under reduced pressure to give a black residual oil. The oil was subjected to column chromatography on silica gel, eluting with heptane, then heptane:ethyl acetate (40:1). The appropriate fractions were combined to give a red oil which was subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 9.2 g of 2-(3-chloro-2methylphenyl)thiophene, b.p. 78° C.±3° C./0.05 mm.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:47]=[CH:46][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][O:42][C:41]2=[O:45])[CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:7].Cl>C1COCC1.O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:44][CH2:43][O:42][C:41]2=[O:45])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:46][CH:47]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCN2CCOC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCN2CCOC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8.75 mg (208 mmol) of lithium hydroxide monohydrate are added to a solution of 25 mg (41.7 μmol) of methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-(2-{[5-(2-oxo-1,3-oxazolidin-3-yl)-pentyl]oxy}phenyl)pent-4-en-1-yl]benzoate (Example 33A) in 0.5 ml of THF and 0.5 ml of water, and the mixture is stirred at room temperature for 16 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by preparative HPLC. This gives 1.5 mg (2.62 μmol, 6.3% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1I.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Clc1nccc(I)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2ccnc(Cl)c2Br)cc1
Temperature: 100 °C
Yield: 38.9 %

Procedure:
To a solution of crude 3-bromo-2-chloro-4-iodopyridine (10.0 g, 31.41 mmol) in toluene (120 mL) at room temperature under argon was added 4-chlorophenylboronic acid (5.8 g, 37.1 mmol), tetrakis(triphenylphosphine)palladium (2.2 g, 1.9 mmol), and a solution of Na2CO3 (6.6 g, 62.3 mmol) in water (20 mL). The resulting suspension was stirred and heated at 100° C. under argon for 2.5 h. After the reaction mixture was cooled to room temperature, water (120 mL) and EtOAc (150 mL) were added. The layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel column eluting with 7% ethyl acetate-hexanes) to isolate 3.7 g of the title compound as a white solid. HPLC/MS: retention time=3.78 min, [M+H]+=302. 1H NMR (CDCl3, 500 MHz): δ 8.35 (d, J=5.0 Hz, 1H), 7.46 (d, J=10.0 Hz, 2H), 7.34 (d, J=10.0 Hz, 2H), 7.14 (d, J=5.0 Hz, 1H).
Reaction SMILES: B1C2C[CH2:8][CH2:9][CH:2]1CCC2.C1COCC1.C(Br)C#C.[OH-].[Na+].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[O:31][CH3:32]>O.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]1([C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[O:31][CH3:32])[CH2:9][CH2:2]1
Reactant: B1C2CCCC1CCC2
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCBr
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1C1CC1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 10.7 %

Procedure:
To a 0.5M 9-BBN/THF solution (26.0 mL, 13.0 mmol) was added propargyl bromide (0.71 mL, 6.37 mmol, 80% in toluene) and the mixture was heated at 65° C. for 5 h. After cooling to 20° C., a previously degassed solution of NaOH (749 mg, 18.7 mmol) in water (6.3 mL) was added and stirring was continued for 1.5 h. The mixture was transferred to a second flask containing 2-bromo-4-nitroanisole (1.29 g, 5.45 mmol) and tetrakis(triphenylphosphine)palladium (0) (187 mg, 0.16 mmol) in THF (8.0 mL). After heating at 60° C. for 14 h, the reaction mixture was quenched with water (15 mL) and extracted with ether (3×40 mL). The combined organic extracts wee washed with 2M NaOH (3×20 mL) and water (3×20 mL), dried (Na2SO4) and concentrated. Purification by two consecutive column chromatographies (SiO2, 1st eluting with 9/1 hexanes/EtOAc, 2nd eluting with 7/3 hexanes/CH2Cl2) allowed to isolate the title compound (113 mg, 11% yield) as a yellowish oil: LCMS (ES) m/z 194 (M+H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:47])[CH2:30][CH2:31][N:32]([S:40]([CH2:43][CH2:44][CH2:45][CH3:46])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:28][N:29]([CH3:47])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:37][CH:38]=1)[S:40]([CH2:43][CH2:44][CH2:45][CH3:46])(=[O:42])=[O:41]
Reactant: CCCCS(=O)(=O)N(CCN(C)C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCCCS(=O)(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-butylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C31H36N4O5S
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[S:15]C#N)[NH:11][C:10](=[O:18])[C:9](=[O:19])[NH:8]2)([CH3:4])([CH3:3])[CH3:2].S.[Na].[BH4-].[Na+].CO>CC(O)=O.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[SH:15])[NH:11][C:10](=[O:18])[C:9](=[O:19])[NH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2[nH]c(=O)c(=O)[nH]c2cc1SC#N
Agent: S
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc2[nH]c(=O)c(=O)[nH]c2cc1S

Procedure:
The title compound was prepared according to General Method 14b using 6-tert-butyl-7-thiocyanato-1,4-dihydro-quinoxaline-2,3-dione (prepared in Example CCC; 1.5 g, 9.1 mmol), sodium hydrogen sulfide (0.51 g, 27 mmol), sodium borohydride (2.1 g, 55 mmol). MeOH (30 mL), H2O (3 mL), and glacial AcOH (5 mL). The crude product was used without purification. MS(APCI): 251 (M+H).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]([OH:17])=O)=[O:7].NC(N)=O.[ClH:22]>>[C:6]([O:8][C:9]1[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]([Cl:22])=[O:17])(=[O:7])[CH3:5]
Reactant: Cl
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: NC(N)=O
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccccc1C(=O)Cl

Procedure:
In a 2 liter, 3-neck flask equipped with a water bath, stirrer and thermometer is placed 200 ml of thionyl chloride (2.75 mols). To this is added about half the 360 g (2 mols) of aspirin. The fairly mobile suspension is stirred and warmed to 30° and 4 g of urea then added. Initiation of the reaction appears to be enhanced by minimal agitation. Evolution of HCl gas, and a fairly rapid fall in temperature indicate that the reaction has started, and a slow to medium stirring rate is then maintained. The temperature of the mixture is held at 25°. As mobility increases the remaining aspirin is fed in via a powder funnel in the third neck of the flask, fitted with a `Y` piece, one arm leading to a gas outlet connected to a scrubber for absorbing HCl and SO2. It is important to avoid the ingress of air containing moisture during this stage of the reaction. The completion of the reaction is indicated by the appearance of the reaction mixture which becomes a clear pale yellow fluid. At this stage a further 30 mins stirring at 25°-30° is given. This is followed by the addition of approximately 500 ml of 60°-80° petroleum ether at ca 30° with vigorous stirring. On cooling, the acid chloride is thrown out of solution as a heavy crystalline off-white solid. It is filtered off, washed with petroleum ether and dried quickly in a forced draught oven at 35°-40°. Exposure to air should be kept to a minimum.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].Cl[C:9]1[CH:30]=[CH:29][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:17]=2)=[O:14])=[C:11]([CH3:31])[N:10]=1>CN(C=O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:29]=[CH:30][C:9]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[N:10][C:11]=2[CH3:31])=[CH:17][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: c1cn[nH]c1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-n2cccn2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A mixture of 52 mg of pyrazole and 18 mg of sodium hydride in 2 mL of DMF were stirred for 10 min. 90 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide was added. The reaction was heated to 140° C. for 5 h. The reaction mixture was quenched with MeOH and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(1H-pyrazol-1-yl)nicotinamide. MS (Q1) 390.0 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]([CH:14]1[O:18][CH2:17][CH2:16][O:15]1)[CH3:13].C1(OC)C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Cu]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)[CH:6]=[C:5]2[CH2:11][CH:12]([CH:14]1[O:18][CH2:17][CH2:16][O:15]1)[CH3:13]
Reactant: CC(Cc1c[nH]c2ccc(Cl)cc12)C1OCCO1
Reactant: Fc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COc1ccccc1
Product: CC(Cc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12)C1OCCO1

Procedure:
A mixture of 15g (0.067 mole) of 5-chloro-3-[2-(1,3-dioxolan-2-yl)propyl] indole, 225 ml of anisole, 30g (0.135 mole) of 4-fluoroiodobenzene, 30g of copper powder and 60g of dry sodium carbonate are heated to reflux for 96 hours.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1>O1CCCC1>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][CH:3]=[O:2])[CH2:6][CH2:7]2)=[CH:12][CH:13]=1)#[N:16]
Reactant: COC=C[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1

Procedure:
A solution of 10.1 g of p-[trans-4-(2-methoxyvinyl)cyclohexyl]benzonitrile in 200 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was heated to reflux for 1 hour while stirring The reaction mixture was subsequently partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and evaporated, there being obtained 9.8 g of 2-[trans-4-(p-cyanophenyl)cyclohexyl]acetaldehyde as a light yellowish, crystalline residue.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[H-].[Na+].Br[CH2:16][C@:17]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:19][CH:18]1[CH2:20]Br.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[C:7]1([S:4]([C:3]2([S:2][CH3:1])[CH2:20][C@@H:18]3[C@@:17]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)([CH2:19]3)[CH2:16]2)(=[O:5])=[O:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CSCS(=O)(=O)c1ccccc1
Reactant: BrCC1C[C@]1(CBr)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSC1(S(=O)(=O)c2ccccc2)C[C@H]2C[C@@]2(c2cccc3ccccc23)C1
Temperature: 40 °C
Yield: 69.5 %

Procedure:
1-((Methylthio)methylsulfonyl)benzene (2.85 g, 14.1 mmole) was dissolved in dry dimethylforamide (DMF, 15 mL). Sodium hydride (1.69 g, 35.3 mmol) was added portion wise under nitrogen atmosphere at 0° C. The reaction mass was gradually heated to 40° C. and maintained for 30 min at 40° C. A solution of (1R)-1,2-bis(bromomethyl)-1-(1-naphthyl)cyclopropane (2.5 g, 7.0 mmol) in DMF (5 mL) was added dropwise for 30 min at 0° C. The temperature of the reaction mass was slowly brought to room temperature and maintained for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (10:90)). The reaction mass was quenched with water. The aqueous layer was extracted with diethyl ether (2×150 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 10.0 g of crude oil that was purified by column chromatography (silica gel, ethyl acetate/hexane (4:96) to yield 1.92 g (69%) of product. 1H NMR δ(300 MHz,CDCl3): 1.93 (2H,m), 2.01 (1H,m), 2.07 (3H,s), 2.28 (2H,m), 2.44 (2H,m), 2.88 (1H,dd, J=15 Hz), 7.36 (1H,m), 7.47-7.68 (7H,m), 7.74 (1H,m), 7.91-7.97 (3H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:11](=[O:33])[N:12](COCC[Si](C)(C)C)[N:13]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=4)[CH:15]=3)[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:42]=1.FC(F)(F)C(O)=O.[OH-].[Na+].Cl>ClCCl.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:11](=[O:33])[NH:12][N:13]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=4)[CH:15]=3)[NH:7][C:6]=2[CH:42]=1
Reactant: Cc1cc(-c2cc(-c3nc4ccc(Cl)cc4n3COCC[Si](C)(C)C)c(=O)n(COCC[Si](C)(C)C)n2)cc(C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(-c3nc4ccc(Cl)cc4[nH]3)c(=O)[nH]n2)cc(C)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[6-Chloro-1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-6-(4-hydroxy-3,5-dimethylphenyl)-2-(2-trimethylsilanylethoxymethyl)-2H-pyridazin-3-one is stirred in dichloromethane:trifluoroacetic acid/1:1 at RT for 30 min. The solvent is stripped off in vacuo, and the residue is dissolved in methanol, and 2M sodium hydroxide solution is added. The solution is stirred at RT for 30 min. After the reaction is complete, water is added and 2N hydrochloric acid is used for acidification. The precipitated product is filtered off with suction and purified by column chromatography (RP-HPLC, gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid)).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16]C(=O)C(C)(C)C)=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])=[CH:23][CH:24]=1
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1COCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N)ccc1COCc1ccc(F)cc1

Procedure:
This material was prepared in analogy to example 86 step B] from N-[5-(4-Fluoro-benzyloxymethyl)-6-methyl-pyridin-2-yl]-2,2-dimethyl-propionamide (0.78 g) and 3M aqueous NaOH (3.93 mL) as an amorphous orange solid (0.58 g). MS (ESI): 247.2 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nncs2)=NC1c1ccc(Cl)cc1Cl
Yield: 55.7 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.7 g, 1.5 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.5 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.44 g, 56%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: N1CCC(O[CH2:8][C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:10]=2)CC1.[CH:20]1([CH2:25][C:26](Cl)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:25][C:26]([N:10]2[CH2:11][CH2:14][CH:8]([C:9]3[O:13][N:12]=[C:11]([C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)[N:10]=3)[CH2:8][CH2:9]2)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: c1cc(-c2noc(COC3CCNCC3)n2)ccn1
Reactant: O=C(Cl)CC1CCCC1
Product: O=C(CC1CCCC1)N1CCC(c2nc(-c3ccncc3)no2)CC1

Procedure:
4-[5-(Piperidin-4-yloxymethyl)-[1,2,4]oxadiazol-3-yl]pyridine (Example 51) was reacted with cyclopentylacetyl chloride, in a similar manner to that described in Example 55, to afford the title compound: RT=3.44 min, m/z (ES+)=341.3 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C@H:15]([CH2:17]O)[O:14][N:13]=2)=[CH:8][CH:7]=1>C(Cl)Cl>[Cl:3][CH2:17][C@@H:15]1[O:14][N:13]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)[CH2:16]1
Reactant: O=S(Cl)Cl
Reactant: OC[C@H]1CC(c2ccc(F)cc2)=NO1
Solvent: ClCCl
Product: Fc1ccc(C2=NO[C@@H](CCl)C2)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
Thionyl chloride (1.0 M in CH2Cl2, 6.0 ml, 6.0 mmol) was added dropwise to a solution of ((R)-3-(4-fluorophenyl)-4,5-dihydroisoxazol-5-yl)methanol (1.1 g, 5.6 mmol) in methylene chloride (10 ml) at 0° C. for 1 hour. Then the reaction mixture was allowed to warm to room temperature over 6 hours. The product was isolated and purified by removal of solvent under reduced pressure, followed by preparative chromatography (1:9 MeOH:CH2Cl2) to yield (5R)-5-(chloromethyl)-3-(4-fluorophenyl)-4,5-dihydroisoxazole (1.0 g, 4.8 mmol) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([NH2:28])[CH3:27]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:28][CH2:26][CH3:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CCN
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and ethylamine (2M in THF).
Reaction SMILES: [Mg].II.Br[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.BrCC1CCC1.C(OCC)C.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[O:23]>C(OCC)C>[CH:6]1([CH2:5][CH:22]([OH:23])[C:21]([O:25][CH2:26][CH3:27])=[O:24])[CH2:9][CH2:8][CH2:7]1
Reactant: BrCC1CCC1
Reactant: CCOC(=O)C=O
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CCOC(=O)C(O)CC1CCC1
Temperature: 0 °C

Procedure:
359 mg (14.8 mmol, 1.1 eq.) of magnesium turnings were covered with diethyl ether and etched by addition of a small piece of iodine for 3-4 min. Under argon and at RT, 5 ml of a solution of 2.0 g (13.4 mmol) of (bromomethyl)cyclobutane in 30 ml of diethyl ether were added with stirring to this mixture, the reaction was stirred for 5 min (until the reaction is initiated) and the remainder of the (bromomethyl)cyclobutane/diethyl ether solution is added dropwise over a further 10 min. The reaction mixture was stirred under reflux for 1 h, cooled under a stream of argon and, with ice-water cooling, added dropwise to a solution of 2.4 ml (12.1 mmol, 0.9 eq.) of ethyl glyoxylate (50% in toluene). The reaction mixture was stirred at RT for 1 h, carefully quenched to pH 7 with 20 ml of a potassium citrate/citric acid solution (pH 5) and then adjusted to pH 4-5 with aqueous hydrochloric acid (1N). After phase separation, the aqueous phase was extracted with diethyl ether. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel 50, mobile phase: cyclohexane/ethyl acetate 20%-33%). Yield: 110 mg (purity 94%, 5% of theory)