Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[O:22]C)=[O:12].B(Br)(Br)Br.CCCCCC.CCOC(C)=O>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[OH:22])=[O:12]
Reactant: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2OC)c(OC)c1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(O)cc1O)c1ccc([N+](=O)[O-])cc1O
Temperature: 40 °C
Reaction time: 16 h

Procedure:
(2,4-Dimethoxy-phenyl)-(2-methoxy-4-nitro-phenyl)-methanone (394) (0.4 g, 1.26 mmol) was dissolved in CH2Cl2 and BBr3 was added. The mixture was heated to 40° C. while shaking in a sealed 40 mL I-Chem vial for 16 h. TLC (Rf: 0.5 compared to Rf: 0.65 for compound 394 in 1:1 hexane/EtOAc, single spot) indicated the complete de-methylation at this point. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (eluding with 15–100% EtOAc/hexane in 30 minutes) gave the desired product (395) as a yellow solid upon concentration (0.255 g, 0.927 mmol, 73.5%). The product was used in the next step without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[CH:10]=[N:9]2)=[N:6][CH:7]=1.[F:16][C:17]1[CH:18]=[CH:19][C:20]([I:26])=[C:21]([CH:25]=1)[C:22]([OH:24])=O>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([I:26])=[C:21]([C:22]([N:6]2[CH2:5][CH2:4][CH2:3][O:15][CH:14]2[CH2:13][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[CH:12]=2)=[O:24])[CH:25]=1
Reactant: OCCc1cnn(-c2ccc(F)cn2)c1
Reactant: O=C(O)c1cc(F)ccc1I
Product: O=C(c1cc(F)ccc1I)N1CCCOC1Cc1cnn(-c2ccc(F)cn2)c1

Procedure:
By using 2-[1-(5-fluoropyridin-2-yl)-1H-pyrazol-4-yl]ethanol obtained in Reference Example 22 (0.21 g, 1.0 mmol) and 5-fluoro-2-iodobenzoic acid (0.16 g, 0.60 mmol), the same procedure as in Reference Example 25 was carried out to obtain the title compound (0.15 g) (pale yellow oil).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[OH-:22].[K+].[O-:24][Mn](=O)(=O)=O.[K+]>C(O)C>[C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])=[O:22])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: Cc1ccc(C(C)(C)CC(C)(C)C)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)CC(C)(C)c1ccc(C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 61.31 grams (0.30 mol) of 4-t-octyltoluene, 161.5 grams of pyridine, and 80.8 grams of 32% KOH was heated on a steam bath. To this mixture was added, in 10 gram portions every 30 minutes, 117.22 grams (0.74 mol) of KMnO4. The reaction mixture was heated overnight and then 10 ml of ethanol was added. After 30 minutes, the mixture was filtered hot and the solid was washed with water. The combined filtrate and washes were heated for another 10 minutes on a steam bath and filtered again with water wash. The yellow filtrate comprised of two layers was acidified with concentrated HCl. On cooling, the upper layer crystallized. This solid was collected, washed with water and dried. The solid was washed with Ligroine (bp=35°-60° C.), dissolved in ether, washed with water, dried over MgSO4 and concentrated. The residue was recrystallized from heptanes. Yield was 14.3 grams (20.34%). Melting point=153°-155° C. Elemental analysis found C=76.72, H=9.39. This compares to calculated values for C15H22O2 of C=76.88, H=9.46. An NMR spectrum, in CDCl3 was obtained in which agreed with the structure of the expected product.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7](/[C:11](/[CH3:19])=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([CH3:21])([CH3:20])[C:3]1=[O:22].[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:23])[C:10]2[C:5](=[CH:6][C:7](/[C:11](/[CH3:19])=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([CH3:21])([CH3:20])[CH:3]1[OH:22]
Reactant: C/C(=C\c1ccccc1)c1ccc2c(c1)C(C)(C)C(=O)C2(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C/C(=C\c1ccccc1)c1ccc2c(c1)C(C)(C)C(O)C2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
1.4 g of 1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]-2-indanone are dissolved in 100 ml of ethanol and treated at room temperature with 6 g of sodium borohydride. After stirring at room temperature for 16 hours the reaction mixture is poured on to ice and extracted repeatedly with ether. The organic phase is washed with saturated sodium chloride solution, dried and evaporated. The residue can be recrystallized from hexane and gives 1.1 g of 1,1,3,3-tetramethyl-5-[(E)-α-methylstyryl]-2-indanol in colourless crystals, melting point 63°-67°.
Reaction SMILES: FC(F)(F)[C:3]([N:5]([CH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)C)=O>Cl.O>[CH3:3][NH:5][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1
Reactant: CN(C(=O)C(F)(F)F)C1CCC(O)CC1
Agent: Cl
Solvent: O
Product: CN[C@H]1CC[C@H](O)CC1

Procedure:
2 g of 2,2,2-trifluoro-N-(4-hydroxy-cyclohexyl)-N-methyl-acetamide (149) were suspended in 10 mL of 1N HCl and heated in a microwave at 150° until conversion was complete. The resulting solution was lyophilized and the residue was taken up in water and lyophilized again, twice to yield 1.45 g of 4-methylamino-cyclohexanol (150). Rt=0.13 min (Method C). Detected mass: 130.3 (M+H+).
Reaction SMILES: S1C=CN=C1.[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[S:24][CH:25]=[C:26]([CH2:28][CH3:29])[N:27]=4)=[CH:18][CH:17]=3)[C:8]=12.Br[CH2:44][C:45]([C:47]1[CH:52]=CC(C)=C[CH:48]=1)=O>>[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:23]4[S:24][CH:25]=[C:26]([C:28]5[CH:44]=[CH:45][C:47]([CH3:52])=[CH:48][CH:29]=5)[N:27]=4)=[CH:20][CH:21]=3)[C:8]=12
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CCc1csc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)n1
Agent: c1cscn1
Product: Cc1ccc(-c2csc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)n2)cc1

Procedure:
The procedure for thiazole synthesis, described in the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-ethyl-1,3-thiazol-2-amine, was employed with the exception that 2-bromo-4′-methylacetophenone (0.118 g, 0.554 mmol) was used as the alkylating agent. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 9.1-10.7 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-(4-methylphenyl)-1,3-thiazol-2-amine as an off-white powder (0.022 g, 0.038 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.88 min; MS (MH)+ 580.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[Mg].C1O[C:17]2([CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[O:16]C1>O1CCCC1>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([C:20]3[CH2:21][CH2:22][C:17](=[O:16])[CH2:18][CH:19]=3)[CH:3]=[CH:4][C:5]=2[O:9]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC1(C)Cc2cc(Br)ccc2O1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C3=CCC(=O)CC3)ccc2O1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 7, using 9.2 grams (0.040 mole) of 5-bromo-2,3-dihydro-2,2-dimethylbenzofuran, 1.1 grams (0.044 mole) of magnesium turnings, and 6.2 grams (0.040 mole) of 1,4-cyclohexanedione mono-ethylene ketal in about 70 mL of tetrahydrofuran, yielding 1-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)-1-cyclohexen-4-one.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:2]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:26])[CH3:25]
Reactant: CCOC(=O)CCN
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN([Si](C)(C)C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 39 h
Yield: 89.6 %

Procedure:
About 7.23 g of ethyl 3-aminopropionate hydrochloride, 15.71 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 23.00 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 39 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl 3-[bis(trimethylsilyl)amino]propionate (3-BTMSAEP) as a colorless oil (11.03 g, 90% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 3.91 (quartet, 2H, OCH2 protons), 3.21 (multiplet, 2H, NCH2CH2 protons), 2.36 (multiplet, 2H, NCH2CH2 protons), 0.91 (triplet, 3H, CH3 protons), 0.07 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34]OS(C)(=O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1ccccn1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4ccccn4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with methanesulfonic acid pyridin-2-ylmethyl ester (described in WO 9955318) gave the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[C:13]([Li])#[C:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1COCC1.CN(P(N(C)C)N(C)C)C>[C:11]([Br:12])#[C:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrCCCCCCCCCCBr
Reactant: [Li]C#CCCCC
Agent: CN(C)P(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC#CBr
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A 3 liter, 2-necked round bottom flask was equipped with a magnetic stir bar, an inlet valve and a septum. After being purged with an argon atmosphere, the flask was charged with 615 g (2.1 mol) of 1,10-dibromodecane in 350 mL of THF and 125 mL of hexamethylphosphorus triamide. A solution containing about 1 mol of hexynyllithium, prepared as described above, was then added to the solution of dibromide via the septum. The reaction mixture was allowed to stir overnight, then quenched by pouring over about 1 L of water. The reaction mixture was diluted with about 500 mL of hexane, phases separated and the organic layer washed twice with 500 mL aliquots of water. The organic layer was then dried over MgSO4, filtered, solvent stripped on the rotary evaporator, then vacuum distilled through a 2 foot column packed with 1/4" glass helices. About 104 g (35 mol % yield) of hexadecynyl bromide was obtained with a boiling point of 135° C. @ 0.3 mm Hg.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7]>C1(C)C=CC=CC=1>[Cl-:1].[C:3]([CH2:2][N+:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][CH3:7])([OH:5])=[O:4]
Reactant: O=C(O)CCl
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC[N+](CC)(CC)CC(=O)O
Product: [Cl-]
Temperature: 100 °C

Procedure:
In 200 cc of toluene was dissolved 47.25 g (0.5 mole) of monochloroacetic acid and 50.5 g (0.5 mole) of triethylamine was added to the solution. When the mixture was heated at about 100° C., a white precipitate was immediately formed. The precipitate was recovered by filtration and washed with ethanol. Carboxymethyl triethylammonium chloride was obtained substantially in the theoretical amount. The obtained chloride was dissolved in 150 cc of ethanol and the solution was maintained at 60° C., and when the above-mentioned ethanol solution of the aminomethanol derivative was added to the solution and the mixture was stirred, a turbid slurry was immediately formed. The reaction was completed within about 2 hours, and the reaction mixture was filtered and the recovered precipitate was rinsed two times with 20 cc of warm methanol and was washed and dried.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:7]=3[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1>CO.CN(C)C=O.[Pd]>[NH2:17][C:14]1[CH:15]=[CH:16][C:6]2[C:5]3[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)[O:9][C:8](=[O:12])[C:7]=2[CH:13]=1
Reactant: O=c1oc2cc(O)ccc2c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc2c(c1)c(=O)oc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-8-nitrobenzo[c]chromen-6-one (Reference Compound No. 1-1-(2), 52.01 g, 202 mmol) was dissolved in methanol (150 mL)-N,N-dimethylformamide (600 mL), 10% palladium on charcoal (5.00 g) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere (3 kgf/cm2) at room temperature overnight. After the unsoluble materials were filtered, the methanol was removed under reduced pressure. Water (2 L) was added to the residue. The precipitated solid was filtered and dried at 90° C. under reduced pressure to give the titled reference compound (44.02 g) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:14]C)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[Na+].Cl.O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)[C@H](Nc1ccc(C#N)c(Br)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(N[C@@H](C(=O)O)c2ccccc2)cc1Br
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a solution of (R)-methyl 2-(3-bromo-4-cyanophenylamino)-2-phenylacetate (98 mg, 0.28 mmol) in THF (2 mL), 1N aq. NaOH (1.00 mL, 1.00 mmol) was added. After being stirred for 18 h, the solution was acidified with 1N HCl to pH 1-2. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(3-bromo-4-cyanophenylamino)-2-phenylacetic acid (90 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][CH2:18][CH2:19][OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][CH2:18][CH:19]=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(CCCO)nc2ccccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(CCC=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of 3-(1-tert-butoxycarbonyl-Benzimidazol-2-yl)propan-1-ol (186 mg, 0.67 mmol) in CH2Cl2 (4 mL) was added Dess-Martin reagent (314 mg, 0.74 mmol) and the resulting mixture was allowed to stir at room temperature under N2 for 1 hour. The mixture was further diluted with 300-mL ethyl acetate, and washed with 1N NaOH, brine and dried over Na2SO4. Evaporation of the solvent and flash chromatograph of residue over silica gel, using 20% ethyl acetate in CH2Cl2, gave the title compound (141 mg, 76%) as pure white solid. 1H NMR (CDCl3) □ 1.72 (s, 9H), 3.13 (t, 2H, J=6.8 Hz), 3.52 (t, 2H, J=6.8 Hz), 7.28-7.34 (m, 2H), 7.66-7.67 (m, 1H), 7.87-7.91 (m, 1H), 9.97 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](CC#N)[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].CO[CH2:15][CH2:16][O:17]C.[OH-:19].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16]([OH:17])=[O:19])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8]
Reactant: Cc1cc(CC#N)cc(Cl)c1O
Reactant: COCCOC
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: Cc1cc(CC(=O)O)cc(Cl)c1O
Yield: 98.3 %

Procedure:
A suspension of (3-chloro-4-hydroxy-5-methyl-phenyl)-acetonitrile (4b) (1.3 g, 0.0071 mol) in water (2.06 mL) was treated with ethylene glycol dimethyl ether (13.93 mL, 0.133 mol) followed by potassium hydroxide (2.8 g, 0.0071 mol). The reaction mixture was heated to reflux for 24 h. At this time, the reaction mixture was concentrated under vacuum. The resulting solid was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The organic layers were discarded. The water layer was acidified to pH=2 by the addition of a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution (50 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting solid was dried under high vacuum overnight to afford (3-chloro-4-hydroxy-5-methyl-phenyl)-acetic acid (5b) (1.4 g, 97%) as a white solid; EI(+)-HRMS m/z calcd for C9H9ClO3 (M+) 200.0240, found 200.0247. Molecular Weight=200.6233; Exact Mass=200.0240
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)N>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:28]1[CH:27]=[CH:25][CH:24]=[C:23]([Cl:22])[CH:29]=1)(=[O:3])[CH3:2]
Reactant: Nc1cccc(Cl)c1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc(Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a stirred solution of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (100 mg, 0.34 mmol) (Dal Piaz, V et al., J. Med. Chem. 1997, 40, 1417) in ethanol (2 mL), 3-chloroaniline (132 mg, 1.04 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 30 min and the final product was collected by filtration and washed with ethanol and diethylether to yield the title compound (65% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]#[N:9])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.S(=O)(=O)(O)[OH:18].[OH-].[Na+]>O>[CH3:1][C:2]1[C:6]([CH2:7][C:8]([NH2:9])=[O:18])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: Cc1nn(-c2ccccc2)c(C)c1CC#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(-c2ccccc2)c(C)c1CC(N)=O
Temperature: 25 °C
Yield: 63 %

Procedure:
10 grams 3,5-dimethyl-1-phenyl-pyrazol-4-acetonitrile were added to 40 milliliters concentrated sulfuric acid and the mixture was stirred over night at room temperature. The reaction mixture was poured into a mixture of ice and water and the pH was adjusted to 8 by the addition of aqueous sodium hydroxide. 6.8 grams 3,5-dimethyl-1-phenyl-pyrazol-4-acetamide, melting at 169°-170° C., were obtained, representing a yield of 63%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:37]=[CH:36][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:28](=[O:31])[CH2:29]Br)[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.[K]>CN(C=O)C.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:37]=[CH:36][C:15]([CH2:16][N:17]2[C:23](=[O:24])[C@H:22]3[CH2:25][CH2:26][CH2:27][C@H:21]3[N:20]([C:28](=[O:31])[CH2:29][N:42]3[C:41](=[O:43])[C:40]4=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]4[C:38]3=[O:48])[C:19]3[CH:32]=[CH:33][CH:34]=[CH:35][C:18]2=3)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CBr)c3ccccc32)cc1)OCc1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
(3aR*,10aS*)-9-[4-(Benzyloxycarbonylamino)benzyl]-4-(bromoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][l,4]diazepin-10(1H)-one (496 mg, 0.88 mmol) and potassium phthalimide (172 mg, 0.93 mmol) were suspended in DMF (3 mL) and the suspension was stirred at room temperature for 1 hour. This reaction mixture was diluted with water and extracted with 3 portions of chloroform. The pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethanol to provide 495 mg (yield 89%) of the title compound. m.p. 144°-147° C.
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=[O:18].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>[OH-].[Na+]>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[S:29]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]([OH:19])=[O:18])(=[O:30])=[O:31]
Reactant: O=S(=O)(Cl)c1nc2ccccc2[nH]1
Reactant: O=C(O)[C@@H]1CCCCN1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 56 h
Yield: 37.6 %

Procedure:
(2S)-2-Piperidinecarboxylic acid L-tartrate (42 g) [see Preparation 1] was dissolved in 10% w/w aqueous sodium hydroxide solution (600 ml) and 1H-benzo[d]imidazole-2-sulfonyl chloride (39 g) [see Preparation 8] was added. The reaction mixture was stirred at room temperature for 56 hours after which time the product was extracted with ethyl acetate. The organic layer was separated, 2N aqueous hydrochloric acid solution added and the acidic aqueous layer extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 95:5:0.5, by volume, dichloromethane:methanol:glacial acetic acid to afford 1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidinecarboxylic acid (17.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])NC2SC(SCC(O)=O)=CN=2)[CH:5]=[CH:6][CH:7]=1.C([O:34][C:35](=[O:46])[C:36]([S:39][C:40]1[S:44][C:43]([NH2:45])=[N:42][CH:41]=1)([CH3:38])[CH3:37])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:45][C:43]2[S:44][C:40]([S:39][C:36]([CH3:37])([CH3:38])[C:35]([OH:34])=[O:46])=[CH:41][N:42]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCc2cccc(Cl)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.