Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([S:8][C@@H:9]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]2[OH:19])[CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[S:8]([C:3]1[CH:2]=[CH:1][C:6]([NH:7][C:20]([CH3:21])=[O:22])=[CH:5][CH:4]=1)[C@@H:9]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[C@H:10]1[OH:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Solvent: O
Product: CC(=O)Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reaction time: 0.12 h

Procedure:
To a solution of 1.77 g of p-aminophenyl-1-thio-β-D-glucopyranoside in 10 ml of water was added 0.9 ml of acetic anhydride. The solution was shaken for 7 minutes, then taken to dryness and evaporated with toluene to a residue. This residue was crystallized from ethyl acetate giving 2.0 g of the desired product, mp. 160°-163° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br.Br[CH2:18][C:19]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1)=[O:20]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:18]=1[C:19]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1)=[O:20]
Reactant: O=C(CBr)c1cc(Cl)ccn1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Agent: Br
Product: CCOC(=O)n1c(C(=O)c2cc(Cl)ccn2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-(bromoacetyl)-4-chloropyridine hydrobromide*.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:30]C(OCC1C=CC=CC=1)=O)=[N:19]C(OCC1C=CC=CC=1)=O)=[O:4].[ClH:41].[H][H]>[Pd].CO>[ClH:41].[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:9]([CH3:12])(=[O:11])=[O:10])[C:7](=[O:13])[C@H:6]1[CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH2:30])=[NH:19])=[O:4]
Reactant: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1S(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H]1[C@H](CCCNC(=N)N)C(=O)N1S(C)(=O)=O
Yield: 30 %

Procedure:
A methanol solution of compound 11 (0.29 g, 0.5 mmol) and 1N HCl (0.5 mL), containing 10% palladium on carbon, was stirred under 35 psi of hydrogen atmosphere for 2 h. The suspension was filtered through a pad of Celite and the filtrate was concentrated to afford 52 mg (30%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([CH3:16])([CH3:15])[C:13]#[N:14])[C:6](=O)[C:5]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1.N.C1COCC1>[Ni].CCO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][N:14]=[C:6]3[C:5]3([O:18][CH2:19][CH2:20][CH2:21][O:22]3)[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)CN1C(=O)C2(OCCCO2)c2cc(Cl)ccc21
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CN=C2N(C1)c1ccc(Cl)cc1C21OCCCO1
Temperature: 135 °C

Procedure:
A mixture of 3-(5′-chloro-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′(2′H)-yl)-2,2-dimethylpropanenitrile (0.81 g, 2.53 mmol ), and wet Raney Nickel (0.88 g), in 2M EtOH.NH3 (60 mL) and THF (10 mL) was hydrogenated in a Parr Hydrogenation Bottle (500 mL) at 56 lb/in2 H2 for 17 hr. The Raney Nickel was removed by filtration through Sulka Floc and the filtrate was poured into a steel pressure vessel and heated at 135° C. for 22 hr. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3OH/NH4OH, (97/2/1) to give the title compound as an off white solid (0.68 g, 88% yield). Anal. Calc'd for C16H19ClN2O2: C, 62.64; H, 6.24; N, 9.13. Found: C, 62.59; H, 6.19; N, 9.04. NMR (300 Mz, DMSO-d6): consistent; IR: consistent MS: (ES+) m/z 307 [M+H], one Cl pattern observed; m.p.: 121-122° C.
Reaction SMILES: Cl.Cl.[Cl:3][CH2:4][CH2:5][N:6]([CH2:14][CH2:15][Cl:16])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.O=C(Cl)[O:19][C:20](Cl)(Cl)[Cl:21]>C1COCC1>[ClH:3].[Cl:3][CH2:4][CH2:5][N:6]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:20]([Cl:21])=[O:19])=[CH:9][CH:8]=1)[CH2:14][CH2:15][Cl:16]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(N(CCCl)CCCl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Cl)Nc1ccc(N(CCCl)CCCl)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of N,N-bis(2-chloroethyl)benzene-1,4-diamine hydrochloride (37) (0.306 g, 1.0 mmol) in dry THF (25 mL) was added dropwise a solution of diphosgene (197 mg, 1.2 mmol) in an ice bath with vigorous stirring. After being stirred for 30 min, it formed the known crude p-[(N,N-bis(2-chloroethyl)amino)]phenylcarbamoyl chloride hydrochloride (38). The reaction mixture was then neutralized by adding Et3N (0.5 mL), continuously stirred for 10 min, filtered through a pad of Celite and washed with THF (5 mL). The filtrate and washings were combined and was added dropwise into a solution of 3-(acridin-9-yl)amino-5-hydroxymethylaniline (6, AHMA)18 (0.351 g, 1.0 mmol) in dry DMF (10 mL) containing Et3N (0.5 mL) at 0° C. After being stirred for 18 h, the reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in a mixture of CHCl3/MeOH, mixed with silica gel (5 gm) and evaporated in vacuo to dryness. The residue was put on the top of a silica gel column (2×20 cm) and chromatographed using CHCl3/MeOH (100:5 v/v) as eluent. The fractions containing the main product were combined and evaporated in vacuo to dryness and residue was recrystalized from CHCl3/MeOH to give 1-[3-(acridin-9-ylamino)-5-hydroxymethylphenyl]-3-{4-[bis(2-chloroethyl)amino]phenyl}urea (15, BO-1037), 205 mg (35%); mp 173-175° C.; 1H NMR (DMSO-d6) δ 3.67 (8H, m, 4×CH2), 4.41 (2H, d, J=6.0 Hz, CH2), 5.14 (1H, t, J=6.0 Hz, exchangeable, OH), 6.37 (1H, s, ArH), 6.68 (2H, d, J=9.1 Hz, 2×ArH,), 6.81 (1H, s, ArH), 7.01 (1H, s, ArH), 7.05-7.19 (1H, m, ArH), 7.24 (2H, d, J=9.1 Hz, 2×ArH), 7.55 (4H, m, 4×ArH) 8.05 (2H, m, 2×ArH), 8.25 (1H, m, ArH) 8.46 (1H, m, ArH), 10.48 (1H, brs, exchangeable, NH). Anal. Calcd. for (C31H29Cl2N5O2): C, 63.81; H, 5.18; N, 12.00. Found: C, 64.07; H, 5.26; N, 11.87.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H][H]>[Pd].C(O)(C)C>[C:4]([O:11][CH:8]1[CH2:9][CH2:10][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH2:6][CH2:7]1)(=[O:3])[CH2:5][CH3:6]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CCOC(=O)C1CCC(OC(=O)CC)CC1
Reaction time: 4 h

Procedure:
289 Grams of ethyl-p-hydroxybenzoate and 4 grams of 5% palladium on carbon are charged to a 1-liter magnetically stirred autoclave. The material is hydrogenated at 125°-140° C. and 50 psig hydrogen pressure. Hydrogenation is continued until the uptake is approximately 70% of theory. GLC analysis indicates that the reaction mass is now 71% ketone and 7.6% alcohol. The reaction product is cooled, diluted with isopropyl alcohol, filters. The isopropyl alcohol is removed by stripping and the remainder is distilled through a short column. 286 Grams of the resulting distillate is admixed with 75 grams of propionicanhydride at 100° C. for a period of four hours. The resulting material is washed until neutral and distilled through an eight plate vigreux column yielding the following fractions:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=2[O:40][CH3:41])[C:4]=1[O:42][CH2:43][O:44][CH3:45].CN(C)P(=[O:55])(N(C)C)N(C)C.CN(C)CCN(C)C.C([Li])CCC>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([O:13][CH2:14][O:15][CH3:16])[C:6]([O:17][CH3:18])=[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]([OH:55])=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=2[O:40][CH3:41])[C:4]=1[O:42][CH2:43][O:44][CH3:45]
Reactant: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c(OC)c1OCOC
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCc1c(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(O)c(OC)c2OCOC)c(OC)c1OCOC
Reaction time: 0.5 h

Procedure:
Under argon gas stream conditions 2 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3-{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]pentyl}benzene was dissolved in 50 ml of a mixed solvent of anhydrous toluene-tetrahydrofuran (4:1), to this solution were added 10 ml of hexamethylphosphoric triamide and 0.94 ml of N,N,N',N'-tetramethylethylenediamine, then the whole mixture was cooled on a dry ice-acetone bath. 4 Milliliter of n-butyllithium (1.5 M, n-hexane solution) was added dropwise to the reaction mixture and stirred 30 minutes. Next, oxygen gas was bubbled into the reaction mixture for 30 minutes, then the temperature of the reaction mixture was returned back to room temperature by taking for 4 hours. The reaction mixture was concentrated, to the residue obtained was added 100 ml of ethyl acetate, then the ethyl acetate layer was washed twice with 30 ml of a saturated sodium bisulfite aqueous solution, once with 30 ml of water, further washed once with 30 ml of a saturated sodium chloride aqueous solution. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated, then the residue obtained was purified by a silica gel column chromatography (eluent: ethyl acetate-n-hexane=1:9) to obtain 1.3 g of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-6-butyl-3{5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-hydroxyphenyl]pentyl}benzene. Colorless oily substance.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:7].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:29]=2[C:30]([NH:32][CH2:33][C:34]#[CH:35])=[O:31])[C:24]([Cl:41])=[CH:23][N:22]=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([NH:19][C:21]3[N:26]=[C:25]([NH:27][C:28]4[C:29]([C:30](=[O:31])[NH:32][CH2:33][C:34]#[CH:35])=[CH:36][CH:37]=[CH:38][C:39]=4[F:40])[C:24]([Cl:41])=[CH:23][N:22]=3)=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCOC(=O)N1CCCOc2cc(N)ccc21
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OCCOC)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 2-methoxy-ethyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1410. Product isolated as a white foam (70 mg, 44%). LCMS (me/) 569 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.47-9.36 (m, 1H), 9.24-9.15 (m, 1H), 9.05-8.95 (m, 1H), 8.19 (s, 1H), 7.57-7.41 (m, 3H), 7.33-7.23 (m, 1H), 7.14-7.05 (m, 1H), 6.93 (d, 1H, J=8.7 Hz), 4.23-3.87 (m, 6H), 3.67-3.49 (m, 2H), 3.46-3.37 (m, 1H), 3.36-3.26 (m, 2H), 3.23-3.14 (m, 2H), 3.11 (t, 1H, J=2.4 Hz), 1.97-1.84 (m, 2H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][CH:38]=[CH:37][C:27]=2[N:28](C(OC(C)(C)C)=O)[N:29]=1)=O)(C)(C)C.[CH3:40][Mg]Br.O>O1CCCC1>[C:18]1([C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][C:9]([C:25]2[C:26]4[S:39][CH:38]=[CH:37][C:27]=4[NH:28][N:29]=2)=[CH:10]3)([OH:24])[CH3:40])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C(=O)c4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of 5-benzoyl-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [Intermediate (13)] in anhydrous tetrahydrofuran (5 mL) is added methylmagnesium bromide (1M in tetrahydrofuran, 0.8 mL) at −78° C. Stirred under nitrogen for 30 minutes. Added another 0.88 mL of methylmagnesium bromide and let the reaction warm to room temperature slowly. After overnight water/saturated ammonium chloride (2 mL) is added at 0° C. and extracted twice with ethyl acetate (25 mL). The combined ethyl acetate phases are washed with brine and dried over sodium sulfate. The residue is chromatographed on 10 g silica gel, eluting with 30 to 50% ethyl acetate gradient in heptane to afford 1-phenyl-1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-ethanol (56 mg, 71%, Example 26) as a beige solid; LC/MS: 360 (M+H); 1H NMR [(CD3)2SO)]: δ 13.20 (1H, s), 11.45 (1H, s), 7.73 (1H, d), 7.62 (1H, s), 7.43 (2H, m), 7.25 (6H, m), 6.59 (1H, s), 5.53 (1H, s), 1.86 (3H, s).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:21][NH:22][C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])C1C=CC=CC=1.[ClH:29]>C(O)C.[Pd]>[ClH:29].[C:25]([C:23]([NH:22][CH2:21][CH:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1)=[O:24])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)C(=O)NCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)C(=O)NCC1CNCCN1
Temperature: 40 °C
Yield: 68.6 %

Procedure:
2.44 g (6.43 mmol) of 1,4-dibenzyl-2-tert-butylcarbonylaminomethylpiperazine are dissolved in 50 ml of ethanol and 1 ml of 12N HCl in a 100-ml ground-necked round-bottomed flask. About 100 mg of palladium (10%) on charcoal are added thereto. The mixture is then placed under a hydrogen atmosphere, stirred vigorously and heated gently (40° C.) for 3 hours. The suspension is filtered on paper and the catalyst is rinsed several times with ethanol and water. The solvents are evaporated off to give 1.2 g of 2-tert-butylcarbonylaminomethylpiperazine hydrochloride. Yield: 68.6%. Melting point: 278.6° C. Rf=0.13 (80/20/[lacuna] v/v/v CHCl3/MeOH/NH4)OH).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH3:11][C:12]1([CH3:19])[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:11][C:12]1([CH3:19])[C:16](=[O:17])[CH:15]=[C:14]([CH:18]=[CH:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])[O:13]1
Reactant: CC1=CC(=O)C(C)(C)O1
Reactant: N#Cc1cccc(C=O)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2cccc(C#N)c2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A solution of 3-cyanobenzaldehyde (2.5 g, 19 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was stirred for one day at room temperature. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The product was recrystallized from hexane-ethyl acetate to afford an analytically pure sample (1.5 g, 43% yield), m.p. 155°-157° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([NH:12][P:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14])[CH2:9][CH:10]=[CH2:11].NC1C=CC=CC=1O.[O-2].[Al+3].[O-2].[O-2].[Al+3].[CH2:40]([N:44](CCCC)[C:45]1C=C[C:48](/C=N/P(C2C=CC=CC=2)(C2C=CC=CC=2)=O)=[CH:47][CH:46]=1)[CH2:41][CH2:42][CH3:43]>ClCCl.C(OCC)C.CO>[CH2:40]([N:44]([CH2:45][CH2:46][CH2:47][CH3:48])[C:6]1[CH:5]=[CH:4][C:3]([C@H:8]([NH:12][P:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:9][CH:10]=[CH2:11])=[CH:2][CH:7]=1)[CH2:41][CH2:42][CH3:43]
Reactant: C=CC[C@@H](NP(=O)(c1ccccc1)c1ccccc1)c1ccccc1F
Reactant: CCCCN(CCCC)c1ccc(/C=N/P(=O)(c2ccccc2)c2ccccc2)cc1
Agent: Nc1ccccc1O
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: C=CC[C@@H](NP(=O)(c1ccccc1)c1ccccc1)c1ccc(N(CCCC)CCCC)cc1
Reaction time: 6 h
Yield: 93 %

Procedure:
The title compound is synthesized analogously to 4b except for the following changes: 1) 2.5 mol % aminophenol 2g (instead of 3 mol % 2g) 2) 1.5 equiv. MeOH (instead of 2.5 equiv.). 3) Reaction time is six h. 4) After NaIO4 workup (see representative procedure above), the unpurified mixture is treated for 12 h while allowing it to stir with ˜1 g basic aluminum oxide in 4 mL dichloromethane:diethyl ether (1:1) to hydrolyze unreacted 3j, after which the aluminum oxide is filtered off and washed with dichloromethane and ethyl acetate (20 mL). The product is purified as described for 4b, affording 4j (44.2 mg, 0.0931 mmol, 93% yield) as a white solid. M.p.=83-84° C. IR (neat): 3154 (w, br), 3071 (w), 2955 (m), 2930 (m), 2870 (m), 1614 (m), 1519 (m), 1455 (m), 1436 (m), 1368 (w), 1283 (w), 1181 (s), 1107 (s), 1066 (m), 925 (m), 900 (m), 752 (w), 722 (s), 693 (s), 553 (s), 521 (s) cm−1; 1H NMR (400 MHz, CDCl3): δ 7.89-7.79 (4H, m), 7.49-7.32 (6H, m), 7.03 (2H, d, J=8.8 Hz), 6.54 (2H, d, J=8.8 Hz), 5.63 (1H, app ddt, J=17.2, 10.0, 7.2 Hz), 5.10-4.99 (2H, m), 4.26-4.19 (1H, m), 3.23 (4H, app dd, J=7.8, 7.2 Hz), 3.26-3.21 (1H, m, overlapping with the dd at 3.23), 2.75-2.58 (2H, m), 1.59-1.52 (4H, m), 1.40-1.30 (4H, app sextet, J=7.6 Hz), 0.96 (6H, t, J=7.6 Hz); 13C NMR (100 MHz, CDCl3): δ 147.3, 134.6, 133.6 (d, J=127.0 Hz), 132.6 (d, J=9.5 Hz), 132.4 (d, J=130.0 Hz), 131.9 (d, J=9.3 Hz), 131.7 (d, J=2.7 Hz), 131.6 (d, J=2.7 Hz), 129.2 (d, J=6.3 Hz), 128.4 (d, J=12.3 Hz), 128.3 (d, J=12.4 Hz), 127.6, 118.1, 111.5, 54.3, 50.9, 43.5 (d, J=3.7 Hz), 29.5, 20.4, 14.1; HRMS Calcd for C30H40N2OP [M+H]+: 475.28782. Found: 475.28783. [α]20D=+61.6 (c=1.33, CHCl3) for a 92:8 er sample. The enantiomeric purity of this compound was determined by HPLC analysis in comparison with authentic racemic material (Chiracel OD-H, 92:8 hexanes:i-PrOH, 0.5 mL/min, 220 nm): tR of 4j: 12 min (major) and 14 min (minor).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[CH2:7]2.[CH:16](OCC)=[O:17]>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[C:7]2=[CH:16][OH:17]
Reactant: CCOC=O
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Agent: [Na]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(=CO)C(=O)N2

Procedure:
To a warm solution of 1.5 g. sodium in 35 ml. ethanol was added 10 g. of 5,6-dimethoxy oxindole [J. Am. Chem. Soc. 77 3844 (1955)]. Then 30 ml. ethyl formate was added. A solid formed. The mixture was stirred and heated 10 minutes. A stream of nitrogen was blown over the mixture to evaporate as much solvent as possible. Then a solution of 6.5 ml. concentrated hydrochloric acid and 50 ml. water was added. The resulting clear solution was concentrated in vacuum and the resulting solid filtered and washed with ice water. Yield: 10.55 g., m.p. 216°-217° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:10]=[C:11]([CH:13]=O)[N:12]=2)=[CH:4][CH:3]=1.[N:25]1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)[CH:10]=[C:11]([C:13]#[N:25])[N:12]=2)=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: CS(=O)(=O)c1ccc(-n2cc(C=O)nc2-c2ccc(Cl)cc2)cc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2cc(C#N)nc2-c2ccc(Cl)cc2)cc1

Procedure:
A solution of 82 mg (0.23 mmole) of 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-4-carboxaldehyde (Example 163) and 51 mg (0.45 mmole) of hydroxylamine O-sulfonic acid in 10 ml of absolute ethanol and 1 ml of pyridine was stirred at reflux overnight. After cooling, the mixture was evaporated, and the residue was taken up in dichloromethane. The solution was washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 50% ethyl acetate in hexane as the eluent gave the title compound; 71 mg, as a pure white crystalline solid: mp (DSC) 205° C. Anal. Calc'd. for C17H12ClN3O2S.¼H2O (MW 362.32): C, 56.36; H, 3.34; N, 11.60. Found: C, 56.49; H, 3.27; N, 11.45.
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:2]([N:21]2[CH:20]=[N:19][N:18]=[CH:22]2)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6])=[CH:12][CH:13]=1
Reactant: C=CC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Solvent: CC#N
Product: C=CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cnnc1
Yield: 20 %

Procedure:
89 g (0.28 mol) of 5-bromo-5-(4-chlorophenoxy)-3,3-dimethylpent-1-en-4-one, dissolved in 120 ml of acetonitrile, were added dropwise, in the course of 30 minutes, to a solution of 115.9 g (1.68 mols) of 1,2,4-triazole in 1,000 ml of acetonitrile at 50° C. After the solution had been heated at the boil for three hours, the solvent was distilled off and the residue was taken up in 300 ml of ethyl acetate. The solution was washed three times with 50 ml of water, and the organic phase, after having been dried over anhydrous sodium sulphate, was concentrated by evaporation under reduced pressure. The residual oil was dissolved in 400 ml of acetone, and a solution of 80.6 g of naphthalene-1,5-disulphonic acid in 400 ml of acetone was added. The salt which had crystallized out was filtered off under suction and washed with acetone, 250 ml each of water and dichloromethane were stirred with the salt, and the mixture was then rendered alkaline with a 10% strength sodium carbonate solution. The oil which remained after the organic phase had been evaporated off was dissolved in a small amount of ether, and petroleum ether was then slowly added to the solution. The product which crystallized out in the process was filtered off and washed with a small amount of ether/petroleum ether. 17.1 g (20% of theory) of 5-(4-chlorophenoxy)-3,3-dimethyl-5-(1,2,4-triazol-4-yl)-pent-1-en-4-one (Compound 3) of melting point 124° to 126° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:27]4=[O:34])[CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][CH:3]=1.CS(C)=O.[ClH:39]>O>[Cl:39][C:9]1[N:10]([CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[C:27]3=[O:34])[CH2:22][CH2:23]2)[C:11]2[C:16]([C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2C1CCN(CCN2CCN(C(C)C)C2=O)CC1
Reactant: Cl
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)c(Cl)n2C1CCN(CCN2CCN(C(C)C)C2=O)CC1
Temperature: 60 °C

Procedure:
A mixture of 3-(4-Fluorophenyl)-5-methyl-1-[1-[2-[3-(2-propyl)imidazolidin-2-on-1yl]ethyl]-4-piperidyl)-1H-indole 4h (3.0 g), dimethylsulphoxide (0.51 g) and conc. aqueous HCl (1 ml) was heated to 60° C. for 0.5 h under stirring. The reaction mixture was cooled to room temperature and water was added. The solution was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with 4N aqueous NaOH and brine. Evaporation of the solvent gave an oil which was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:3). This afforded the title compound which crystallized from diethyl ether. Yield 0.4 g, mp 127°-130° C.