Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([C:83]([O:85][C:86]([CH3:89])([CH3:88])[CH3:87])=[O:84])[CH2:79][CH2:78]1>CN(C)C=O>[C:86]([O:85][C:83]([N:80]1[CH2:81][CH2:82][CH:77]([NH:76][C:26](=[O:27])[C:25]2[CH:29]=[C:30]([F:31])[C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[CH:23][C:24]=2[F:32])[CH2:78][CH2:79]1)=[O:84])([CH3:89])([CH3:87])[CH3:88]
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3F)ncc21
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
To a mixture of 0.1055 g (0.233 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) and 4 mL of dimethylformamide was added 0.0515 g (0.382 mmole) of 1-hydroxybenzotriazole, 0.1361 g (0.359 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1778 g (1.378 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0742 g (0.370 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.1183 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-239) as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.C(OC[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)(=O)CC(C)=O.[NH2:41]/[C:42](/[CH3:48])=[CH:43]\[C:44]([O:46][CH3:47])=[O:45]>C(O)(C)C>[CH3:48][C:42]1[NH:41][C:42]([CH3:48])=[C:43]([C:44]([O:46][CH3:47])=[O:45])[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=2)[C:43]=1[C:44]([O:46][CH2:47][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:24][CH2:23]1)=[O:45]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc(C(F)(F)F)c1
Yield: 52.5 %

Procedure:
A mixture of m-trifluoromethylbenzaldehyde, 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-(4-benzhydryl-1-piperazinyl)ethyl methyl 2,6-dimethyl-4-(3-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 70°-72° C. Yield 52.5%. The product was further treated with methanolic hydrogen chloride and recrystallized from methanolethyl ether to give the dihydrochloride as colorless crystals, m.p. 168°-170° C.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:35])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:69]1([O:73][C:74]([N:76]2[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]2)=[O:75])[CH2:72][CH2:71][CH2:70]1>CN(C=O)C.ClCCl>[CH:69]1([O:73][C:74]([N:76]2[CH2:81][CH2:80][N:79]([C:31](=[O:32])[C@@H:30]([NH:29][C:27]([C:18]3[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[C:6](=[O:7])[NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:35])[N:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:19]=3)=[O:28])[CH3:34])[CH2:78][CH2:77]2)=[O:75])[CH2:72][CH2:71][CH2:70]1
Reactant: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: O=C(OC1CCC1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Reaction time: 1 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-propionic acid in 2 ml DMF were added 0.14 ml DIPEA, 78 mg HATU and 0.38 mg 1-cyclobutoxycarbonyl-piperazine. After stirring for 1 h it was diluted with dichloromethane and extracted with aqueous LiCl (4 w/w), aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]([O-])=O.[Na+].[ClH:16]>O>[ClH:16].[Br:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][NH2:12])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=N[O-]
Reactant: Nc1ccc(Br)cc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Br)cc1C(=O)O
Reaction time: 2 h

Procedure:
To a suspension of 2-amino-5-bromobenzoic acid (50.0 g, 231.5 mmol) in conc. HCl (250 mL) at −10° C. was added a solution of sodium nitrite (23.92 g, 347.2 mmol) in water (250 mL), slowly, followed by stirring for 2 h. To this reaction mixture was slowly added a solution of stannous chloride (130.50 g, 225.6 mmol) in conc. HCl (125 mL) with continued stirring at RT for 12 h. The reaction mixture was filtered, the residue washed with the minimum amount of water and vacuum dried to afford the title compound as and ‘off white’ solid 61 g (100%), which was used for next step without further purification. Rf=0.10 (ethyl acetate); 1H NMR (400 MHz, DMSO-d6): δ 11.60-9.60 (brs, 3H), 7.93 (d, J=2.4 Hz, 1H), 7.72 (dd, J=2.4 & 8.8 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H); ES-MS: m/z 229.1 (M−H).
Reaction SMILES: O1C2=CN=CC=C2C(=O)C1.C(OC([C:16]1[O:27][C:19]2=[C:20]([CH:24]3[CH2:26][CH2:25]3)[N:21]=[CH:22][CH:23]=[C:18]2[C:17]=1[OH:28])=O)C>>[CH:24]1([C:20]2[N:21]=[CH:22][CH:23]=[C:18]3[C:17](=[O:28])[CH2:16][O:27][C:19]=23)[CH2:26][CH2:25]1
Reactant: CCOC(=O)c1oc2c(C3CC3)nccc2c1O
Agent: O=C1COc2cnccc21
Product: O=C1COc2c1ccnc2C1CC1

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridin-3(2H)-one (A.2.4.3), 3-hydroxy-7-cyclopropylfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester replacing 3-hydroxyfuro[2,3-c]pyridine-2-carboxylic acid ethyl ester;
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:2]1.C(N(CC)CC)C.[C:26](=[S:28])=[S:27].[CH3:29]I>C(O)C>[CH3:29][S:27][C:26]([N:2]1[C@@H:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:28]
Reactant: S=C=S
Reactant: CI
Reactant: CCOC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SC

Procedure:
In the same manner as described in Example 53, ethyl (3R)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (224 mg), triethylamine (120 mg), carbon disulfide (0.08 ml), ethanol (25 ml) and methyl iodide (0.08 ml) are reacted and treated. The product is crystallized from ether to give the title compound (140 mg) as colorless prisms, m.p. 139°-141° C.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4].[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>>[CH2:3]([O:5][C:6](=[O:35])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:39]([CH:36]3[CH2:38][CH2:37]3)=[O:40])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CNCc2ccccc2)c1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: {3-[2-(benzylamino-methyl)-quinolin-3-yl]-4-methoxy-phenyl}-acetic acid ethyl ester, dihydrochloride and cyclopropanecarbonyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C1COCC1.C([Li])CCC.[Cl-:26].[Cl-].[CH3:28][Zr:29]([CH3:51])(=[SiH2:50])([CH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[C:41]1[CH3:49])[CH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH3:39]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O-:15])([CH3:4])([CH3:3])[CH3:2].[Cl-:26].[CH3:51][Zr:29]([CH3:28])(=[SiH2:50])([CH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[C:41]1[CH3:49])[CH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[CH3:39]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: CC1=Cc2ccccc2C1[Zr](C)(C)(=[SiH2])C1C(C)=Cc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc([O-])c(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.03 g (5 mmol) of 2,4-di-tert-butylphenol in 10 ml of toluene/1 ml of THF were admixed at room temperature with 1.85 ml (5 mmol) of a 20% strength solution of butyllithium in toluene. The mixture was stirred for another 1 hour at 60° C. At room temperature, 1.19 g (2.5 mmol) of dimethylsilanediylbis-(2-methylindenyl)zirconium dichloride were added as a solid. The suspension was stirred for 2 hours at 60° C. and subsequently filtered hot through Celite. The filter cake was extracted 3 times with 10 ml each time of toluene (60° C.). After evaporation of part of the solvent, the yellow solid which precipitated was filtered off and dried under reduced pressure. This gave 0.87 g (53%) of dimethylsilanediylbis(2-methylindenyl)zirconium monochloride mono(2,4-di-tert-butylphenoxide) (2).
Reaction SMILES: C(N=NC(SCCO)(C)C)(C)(C)C.C(Cl)(Cl)=O.[Cl:18][C:19]([O:21][CH2:22][CH2:23][S:24][C:25]([N:31]=[N:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:30])[CH2:26]C(C)C)=[O:20]>>[Cl:18][C:19]([O:21][CH2:22][CH2:23][S:24][C:25]([N:31]=[N:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:30])[CH3:26])=[O:20]
Reactant: CC(C)CC(C)(N=NC(C)(C)C)SCCOC(=O)Cl
Agent: CC(C)(C)N=NC(C)(C)SCCO
Agent: O=C(Cl)Cl
Product: CC(C)(C)N=NC(C)(C)SCCOC(=O)Cl

Procedure:
4-t-Butylazo-4-methyl-3-thiapentyl chloroformate was prepared from 2-t-butylazo-2-(β-hydroxyethylthio)propane and phosgene using the procedure described for the synthesis of 4-t-butylazo-4,6-dimethyl-3-thiaheptyl chloroformate in Example VIb.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:13]1[S:17][C:16]([C:18]([O:20]CC)=[O:19])=[N:15][C:14]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]#[N:31])[CH:24]=1.C(=O)(O)[O-].[Na+]>COCCOC.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>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[S:17][C:16]([C:18]([OH:20])=[O:19])=[N:15][C:14]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]#[N:31])[CH:24]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
Reactant: OB(O)c1cc(F)cc(Cl)c1
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: COCCOC
Product: N#Cc1cc(-c2nc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)ccc1F

Procedure:
At room temperature, 256 mg (1.48 mmol) of (3-chloro-5-fluorophenyl)boronic acid are added to 350 mg (0.985 mmol) of the compound from Example 29A and 56.9 mg (0.049 mmol) of tetrakis(triphenylphosphine)palladium in 26 ml of DME. 252 mg (3.01 mmol) of sodium bicarbonate in 11 ml of water are subsequently added, and the mixture is stirred under reflux for 1 h. The reaction solution is subsequently concentrated under reduced pressure and the residue is taken up in ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 50.0 mg (13% of theory) and 41 mg (9% of theory, purity 84%) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].[C:30]([C:32]1[N:33]=[C:34]([C:45]([O-])=[O:46])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=1)#[N:31].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:45]([C:34]3[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=[C:32]([C:30]#[N:31])[N:33]=3)=[O:46])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)CC=C(c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A solution of 89.0 mg (0.231 mmol) 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH2Cl2 was treated with 77.8 mg (0.255 mmol) 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), 162 mg (0.347 mmol) PyBrOP, and 121 μL (0.694 mmol) DIEA and stirred at RT for 2 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated NaHCO3 (1×15 mL) and water (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 50-gm column with 10-25% EtOAc-hexane afforded 124 mg (84%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C31H44N5O4Si, 578.3 (M−C4H9+2H), found 578.0.
Reaction SMILES: [CH3:1][CH:2]([C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[C:14]([CH:16]=1)[OH:15])[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:18]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=O)(=O)[CH3:19].Cl.[C:29](O)(=[O:31])[CH3:30]>>[C:29]([O:17][C:12]1[C:13]2[CH:18]([CH3:19])[C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[O:15][C:14]=2[CH:16]=[C:10]([CH:2]([CH3:1])[CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:11]=1)(=[O:31])[CH3:30]
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: CC(=O)O
Reactant: CC(=O)C1CCCCC1=O
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC1=C(CCCC1)C2C
Reaction time: 48 h

Procedure:
A solution of 26.2 g. of 5-(1,2-dimethylheptyl)resorcinol and 16.5 g. of 2-acetylcyclohexanone in 150 ml. of acetic acid is cooled to 15° and saturated with hydrogen chloride gas. The mixture is allowed to warm to 25°, stirred for 48 hours and then quenched by pouring into 500 ml. of methanol at 0° and adding 40 g. of sodium bicarbonate to the methanol solution. Sodium cyanoborohydride is then added to the reaction mixture until the bright orange color is dissipated. The solution is concentrated in vacuo, water is added to the residue and the aqueous mixture is extracted with ether. The extract is washed with water and 5% aqueous sodium bicarbonate, dried (MgSO4) and concentrated to give a residue which is chromatographed on silica. The less polar fraction is collected and dissolved in 150 ml. of pyridine. Acetic anhydride (64 g.) is added and the solution is refluxed 10 minutes then allowed to stir at 25° for 18 hours. The mixture is concentrated in vacuo, the residue is dissolved in hexane and the hexane solution is washed with water, dilute hydrochloric acid and water, dried (Na2SO4) and concentrated to give a residue which is chromatographed on silica with 1:1 methylene chloride-petroleum ether to give 1-acetoxy-3-(1,2-dimethylheptyl)-5,6,7,8-tetrahydro-9-methylxanthene.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([CH:10]=O)=[N:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:13]([C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[NH2:14]>>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:13][N:14]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NNc1cccnn1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2cccnn12

Procedure:
4 g. lead tetraacetate were suspended in 40 ml. glacial acetic acid, 1.5 g. of the hydrazone obtained from 1.55 g. 5-nitro-1-methyl-imidazole-2-aldehyde and 1.1 g. 3-hydrazinopyridazine hydrochloride (prepared by heating for 30 minutes in 20 ml. 50 percent aqueous methanol at 50° C. and subsequent neutralization with sodium acetate) were added, while stirring at 50° - 60° C., the reaction mixture further stirred for 15 minutes, considerably evaporated in a vacuum, the resultant crystals filtered off with suction, triturated with water and dried for 2 hours in a vacuum at 120° C., 1.05 g. of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-s-triazolo[4,3-b]pyridazine being obtained, which has a melting point of 235° - 237° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:34][NH:35][O:36][CH3:37].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]([CH3:17])[CH2:13][C:14]([N:35]([O:36][CH3:37])[CH3:34])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CC(=O)O)NC(=O)OCc1ccccc1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)CC(C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 3-{[(benzyloxy)carbonyl]amino}-butanoic acid (Step A; 9.0 g; 38 mmol) in CH2Cl2 (90 mL) at 0° C. under N2 were added N-methylmorpholine (10.4 mL; 95 mmol) and isobutyl chloroformate (6.2 ml; 47.5 mmol). The resultant yellow solution was stirred at 0° C. for 5 min prior to portionwise addition of N,O-dimethylhydroxylamine hydrochloride (4.45 g; 45.6 mmol) over 5 min. The reaction was allowed to warm to room temperature and stirred for 14 h, then poured into 1 N HCl (200 mL) and extracted with CH2Cl2 (3×100 mL). The combined extracts were washed with 1 N HCl (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient) to afford benzyl-{3-[methoxy(methyl)amino]-1-methyl-3-oxopropyl}carbamate as a clear oil. LCMS=281.3 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.35-7.29 (m, 5H), 5.61 (br s, 1H), 5.09 (s, 2H), 4.16-4.10 (m, 1H), 3.66 (s, 3H), 3.16 (s, 3H), 2.77-2.72 (m, 1H), 2.59-2.54 (m, 1H), 1.27 (d, J=6.6 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(NC)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27].C[CH2:29][N:30](C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26]([NH:30][CH2:29][C:8]1([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]1)=[O:27]
Reactant: CNC1(c2ccc(I)cc2)CCN(C)CC1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCC(CNC(=O)Nc2ccc(F)cc2F)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of [4-(4-iodo-phenyl)-1-methyl-piperidin-4-yl]-methylamine (0.20 g, 0.606 mmol) in CH2Cl2 (2 mL) under Ar was added 2,4-difluorophenylisocyanate (0.08 mL, 0.667 mmol, 1.1 eq.) and DIEA (0.106 mL, 0.606 mmol, 1 eq.). The mixture was stirred at room temperature for 16 h then diluted with EtOAc (25 mL) and washed with H2O (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil which was purified by flash column chromatography by eluting with 3% MeOH/CH2Cl2 (1% TEA) to furnish 1-(2,4-difluoro-phenyl)-3-[4-(4-iodo-phenyl)-1-methyl-piperidin-4-yl-methyl]-urea as a white solid (0.211 g, 0.435 mmol, 72%). 1H NMR (300 MHz, CDCl3): δ 7.84 (br.d, NH), 7.68 (d, 2H), 7.36 (s, 1H), 7.11 (d, 2H), 6.87 (d, 2H), 5.32 (br.s., NH), 3.40 (s, 2H), 2.66 (m, 4H), 2.28 (s, 3H), 2.10 (m, 2H), 1.96 (m, 2H), 1.14 (t, 3H). MS (ESI): 486.1,487.0 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][C:25]([CH3:27])=O.C1COCC1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH:25]([N:10]([C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:27])[CH3:24]
Reactant: CC(C)=O
Reactant: Oc1ccc([C@H]2CC[C@H](NCCCc3ccccc3)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of trans-4-[4-(3-phenylpropyl amino) cyclohexyl]-phenol and acetone (2 mL) in a 2:1 mixture of THF:MeOH (10 mL) was added sodium cyanoborohydride (153 mg, 2.42 mmol). The reaction mixture was heated to 60° C. and the acidity was maintained by the addition of acetic acid. The mixture was stirred overnight, quenched with 2N NaOH and concentrated under reduced pressure. Purification by flash chromatography (90:9:1 CH2Cl2:MeOH:NH4OH) gave trans-4-{4-[N-isopropyl-N-(3-phenylpropyl) amino]cyclohexyl}phenol (130 mg, 48%), as a white solid: mp 146-154° C.; IR (KBr): 3198, 2941, 1613 cm−1; 1H NMR (500 MHz, DMSO-d6) δ or s δ 7.32-7.21 (m, 5H), 6.98 (d, J=8 Hz, 2H), 6.66 (d, J=8 Hz, 2H), 3.67 (m, 1H), 3.28 (m, 2H), 3.10 (m, 2H), 2.66 (m, 2H), 2.48 (m, 1H), 2.04 (m, 1H), 2.02 (m, 2H), 1.84 (m, 2H), 1.83 (m, 2H), 1.49 (m, 2H), 1.24 (d, J=8 Hz, 3H), 1.19 (d, J=8 Hz, 3H); CI-MS (methane) (m/z): 352 [M+H]+; HRMS-API (m/z): [M+H]+ Calcd for C24H33NO, 352.2640. found: 352.2637. HPLC: method A, 6.37 minutes (95.3%); method B, 10.85 minutes (100%); Anal. Calcd for C24H33NO.HCl.0.5 NaCl: C, 69.09; H, 8.21; N, 3.36. Found: C, 69.33; H, 8.32; N, 3.22.