Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[N:15][C:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:17][N:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Na+].Br[CH2:31][C:32]([NH2:34])=[O:33]>CN(C=O)C>[NH2:34][C:32](=[O:33])[CH2:31][N:20]([C:16]1[N:15]=[C:14]2[CH:13]=[CH:12][N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:2])=[O:3])[C:19]2=[N:18][CH:17]=1)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: NC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(N)=O)C(=O)OC(C)(C)C)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of tert-butyl 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-ylcarbamate (1.00 g, 2.57 mmol, Example #3 Step E) and DMF (13 mL) under nitrogen at about 0° C. was added NaH (60% dispersion in mineral oil, 0.113 g, 2.83 mmol) in one portion. After about 30 min, 2-bromoacetamide (0.391 g, 2.83 mmol) was added in one portion. After about 30 min, the ice bath was removed and the solution was stirred at ambient temperature for about 2 h. Saturated aqueous NH4Cl/water (1:1, 100 mL) was added. After stirring for about 10 min, the mixture was filtered using water to wash the filter cake. The aqueous phase was extracted with EtOAc (50 mL). The filter cake was dissolved in EtOAc and added to the organic layer. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 20-100% EtOAc/heptane to give tert-butyl 2-amino-2-oxoethyl(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-yl)carbamate (0.980 g, 82%): LC/MS (Table 1, Method n) Rt=0.70 min; MS m/z 446 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6](=[S:12])[NH:5][C:4](=[O:13])[CH:3]=1.[N:14]([O-])=[O:15].[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][O:10][CH3:11])[C:6](=[S:12])[NH:5][C:4](=[O:13])[C:3]=1[N:14]=[O:15]
Reactant: COCCn1c(N)cc(=O)[nH]c1=S
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCn1c(N)c(N=O)c(=O)[nH]c1=S
Temperature: 75 °C
Yield: 36.5 %

Procedure:
6-Amino-1-(2-methoxy-ethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.0 g, 5.0 mmol) was suspended in 10% acetic acid (20 mL). Sodium nitrite (0.38 g, 5.5 mmol) was added and the resulting mixture was heated at 75° C. for 1 h. The reaction mixture became first pink and then purple. Water (20 mL) was added and the reaction mixture was put in the fridge overnight. The purple solid was collected by filtration and washed with water to give the title compound (0.42 g, 37%). A second crop of product (0.22 g, 19%) was obtained by reducing the volume of the purple filtrate. The crude product was used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccc(Cl)cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 4-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]3[NH:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=4)[C:20]3=[CH:19][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH2:40][NH2:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]3[NH:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:41][CH2:40][C:39]5[CH:42]=[CH:43][CH:44]=[C:37]([Cl:36])[CH:38]=5)[N:27]=4)[C:20]3=[CH:19][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2ncc3c(-c4ccnc(S(C)(=O)=O)n4)n[nH]c3n2)CC1
Product: CC(C)(C)OC(=O)N1CCN(CCNc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
The mixture of 4-{2-[3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester (from Example 27 supra) (153 mg, 0.304 mmol) and 3-chlorobenzylamine (171 mg, 1.21 mmol) was heated at 130° C. with stirring for 3 hours. The resulting oil was purified by chromatography (silica gel, 7 g, 100-200 mesh, eluting with dichloromethane:methanol, 10:1) and further purified by prep-HPLC to afford 4-(2-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester. (Yield 90 mg, 52%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[C:25]3=[N:26][C:27](S(C)(=O)=O)=[N:28][CH:29]=[C:24]3[CH2:23][N:22]([C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])C2=O)[CH:15]=1)([CH2:12][CH3:13])[CH2:10][CH3:11])(C)(C)C.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54]>ClCCl>[F:51][C:52]([F:57])([F:56])[C:53]([OH:55])=[O:54].[NH2:7][CH2:8][C:9]([C:14]1[CH:15]=[C:16]([N:20]2[C:25]3=[N:26][C:27]([NH:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[N:28][CH:29]=[C:24]3[CH2:23][N:22]([C:34]3[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=3[Cl:40])[C:53]2=[O:55])[CH:17]=[CH:18][CH:19]=1)([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: CCC(CC)(CNC(=O)OC(C)(C)C)c1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(S(C)(=O)=O)nc32)c1
Reactant: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(CN)c1cccc(N2C(=O)N(c3c(Cl)cccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Temperature: 140 °C
Yield: 19 %

Procedure:
A mixture of 400 mg (0.62 mmol) of (2-[3-[3-(2,6-dichlorophenyl)-7-methanesulfonyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-2-ethyl-butyl)-carbamic acid tert-butyl ester and 600 mg (6.5 mmol) of aniline was heated at 140° C. for 45 minutes and cooled. The residue was dissolved in 20 ml of a 1:1 mixture of dichloromethane and trifluoroacetic acid. After 10 minutes the mixture was evaporated and the product purified by flash chromatography on silica gel using a gradient elution from dichloromethane/methanol 98:2 to dichloromethane/methanol 95:5. Product-containing fractions were evaporated and the residue dissolved in 4 ml of dichloromethane. The product was precipitated by the addition of pentane and subsequently filtered and dried to give 65 mg (19%) of 1-[3-(1-aminomethyl-1-ethyl-propyl)-phenyl]-3-(2,6-dichloro-phenyl)-7-phenylamino-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one trifluoroacetate as a white solid of melting point 232° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22]I.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC[C@H]1CC[C@H](CCNC(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1CC[C@H](CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To an ice-cooled and stirred solution of the crude 26.0 g trans-acetic acid 4-(2-tert-butoxycarbonylamino-ethyl)-cyclohexylmethyl ester and 5.77 ml (92.6 mmol) methyliodide in 300 ml of N,N-dimethylformamide was added within 15 minutes 4.04 g (92.58 mmol) sodium hydride (55% in oil). After stirring over night at room temperature, additional 1.65 ml (26.5 mmol) methyliodide and 1.16 g (26.5 mmol) of sodium hydride were added and the reaction-mixture was then stirred for another 1 hour at room temperature. It was then partitioned between Et2O, 1N hydrogen chloride solution and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure and the residue then chromatographed on silica gel with a 4:1 v/v mixture of hexane and ethylacetate as the eluent giving 18.7 g (68% over 3 steps) of pure trans-acetic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester as colorless viscous oil, MS: 214 [(M-(tert-butoxycarbonyl)) H+].
Reaction SMILES: [CH:1]([C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH3:11])=[CH2:4])=[O:2].[N+](=C)=[N-].C[OH:27]>C(OCC)C>[C:1]([C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH3:11])=[CH2:4])([OH:27])=[O:2]
Reactant: C=C(C=O)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Reactant: CO
Agent: C=[N+]=[N-]
Solvent: CCOCC
Product: C=C(C(=O)O)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1

Procedure:
(3S,4S)-4-(1-Carboxyethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone (37 g), which was prepared from (3S,4S)-4-(1-formylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone in the similar procedure to Example 6, was dissolved in methanol and then diluted with diethyl ether. A solution of diazomethane in diethyl ether was added dropwise thereto with ice-cooling, and the resultant mixture was stirred for 0.5 hour. After removal of excess diazomethane, the reaction mixture was concentrated in vacuo to give (3S,4S)-4-(1-methoxycarbonylethenl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]([NH:19][NH2:20])=[O:18]>C(O)C>[CH3:15][O:16][C:17]([NH:19][N:20]=[C:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C:8]1=[CH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:18]
Reactant: O=C1CCCCC1=Cc1ccccc1
Reactant: COC(=O)NN
Solvent: CCO
Product: COC(=O)NN=C1CCCCC1=Cc1ccccc1
Yield: 98 %

Procedure:
To a solution of 37.2 g (0.2 moles) of 2-phenylmethylenecyclohexan-1-one in 200 ml of anhydrous ethanol a solution of 18.0 g (0.2 moles) of N-methoxycarbonyl hydrazine in 40 ml of anhydrous ethanol is added, under stirring. The reaction mixture is boiled for a short while, then cooled, clarified with activated carbon, filtered and the filtrate is cooled. The separated white crystals are filtered off and dried. 50.63 g of the desired compound are obtained. Yield: 98%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6](=O)[CH2:7][CH2:8][CH3:9]>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH2:7][CH2:8][CH3:9]
Reactant: c1cc[nH]c1
Reactant: CCCC=O
Product: CCCC(c1ccc[nH]1)c1ccc[nH]1
Yield: 45 %

Procedure:
This was prepared as described in example 2/4, reacting the pyrrole derivative with butyraldehyde. Yield 45%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>C(Cl)(Cl)Cl>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 82 %

Procedure:
To a solution of 15.0 mg 0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 3.0 mL chloroform were added 9.3 mg 0.131 mMol) ethyl isocyanate. The reaction was mixed for 48 hours and to it were then added 0.23 gm 0.131 mMol)aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 16.1 mg (82%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([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)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)=O.Cl.[NH2:29][OH:30].N1C=CC=CC=1>C(O)C>[F:27][C:5]1[N:6]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:3]([CH:1]=[N:29][OH:30])[N:4]=1
Reactant: NO
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 18 h

Procedure:
To a stirred mixture of 4-formyl-2-fluoro-1-triphenylmethylimidazole (0.356 g.) and hydroxylamine hydrochloride (0.035 g.) in ethanol (4 ml.) was added pyridine (0.2 ml.). Stirring was continued at ambient temperature for 18 hours and the precipitated solid was filtered to give 2-fluoro-4-hydroxyiminomethyl-1-triphenylmethylimidazole, m.p. 147°-149°. Further amounts of product could be isolated from the mother liquors.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[NH:16])[NH:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1.Cl>O1CCOCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[NH:16][C:22](=[O:23])[O:15][N:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=N)NO)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2noc(=O)[nH]2)C1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Crude (R)-3-(N-hydroxycarbamimidoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (887 mg, 3.86 mmol) and CDI (94 mg, 5.8 mmol) were dissolved in dioxane (30 mL) and heated to reflux. After 1 h, the reaction was concentrated in vacuo. The crude reaction mixture was dissolved in CH2Cl2 and the pH was adjusted to 3 by adding 1M HCl to the solution. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to yield 872 mg of crude (R)-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1.[CH3:27][NH2:28]>CO>[CH3:27][NH:28][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cc(Cl)ncn3)CC2)CC1
Reactant: CN
Solvent: CO
Product: CNc1cc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)ncn1
Temperature: 50 °C

Procedure:
The tert-butyl 1′-(6-chloropyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (19 mg, 0.05 mmol) was added to methyl amine in MeOH (1N, 2 mL) in a sealed bottle and heated to 50° C. for 2 days. The reaction crude were cooled down to r.t. and concentrated on rotavapor. The crude mixture was purified by preparative TLC with 10% methanol: dichloromethane to yield title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](OCC)=[O:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[CH2:12][OH:13])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(C(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(/C=C/CO)cc1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a suspension of ethyl (E)-3-(4-isopropylphenyl)-2-propenoate (20.0 g, 91.6 mmol) in tetrahydrofuran (200 ml) was added in four portions at −40° C. for 30 minutes lithium aluminum hydride (2.61 g, 68.7 mmol) and the resulting mixture was stirred at the same temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 8:1) to obtain 10.5 g (65% yield) of the oily title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[N:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:18][CH2:19][C:20](Br)=[O:21].O>ClCCl>[Br:18][CH2:19][C:20]([NH:9][C:6]1[N:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(C(F)(F)F)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)Nc1ccc(C(F)(F)F)nn1
Reaction time: 1.5 h

Procedure:
6-Trifluoromethyl-pyridazin-3-ylamine (0.042 g) (prepared by a procedure similar to that described in WO2007048779) was dissolved in dichloromethane (40 mL) and stirred with potassium carbonate (0.214 g). 2-Bromoacetyl bromide (0.12 mL) was added and stirring continued for 1.5 hours. Water (0.24 mL) was added and the reaction mixture was stirred for 1.5 hours after which water (40 mL) was added and the reaction mixture stirred for a further 1.5 hours. The dichloromethane was separated, dried (MgSO4) and evaporated to afford the sub-titled compound as a white solid (0.053 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:7]=2[CH:6]=[CH:5][N:4]=1.Br[CH2:37][C:38]1([CH3:42])[CH2:41][O:40][CH2:39]1>>[CH3:1][O:2][C:3]1[C:8]2[C:9]([C:31]3[CH:35]=[N:34][N:33]([CH2:37][C:38]4([CH3:42])[CH2:41][O:40][CH2:39]4)[CH:32]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: CC1(CBr)COC1
Reactant: COc1nccc2c1c(-c1cn[nH]c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1nccc2[nH]nc(-c3cnn(CC4(C)COC4)c3)c12
Yield: 35 %

Procedure:
Prepared according to the general procedure described in Example 86, by reacting 4-methoxy-3-(1H-pyrazol-4-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine with 3-(bromomethyl)-3-methyloxetane to give the title compound (23.1 mg, 35% over two steps). LC-MS (Method G): m/z=300.0 [M+H]+; 2.54 min. 1H-NMR (400 MHz, DMSO) δ 8.75 (s, 2H), 7.47 (d, J=5.8, 1H), 7.00 (d, J=6.0, 1H), 4.54 (d, J=11.7, 2H), 4.31 (d, J=11.8, 2H), 4.01 (s, 2H), 3.50 (s, 5H), 1.31 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]([C@@H:10]1[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9]>N1C=CC=CC=1.ClCCl>[CH3:6][O:7][C:8]([C@@H:10]1[CH2:14][C@@H:13]([O:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
Add methanesulfonyl chloride (1.56 mol, 179 g) drop wise to a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.65 mol, 160 g) in pyridine (600 mL) at 0° C. under a nitrogen atmosphere. Upon complete addition, warm the reaction mixture to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane, wash with 0.1 N hydrochloric acid solution and saturated sodium bicarbonate solution. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under vacuum to obtain the title compound (185 g, 91%) as a thick oil. ES-MS m/z 324.1 [M+1]+, 224.0 [M−Boc]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].[CH3:11][CH:12]1[CH2:17][C:16](=[O:18])[CH2:15][CH2:14][O:13]1.Cl>BrCCBr.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:16]2([OH:18])[CH2:15][CH2:14][O:13][CH:12]([CH3:11])[CH2:17]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC1CC(=O)CCO1
Agent: Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC1CC(O)(c2cc(F)cc(F)c2)CCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
A Grignard reagent was prepared from 3,5-difluorobromobenzene (0.772 g), 1,2-dibromoethane (2 drops), magnesium (0.106 g) and THF (5 ml). The mixture was stirred at ambient temperature for 15 minutes and then heated to 50° C. for 15 minutes. The mixture was allowed to recool to ambient temperature and a solution of 2-methyltetrahydropyran-4-one (J. Amer. Chem. Soc., 1982, 104, 4666) in THF (1 ml) was added dropwise. The mixture was stirred at ambient temperature for 1 hour. The mixture was poured into dilute aqueous hydrochloric acid and extracted with diethyl ether. The organic phase was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 9:1 v/v mixture of methylene chloride and diethyl ether as eluent. There was thus obtained a less polar isomer, (2RS,4SR)-4-(3,5-difluorophenyl)-4-hydroxy-2-methyltetrahydropyran (0.25 g, 36%), having the 2-methyl and 4-hydroxy substituents in a trans-relationship.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:25]([C:29]1[CH:38]=[CH:37][C:32]([C:33](=[N:35]O)[NH2:34])=[CH:31][CH:30]=1)([O:27][CH3:28])=[O:26]>C(Cl)Cl.CN(C=O)C>[C:25]([C:29]1[CH:38]=[CH:37][C:32]([C:33]2[N:34]=[C:16]([C:9]3[S:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[O:18][N:35]=2)=[CH:31][CH:30]=1)([O:27][CH3:28])=[O:26]
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: COC(=O)c1ccc(C(N)=NO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
A solution of 408 mg (1.5 mmol) of 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid and 1 mL of oxalyl chloride in 5 mL of CH2Cl2 was treated with 5 drops of DMF. The resulting mixture was stirred at rt for 1 h, then concentrated. The crude acid chloride and 291 mg (1.5 mmol) of 4-(carbomethoxy)benzamidoxime were dissolved in 7 mL of 6:1 v/v xylenes/pyridine. The resulting solution was heated at 140° C. for 1 h, then cooled. The mixture was partitioned between 50 mL of 1:1 EtOAc/ether and 50 mL of 1 N HCl. The organic layer was separated, washed with 3×50 mL of 1 N HCl, 50 mL of sat'd NaHCO3, dried and concentrated. Chromatography on a Biotage 40 M cartridge using hexanes (1L), then 20:1 v/v hexanes/EtOAc (1 L) as the eluant afforded 423 mg (65%) of the title compound: 1H NMR (500 Mhz) δ0 3.97 (s, 3H), 7.48 (app s, 5H), 7.92 (s, 1H), 8.18 (app d, J=8.5, 2H), 8.23 (app d, J=8.5, 2H).
Reaction SMILES: [CH2:1]([C:8]1([OH:31])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:32][S:33]([OH:36])(=[O:35])=[O:34]>CO>[CH2:1]([C:8]1([OH:31])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][NH:16][C:17]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:30])[CH:21]=2)=[O:18])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:33]([O-:36])([O-:35])(=[O:34])=[O:32]
Reactant: O=S(=O)(O)O
Agent: Cc1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)c2ccccc2n1
Solvent: CO
Product: O=S(=O)([O-])[O-]
Temperature: -2 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea (21.36 kg) in CH3OH (178 L) is added aqueous H2SO4 (6 L, 9.91%) during 10 min. The clear solution is filtered and further aqueous H2SO4 (33.8 L, 1.07 M) is added during 45 min. The solution is cooled to −2° C. during 1.5 h and stirred at −5 to −9° C. for 1 h. The formed precipitate is filtered, washed with cooled CH3OH (−5° C., 54 L) and dried under a stream of nitrogen provide 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea of formula I sulfate as a non-defined hydrate. The so obtained salt is exposed to humid atmosphere (>70% RH) at 25° C. to provide the title compound.