Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1ccc(O)cc1
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of 17 gm (0.1 mole) of 3-(4-hydroxyphenyl)propionic acid in 500 mL methanol and 2 mL concentrated sulfuric acid was placed in a Soxhlet extractor charged with 3A molecular sieves. The solution was refluxed for 72 hours and the sieve were exchanged at 24 hour intervals. The reaction medium was then evaporated to an oil which was dissolved in 100 mL toluene and extracted with 3×100 mL water. The toluene phase was dried over magnesium sulfate, treated with activated charcoal and evaporated to provide 15 gm (80%) of a clear oil. The NMR spectrum was consistent with the assigned structure and this material was utilized directly in the next reaction step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][Sn:15](Cl)([CH3:17])[CH3:16].O>CCOCC>[CH3:14][Sn:15]([CH3:17])([CH3:16])[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1ccc([Sn](C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
100 g (0.585 mol) of 1-bromo-4-methylbenzene was dissolved in 500 mL of anhydrous ether in an argon atmosphere, and then cooled to −78° C. 252 mL (2.5M in hexane, 0.615 mol) of an n-butyl lithium solution was slowly added dropwise. The mixture was stirred for 15 minutes, and a solution of 122.6 g (0.615 mol) of trimethyltin chloride in 500 mL of ether was added. The mixture was stirred for 2 hours while the temperature was gradually increased to room temperature, followed by the addition of 700 mL of distilled water and then stirring. The organic layer was separated, treated with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding trimethyl(p-tolyl)tin as represented below in a 77% yield.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:41]=[CH:40][CH:39]=[CH:38][C:7]=1[CH2:8][N:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2].BrCCCCCCN(CC1C=CC=CC=1OC(C)(C)C)CCN[C:53](=O)[O:54]C(C)(C)C.COC1CC(C2C=CC=CC=2)CCN1.C([O-])([O-])=O.[K+].[K+]>>[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:7]1[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=1[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=2[O:54][CH3:53])[CH2:28][CH2:27]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCN(CCCCCCN1CCC(c2ccccc2)CC1)Cc1ccccc1OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCN(CCCCCCBr)Cc1ccccc1OC(C)(C)C
Agent: COC1CC(c2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1C1CCN(CCCCCCN(CCNC(=O)OC(C)(C)C)Cc2ccccc2OC(C)(C)C)CC1
Yield: 63.4 %

Procedure:
The same procedure as described for compound 16 was applied to starting material 15 (1.9 g, 4.66 mmol), 2-methoxy-4-phenylpiperidin (1.338 g, 6.99 mmol) and K2CO3 (0.644 g, 4.66 mmol). Purification was carried out on a silica gel TLC plate that was developed in with a 3% methanolic NH3 (7 M NH3 in methanol/97% CH2Cl2. The product was isolated as pale yellow oil (63.4%). Mass Spec.=596.44 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[OH:4].[C:15](=[S:17])=[S:16].C(N(CC)CC)C.C(Cl)C1C=CC=CC=1>N1C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:15](=[S:16])[SH:17])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc(C(O)CN)cc1OC
Reactant: S=C=S
Solvent: ClCc1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COc1ccc(C(O)CNC(=S)S)cc1OC
Reaction time: 1 h

Procedure:
10 mmol of 2-amino-1-(3,4-dimethoxyphenyl)-ethanol is dissolved in 6 ml. of pyridine and, under cooling to 0°, combined dropwise with 11 mmol of carbon disulfide in 10 mmol of triethylamine. During this step, the temperature rises greatly. The mixture is agitated for one hour at 0° and then, at the same temperature, 10 mmol of benzyl choride is added dropwise thereto. After agitation overnight at 0°, the batch is taken up in 40 ml. of 3 N sulfuric acid and extracted three times with respectively 50 ml. of chloroform. The combined chloroform phases are washed in succession with sodium bicarbonate and water, dried, filtered, and concentrated. The residue, which crystallizes spontaneously, is recrystallized from benzene and ethyl acetate, thus obtaining in a quantitative yield the benzyl ester of [2-(3,4-dimethoxyphenyl)-2-hydroxyethyl]-dithiocarbamic acid, m.p. 130°-132°.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]2)(=[O:9])[CH3:8].[N:22](OCCCC)=[O:23].Cl>O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:7]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[C:19](=[O:21])[C:18](=[N:22][OH:23])[CH2:17][CH2:16]2)(=[O:9])[CH3:8]
Reactant: CC(=O)Nc1cccc2c1C(=O)CCC2
Reactant: CCCCON=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc2c1C(=O)C(=NO)CC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a reaction solution obtained by suspending 316 mg of potassium tert-butoxide in 18 ml of tetrahydrofuran (hereinafter abbreviated as THF) and cooling the suspension to 0° C. under a nitrogen stream was added a solution of 500 mg of the compound prepared in (1) above in 2 ml of THF, a bit at a time. After stirring for 10 minutes at the same temperature and an addition of 0.35 ml of butyl nitrite, the mixture was heated at 50° C. for 1 hour while stirring. Precipitates obtained by the addition of diethyl ether to the reaction mixture were collected by filtration. The powder thus obtained was suspended into a 10% aqueous solution of hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The residue obtained by the concentration of the solvent was subjected to silica gel column chromatography using an ethyl acetate-hexane (1:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 320 mg of the title compound.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][C:14]=2[F:27])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[CH:15][C:14]=1[F:27])[N:10]=2
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(N)cn2)c(F)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc3nc(N)sc3n2)c(F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
To a solution of potassium thiocyanate (6.1 g, 62.6 mmol) in acetic acid (60 mL) was added a solution of tert-butyl {4-[(5-aminopyridin-2-yl)oxy]-3-fluorophenyl}carbamate (5.0 g, 15.7 mmol) in acetic acid (40 mL) at 0° C. A solution of bromine (3.25 g, 20.4 mmol) in acetic acid (20 mL) was added at 0° C., and the mixture was stirred at room temperature for 6 hr. Acetic acid was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone) to give the title compound (2.07 g, 35%).
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:29][C@@H:30]4[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]4[F:36])[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:37])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:36][C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@H:30]1[O:29][C:20]1[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]2[N:24]=[C:16]([C:12]3[CH:11]=[C:10]([CH3:37])[C:9]([O:8][CH2:7][C:6]([OH:38])=[O:5])=[C:14]([CH3:15])[CH:13]=3)[O:17][C:18]=2[N:19]=1
Reactant: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1nc(O[C@@H]2CCCC[C@H]2F)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Yield: 109.6 %

Procedure:
98 mg of {4-[5-(trans-2-fluoro-cyclohexyloxy)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetic acid tert-butyl ester were dissolved in 3.5 ml of dichloromethane and treated with 1.5 ml of trifluoroacetic acid. After 16 h the mixture was concentrated and freeze-dried. 96 mg of the title compound were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH:10]2[N:22]([C:25](=[O:48])[CH:26]([NH:31][C:32](=[O:47])[CH:33]([N:35]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[CH3:36])[CH3:34])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:40]([O:39][C:37](=[O:38])[N:35]([CH:33]([C:32](=[O:47])[NH:31][CH:26]([C:25]([N:22]1[CH2:23][CH2:24][CH:9]2[NH:8][CH2:12][CH:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[CH:10]12)=[O:48])[C:27]([CH3:28])([CH3:30])[CH3:29])[CH3:34])[CH3:36])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C(=O)OC(C)(C)C)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)NC(C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
The Boc-containing compound 34 (2.0 g, 3.0 mmol) was dissolved in DCM (30 mL) and cooled to 0° C. TFA (10 mL) was added and the reaction mixture was slowly warmed to ambient temperature. After 2 h, the reaction mixture was concentrated in vacuo and the crude residue was dissolved in EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.75 g of compound 35 as a white solid. Mass spectrum, m/z [573.1] (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[CH3:27][C:28]1([CH3:35])[O:32][CH:31]([CH2:33]O)[CH2:30][O:29]1>ClCCl.O>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:33][CH:31]1[CH2:30][O:29][C:28]([CH3:35])([CH3:27])[O:32]1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC1(C)OCC(CO)O1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)OCC1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution from 2-acetoxybenzoic acid (10.0 g, 55.5 mmol) in dichloromethane (200 ml) is treated with triethylamine (7.7 ml, 55.5 mmol), cooled to 0° C., treated dropwise with ethyl chloroformate (5.3 ml, 55.5 mmol), stirred at 0° C. for 1 h and filtered. The filtrate is added at room temperature to a solution of (±)-2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (7.33 g, 55.5 mmol) and triethylamine (50 ml) in dichloromethane (100 ml). After 4 h, water (50 ml) is added and the mixture is stirred. The organic phase is washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and water, dried over magnesium sulphate and concentrated. The residue is purified by column chromatography on silica gel 60 (hexane/ethyl acetate =15/1). Yield: 8.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:29])[C:12]([OH:28])([C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=2[CH:27]=1)[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[NH2:30][C@H:31]([C:36]([O-:38])=[O:37])C(C)(C)C.O>CN(C=O)C>[C:4]([O:38][C:36](=[O:37])[CH2:31][NH:30][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([CH:11]([CH3:29])[C:12]([OH:28])([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]=3[CH:27]=2)[C:13]([F:15])([F:14])[F:16])=[C:2]([Cl:1])[CH:3]=1)([CH3:8])([CH3:5])[CH3:3]
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: CC(C)(C)[C@H](N)C(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1ccc(C(=O)NCC(=O)OC(C)(C)C)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Temperature: 50 °C
Reaction time: 1 h
Yield: 199.9 %

Procedure:
3-Chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-benzoic acid (80 mg) and 1,1-carbonyldiimidazole (45 mg) were dissolved in dry DMF (2.0 mL) and stirred at 50° C. for 1 hour. The mixture was cooled to r.t. and a solution of tert-butylglycinate (391 mg) in DMF (0.7 mL) was added drop by drop. Stirring was then continued for 2 hours. The reaction mixture was poured into a mixture of water and ice and the aqueous phase was extracted with ethyl acetate. The organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to provide the title compound {3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydrobenzooxazol-5-yl)-propyl]-benzoylamino}-acetic acid tert-butyl ester as a colorless solid (101 mg). MS (m/e)=560.3 [M+NH4+].
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH2:4]=[C:5]1[C:22]2[C@:17]([CH3:24])([CH2:18][CH2:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:7]([C@H:8]3[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C@@H:11]([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[O:26])[CH2:10][CH2:9]3)[CH2:6]1>CCOCC.Cl[Cu]>[CH2:4]([C:5]1[CH2:6][C@@H:7]2[C@@H:16]([C@:17]3([CH3:24])[C:22]=1[CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)[CH2:15][CH2:14][C@@:12]1([CH3:13])[C@H:8]2[CH2:9][CH2:10][C@@H:11]1[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=1)=[O:26])[CH3:1]
Reactant: C[Mg+]
Reactant: C=C1C[C@H]2[C@@H]3CC[C@H](C(=O)Nc4ccc(C(F)(F)F)cc4)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C=C12
Agent: Cl[Cu]
Agent: [Br-]
Solvent: CCOCC
Product: CCC1=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(=O)Nc4ccc(C(F)(F)F)cc4)CC[C@H]3[C@@H]2C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3.0 M MeMgBr (0.36 mL, 1.09 mmol) in ether under N2 was added 2.2 mL Argon-purged, anhydrous THF. The mixture was cooled to 0° C. CuCl (0.014 g, 0.14 mmol) was added, and the reaction was stirred for 5 min before adding (17β)-6-methylene-3-oxo-N-[4-(trifluoromethyl)phenyl]androst-4-ene-17-carboxamide (3-4) (0.12 g, 0.25 mmol) as a solid. After several hours the reaction was quenched by dropwise addition of 5.0 mL of Ar-purged water, then partitioned between CHCl3 and 10% KHSO4 solution. The organic phase was washed with saturated NaHCO3 solution and brine, then dried with MgSO4 and concentrated. The residue was purified by flash silica gel chromatography (0 to 30% EtOAc/hexane) and concentrated to yield a clear, colorless oil, which was further purified by preparative HPLC (C18; 70% MeOH with 5 to 30% MeCN-water) to provide the desired product.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1
Reactant: CN1CCN(c2ccc(CO)cc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(C=O)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A solution of 4-(4-formyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 4.47 mmol) in THF (50 mL) was mixed with LAH (0.7 g, 17.87 mmol) and stirred at reflux for 14 h. The reaction was quenched at room temperature by adding KOH aqueous (14 N, 20 mL). The supernatant was decanted and combined with DCM washings, then diluted with water (50 mL). The mixture was extracted with DCM (3×50 mL) followed by concentration using a rotary evaporator to give [4-(4-methyl-piperazin-1-yl)-phenyl]-methanol (0.82 g, 89%). To a solution of DMSO (0.56 mL, 7.96 mmol) in DCM (50 mL) at −78° C. was added oxalyl chloride (0.7 mL, 7.96 mmol) and the resulting mixture was stirred at −78° C. for 0.5 h. A solution of [4-(4-methyl-piperazin-1-yl)-phenyl]-methanol (0.82 g, 3.98 mmol) in DCM (20 mL) was slowly added. The reaction was stirred at −78° C. for 1.5 h. Triethylamine (1.7 mL, 11.94 mmol) was added and the reaction was allowed to gradually warm up to room temperature. After stirring for 4 h the reaction was quenched by adding sodium bicarbonate aqueous (1 N, 50 mL). The mixture was extracted with DCM (3×50 mL) followed by concentration to afford a residue, which was further purified by column chromatography to yield 4-(4-methyl-piperazin-1-yl)-benzaldehyde (0.5 g, 61%).
Reaction SMILES: C(C1N=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24]C2)[C:8]2N=NN(CC3C=CC=CC=3Cl)[C:9]=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].C(O)(=O)C(O)=O.C1C2(CCCN2)CO1>>[C:28]([C:32]1[N:33]=[C:34]([N:22]2[CH2:7][CH2:8][CH2:9][C:27]32[CH2:24][O:25][CH2:26]3)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: C1CNC2(C1)COC2
Agent: O=C(O)C(=O)O
Product: CC(C)(C)c1nc(N2CCCC23COC3)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-oxa-5-azaspiro[3.4]octane oxalate and isolated as white solid (8.4 mg, 43%). MS (m/e): 413.4 (MH+).
Reaction SMILES: ClCl.[C:3]([NH:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Cl)[CH:11]=1)([CH3:6])([CH3:5])[CH3:4].C(NNC(=O)C1C=CC(C#N)=CC=1)(C)(C)C.C(NNC(=O)C1C(=CC=CC=1)N)(C)(C)C.[H][H]>>[C:3]([NH:7][NH:8][C:9](=[O:17])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)NNC(=O)c1cccc(Cl)c1
Reactant: [H][H]
Agent: CC(C)(C)NNC(=O)c1ccc(C#N)cc1
Agent: CC(C)(C)NNC(=O)c1ccccc1N
Agent: ClCl
Product: CC(C)(C)NNC(=O)c1ccccc1

Procedure:
The above reactions are illustrated below: ##STR15## wherein Q is halogen, preferably chlorine; R is tert-butyl or tert-amyl. Other compounds that can be prepared by the above procedure using the appropriately substituted benzoyl halide include: m-chlorobenzoic acid, 2-tert-butylhydrazide, mp 120°-123° C.; p-cyanobenzoic acid, 2-tert-butylhydrazide, mp 135°-136° C.; anthranilic acid, 2-tert-butylhydrazide, mp 165°-167° C.; tert-butyl or isopropyl; and X is hydrogen, halogen, C1 -C3 alkyl, methoxy, methylamino, NH2, nitro or CF3.
Reaction SMILES: O=C(CC)CC(OCC)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][NH2:18].[CH:19]1([C:22]2N(C(C)C)N=[CH:24][C:23]=2[CH:30]=[O:31])C[CH2:20]1>>[CH2:19]([C:22]1[N:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[N:18]=[CH:24][C:23]=1[CH:30]=[O:31])[CH3:20]
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Reactant: NNc1ccccn1
Agent: CCOC(=O)CC(=O)CC
Product: CCc1c(C=O)cnn1-c1ccccn1

Procedure:
5-Ethyl-1-pyridin-2-yl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 3-oxo-pentanoate and 2-pyridyl hydrazine in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]([CH2:29][CH3:30])[C:21](=[O:28])[CH:22]([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:33](I)[CH2:34][CH2:35][CH3:36]>C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]([CH2:29][CH3:30])[C:21](=[O:28])[C:22]([CH2:33][CH2:34][CH2:35][CH3:36])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCCI
Reactant: CCN1C(=O)C(C)C(=O)N(C)c2cc(OCc3ccccc3)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC1(C)C(=O)N(C)c2cc(OCc3ccccc3)ccc2N(CC)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Under ice cooling, sodium hydride (60% in oil) (129 mg, 3.23 mmol) was added to a N,N-dimethylformamide (5 mL) solution of 7-benzyloxy-1-ethyl-3,5-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (500 mg, 1.48 mmol), and the mixture was stirred at 0° C. for 30 minutes. Thereafter, butyl iodide (0.336 mL, 2.95 mmol) was added. The reaction solution was stirred at 0° C. for 30 minutes, and then stirred at room temperature for 2 hours. The reaction solution was poured into ice water, and ethyl acetate (20 mL) extraction was performed. The resulting organic layer was washed with water, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (elution solvent: 1:2=ethyl acetate:n-hexane). The solvent was distilled off, thereby obtaining 520 mg of a colorless, liquid target compound (yield: 89%).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)(Cl)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].C(OCC)(=O)C.C(O)C>[CH:1]([N:14]1[CH2:17][CH:16]([C:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH:20]=2)[CH2:15]1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC1(c2coc3ccccc23)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: c1ccc(C(c2ccccc2)N2CC(c3coc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-benzhydryl-3-(benzofuran-3-yl)-3-chloroazetidine as obtained in the previous step (873 mg, ≦2.14 mmol), triethylamine (299 μL, 2.14 mmol) and 10% palladium on carbon (227 mg) in ethyl acetate (15 mL) and ethanol (15 mL) was stirred at room temperature under hydrogen atmosphere (˜1 atm) for 3 days. After removal of hydrogen, the mixture was diluted with dichloromethane (100 mL), filtered through Clarcel® and concentrated. The residue was taken up in dichloromethane (50 mL) and washed with aqueous saturated sodium hydrogencarbonate (50 mL). The aqueous layer was back-washed with dichloromethane (2×50 mL) and all the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (100:0 to 95:5) as eluent followed by preparative TLC on reversed phase C18 using acetonitrile/water (90:10) as eluent. The title compound was obtained as a yellow gum (52 mg, 7%).