Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]([C:17]([OH:19])=[O:18])[CH2:11][CH2:10]2)=[O:4].[BH4-].[Na+].O.Cl.[CH3:24]O>[Cu]Cl>[CH2:1]([O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]([C:17]([OH:19])=[O:18])[CH2:11][CH2:10]2)=[O:4])[CH3:24]
Reactant: COC(=O)/C=C/c1ccc2c(c1)CCC(C(=O)O)O2
Reactant: CO
Agent: Cl[Cu]
Agent: Cl
Agent: [BH4-]
Solvent: O
Product: CCOC(=O)CCc1ccc2c(c1)CCC(C(=O)O)O2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a round bottom flask the compound from Example 31 (0.455 g, 1.74 mmol) was stirred in anhydrous methanol (10 mL) under an argon atmosphere. Copper (I) chloride (0.26 g, 2.6 mmol) was added and the mixture was cooled to 0° C. Sodium borohydride (0.457 g, 17.4 mmol) was added in four portions over 40 minutes. Gas evolution was observed with each addition. The resulting black mixture was stirred for 15 min and then poured into 100 mL water. The aqueous mixture was made acidic by addition of 1.0 N aqueous HCl and extracted with ethyl acetate (3×). The combined organic layers were dried (MgSO4), filtered through celite, and concentrated to a white solid (0.412 g, 90%). 1H NMR (300 MHz, acetone-d6) δ 11.18 (s, 1H), 6.90 (m, 2H), 6.72 (m, 1H), 4.74 (m, 1H), 3.57 (s, 3H), 2.77 (m, 4H), 2.55 (m, 2H), 2.17 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:13][N:12]2[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:25]=2)=O)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:10])[N:11]3[CH2:15][CH:14]([N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[CH2:13][N:12]3[C:22]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:25]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccc(F)cc1)N1CC(N2CCOCC2)CN1C(=O)c1ccnc(Oc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(F)cc2)c(-c2ccnc(Oc3ccccc3)n2)n2n1CC(N1CCOCC1)C2
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-[4-morpholin-4-yl-2-(2-phenoxy-pyrimidine-4-carbonyl)pyrazolidine-1-yl]ethanone, 19, (0.2 g, 0.4 mmol) in DMF (10 mL) at 0° C. is added NaH (0.024 g, 0.6 mmol) and the resulting solution is stirred 2 hours. The solvent is removed in vacuo the residue dissolved in methylene chloride and extracted with water, dried, and re-concentrated to afford 37 mg (20% yield) of the desired product as a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].N1C=CN=C1.Cl[Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37].[Cl-].[NH4+]>ClCCl>[CH2:36]([Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[O:27][CH:22]1[CH2:23][CH2:24][C@@:25]2([CH3:26])[C:20](=[CH:19][CH:18]=[C:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH2:21]1)[CH3:37]
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Reactant: CC[Si](Cl)(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC[Si](CC)(CC)OC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 12 h
Yield: 87.1 %

Procedure:
Commercially available 7-dehydrocholesterol (10.6 g, 27.6 mmol) was dissolved in dichloromethane (90 mL), and then imidazole (3.75 g, 55.1 mmol) and chlorotriethylsilane (6.94 mL, 41.3 mmol) were added at room temperature, followed by stirring for 12 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with chloroform twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography to obtain the title compound (12.0 g, 87%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([O-:8])=[O:7].[Li+].[OH-]>COCCOC>[F:1][C:2]([F:15])([F:16])[CH2:3][O:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C([O-])C(OCC(F)(F)F)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C(O)C(OCC(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 2-(2,2,2-trifluoroethoxyphenylacetate (2 g, 8 mmol) from Step 1 above in DME (20 mL) was added aqueous LiOH (20 mL of a 1.0 M solution, 20 mmol). The solution was stirred at ambient temperature for 1 h. The solution was concentrated under reduced pressure to ~10 mL and 0.25 M aqueous citric acid (20 mL) was added. The precipitate was removed by filtration and dried under reduced pressure to give 2-(2,2,2-trifluoroethoxyphenylacetic acid as a crystalline solid (HPLC retention time=7.4 min (method E)).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-]>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:31]([NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)c(C(F)(F)F)c1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(F)cc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]azetidine hydrochloride (125) (0.25 mmol), tert-butyl isocyanate (0.25 mmol) and MP-carbonate (2.62 mmol/g, 0.76 mmol) using the procedure described for compound (10) (72.4 mg, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][NH2:15]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8]([NH:15][CH3:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 5-Chloro-2-methoxy-benzenesulfonyl chloride (1.0 g, 4.15 mmol) in tetrahydrofuran(8 ml) was bubbled methylamine gas until saturated. The reaction mixture was sealed with a septa and stirred overnight at ambient temperature. The reaction mixture was then concentrated, triterated in dichloromethane and ether, filtered and dried yielding the above titled compound 1.05 g (>100%) white solid.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.Br[C:31]1[CH:40]=[C:39]2[C:34]([C:35]3[N:44]4[C@@H:45]([CH3:49])[CH2:46][O:47][CH2:48][C:43]4=[N:42][C:36]=3[C:37]([NH2:41])=[N:38]2)=[CH:33][CH:32]=1.[C:50]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)(=[O:53])[CH:51]=[CH2:52].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:49][C@@H:45]1[N:44]2[C:35]3[C:34]4[C:39](=[CH:40][C:31](/[CH:52]=[CH:51]/[C:50]([N:54]5[CH2:59][CH2:58][O:57][CH2:56][CH2:55]5)=[O:53])=[CH:32][CH:33]=4)[N:38]=[C:37]([NH2:41])[C:36]=3[N:42]=[C:43]2[CH2:48][O:47][CH2:46]1
Reactant: C=CC(=O)N1CCOCC1
Reactant: C[C@H]1COCc2nc3c(N)nc4cc(Br)ccc4c3n21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@H]1COCc2nc3c(N)nc4cc(/C=C/C(=O)N5CCOCC5)ccc4c3n21
Temperature: 120 °C
Yield: 63.5 %

Procedure:
A scintillation vial was charged with palladium acetate (22 mg, 0.10 mmol), tri-o-tolylphosphine (61 mg, 0.20 mmol), anhydrous DMF (1.0 mL) and triethylamine (0.4 mL, 3.0 mmol). The orange homogeneous solution was then added to a solution of (11S)-3-bromo-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (333 mg, 1.00 mmol) dissolved in 10 mL of anhydrous DMF followed by the addition of a solution of 4-acryloylmorpholine (169 mg, 1.20 mmol) dissolved in 1.0 mL of anhydrous DMF. The mixture was transferred to a glass vessel and the vessel was purged with N2, sealed and heated to 120° C. for 18 hours. The reaction mixture was cooled and concentrated to dryness under reduced pressure to give a golden solid. The solid was treated with CH2Cl2 and saturated aqueous K2CO3 solution and the layers were separated. The organic layer was concentrated to dryness to give a light-brown solid. Chromatography (SiO2, 0-15% CMA/CHCl3) gave a tan solid that was crystallized from acetonitrile to give 250 mg of the title compound as beige crystals, mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([Mg]Br)[CH3:12]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[CH2:11][CH3:12])[CH:9]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cc(Cl)ccc1F
Solvent: CCOCC
Product: CCC(O)c1cc(Cl)ccc1F
Temperature: 0 °C
Yield: 71 %

Procedure:
To a solution of 5-chloro-2-fluorobenzaldehyde (1 g, 6.3 mmol) in diethyl ether (20 mL) cooled at −78° C. was added a solution of 3.0M ethylmagnesium bromide in ether (4.2 mL, 13 mmol) dropwise over 5 minutes. The reaction mixture was warmed to 0° C. and after 30 minutes was quenched with a few drops of saturated aqueous ammonium chloride solution. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-30% ethyl acetate in heptane) to afford the title compound as a pale yellow oil (850 mg, 71%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.[Pd]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([CH2:24][S:25]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(OC2CCCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(OC2CCCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Yield: 88.3 %

Procedure:
A mixture of 1-benzyl-3-[3-(1-naphthylsulfonylmethyl)-4-nitro-phenoxy]-piperidine (1.2 g, 2.3 mmoles) and 10% Pd/C in THF and methanol was hydrogenated in a Parr hydrogenation bottle at 52 lb/in2 overnight. The reaction mixture was filtered through Celite, and the filtrate was concentrated under vacuum to afford the title compound as an off-white solid (1.0 g, 2.03 mmoles).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br.C(N(C(C)C)CC)(C)C>C1C=CC=CC=1.O>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCCCCBr
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1ccc(N2CCCC2)cc1

Procedure:
1.69 g (10.2 mmol) of ethyl 4-aminobenzoate was dissolved in 10 ml of benzene. 2.18 g (10.1 mmol) of 1,4-dibromobutane and 3.53 ml (20.2 mmol) of diisopropylethylamine were added to the solution, and they were heated under reflux for 48 hours. The reaction solution was diluted with water. After the extraction with ethyl acetate, the organic layer was washed with water and then with saturated Aqueous NaCl solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[OH:11]O>>[CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])=[CH:5][C:6](=[O:11])[C:7]=1[CH3:8]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: OO
Product: CC1=CC(=O)C(C)=C(C)C1=O

Procedure:
The method according to claim 3, wherein 2,3,6-trimethylphenol is reacted with hydrogen peroxide to obtain 2,3,6-trimethylbenzoquinone.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl.C(O)C>[ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CCc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCO
Product: N=C(N)c1ccc(CCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccc4)ccc3s2)cc1
Yield: 77 %

Procedure:
Prepared analogously to Example 10 from 2-[2-(4-amidinophenyl)ethyl]-benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 77% of theory, C26H24N4O3S (472.57) Rf value: 0.18 (silica gel; methylene chloride/ethanol=4:1+a few drops of acetic acid) ##EQU5##
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](CC)(C)C)=[CH:6][C:5]([C:13]([CH2:16]C)([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-])=O.OC1C(C)=CC(C(C)(C)C)=CC=1N=NC1C=CC=CC=1[N+]([O-])=O>>[OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:4][C:3]=1[N:18]1[N:19]=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=[N:26]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: Cc1cc(C(C)(C)C)cc(N=Nc2ccccc2[N+](=O)[O-])c1O
Product: Cc1cc(C(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Yield: 81 %

Procedure:
When in Example 1, the 2'-hydroxy-3',5'-di-tert-amyl-2-nitroazobenzene was replaced by an equivalent amount of 2'-hydroxy-3'-methyl-5'-tert-butyl-2-nitroazobenzene, the product 2-(2-hydroxy-3-methyl-5-tert-butylphenyl)-2H-benzotriazole was obtained after a reaction time of 5 hours in an isolated yield of 81% of theory with a melting point of 145°-146° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:9]([C:24]2[N:28]([CH3:29])[N:27]=[N:26][N:25]=2)/[CH:10]=[CH:11]\[C@H:12]2[O:17]C(C)(C)[O:15][C@@H:14]([CH2:20][C:21](O)=[O:22])[CH2:13]2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.Cl>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:9]([C:24]2[N:28]([CH3:29])[N:27]=[N:26][N:25]=2)/[CH:10]=[CH:11]/[C@H:12]2[O:17][C:21](=[O:22])[CH2:20][C@H:14]([OH:15])[CH2:13]2)=[CH:31][CH:32]=1
Reactant: Cn1nnnc1C(/C=C\[C@@H]1C[C@H](CC(=O)O)OC(C)(C)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1nnnc1C(/C=C/[C@@H]1C[C@@H](O)CC(=O)O1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 16 h
Yield: 40.7 %

Procedure:
Cis-(4R,6S)-6-[4,4-bis(4-fluorophenyl)-3-(1-methyl-1H-tetrazol-5-yl)-1,3-butadienyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid (3.7 g, 7.45 mmol) was dissolved in a solution of THF (90 mL) and 0.2N HCl (60 mL) and allowed to stand for 16 hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated under reduced pressure. The residue was dissolved in dry methylene chloride (60 mL) and stirred for 4 hours in the presence of 1-cyclohexyl-3-(2-morpholinomethyl) carbodiimide metho-p-toluenesulfonate (6.6 g, 15.6 mmol). The solution was concentrated under reduced pressure and the residue was partioned between ethyl acetate and water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (1:1/ethyl acetate:diethyl ether). After recrystallization from ethyl acetate-hexane, 1.33 g (40.1%) of the title compound was obtained as a white solid; m.p.=172°-173° C. [α]D25 =+237.8° (c=2.17, CHCl3).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17](C4CCCCO4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][N:28]3[CH2:33][CH2:32][NH:31][C@H:30]([CH2:34][C:35]([F:38])([F:37])[F:36])[CH2:29]3)[CH:12]=2)=[CH:7][CH:6]=1.Cl>O1CCOCC1>[CH3:20][C:19]1[C:14]2[C:15](=[N:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=3)=[CH:12][C:13]=2[CH2:27][N:28]2[CH2:33][CH2:32][NH:31][C@H:30]([CH2:34][C:35]([F:38])([F:37])[F:36])[CH2:29]2)[NH:17][N:18]=1
Reactant: COCOc1ccc(-c2cc(CN3CCN[C@H](CC(F)(F)F)C3)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CCN[C@H](CC(F)(F)F)C3)c12
Reaction time: 1.5 h
Yield: 51.1 %

Procedure:
188 mg of 6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-4-[(R)-3-(2,2,2-trifluoro-ethyl)-piperazin-1-ylmethyl]-1H-pyrazolo[3,4-b]pyridine were dissolved in 2 ml of 1,4-dioxane and treated with 2 ml of hydrochloric acid (4M in dry dioxane). After standing at rt for 1.5 h the volatiles were removed in vacuo. The residue was purified by preparative HPLC (C18 column, acetonitrile/water gradient) and 73 mg (50%) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[NH:11][CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:9]([CH3:16])[CH2:10][N:11]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C@@H:12]([CH2:14][OH:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1CN[C@@H](CO)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)[C@@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (21 g, 90 mmol) in THF (210 mL) at 3-4° C. (ice bath) was added 1 M aqueous NaOH (99.5 mL) and benzyl chloroformate (12.9 mL, 90.43 mmol). After stirring for 1 h at the same temperature, the mixture was left to stir for another 1 h and then warmed to RT. The organic layer was separated and the aqueous phase extracted with EtOAc (2×50 mL). The combined organic extracts were washed with saturated brine solution (150 mL), then dried over sodium sulfate, filtered and concentrated. The crude oil was purified by column chromatography on silica gel (gradient elution, 0-100%, EtOAc/petrol), to give the title compound (26 g) as a pale yellow oil, used directly in Preparation 11. 1H NMR (Me-d3-OD): 7.47-7.15 (5H, m), 5.26-5.07 (2H, m), 4.25 (2H, s), 4.04-3.88 (1H, m), 3.83 (1H, d), 3.61 (2H, bs), 3.31-3.09 (2H, m), 1.48 (9H, s), 1.14 (3H, t).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:17]=[C:16]([CH2:18][CH:19]([NH:25][C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:15][N:14]=1)=O)(C)(C)C.[ClH:32]>O1CCOCC1>[ClH:32].[CH2:23]([O:22][C:20](=[O:21])[CH:19]([NH:25][C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH2:18][C:16]1[O:15][N:14]=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:17]=1)[CH3:24]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[5-(2-Allyloxycarbonylamino-2-ethoxycarbonyl-ethyl)-isoxazol-3-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (3.44 g, 7.86 mmol) was dissolved in 4M hydrochloric acid in dioxane (10 mL) and stirred at room temperature for 2 hours. The reaction was then concentrated in vacuo and co-evaporated with dichloromethane to give the desired product as a brown waxy solid. MS (CI) m/z 509.9 (M+1)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:51][C:52]([F:66])([F:65])[C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH2:60][CH2:61][NH:62][CH2:63][CH:64]=2)=[CH:55][CH:54]=1>CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:62]2[CH2:61][CH:60]=[C:59]([C:56]3[CH:57]=[CH:58][C:53]([C:52]([F:51])([F:65])[F:66])=[CH:54][CH:55]=3)[CH2:64][CH2:63]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)N2CC=C(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.17 mmol 5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid in 0.75 ml dimethylformamide, 0.19 mmol TBTU, 0.855 mmol N-ethyldiisopropylamine and 0.205 mmol 4-(4-trifluoromethyl-phenyl)-1,2,3,6-tetrahydro-pyridine were successively added. The reaction was then stirred at RT for 45 min., concentrated in vacuo and purified by column chromatography (SiO2, 10 g, heptane, ethylacetate 0 to 100%), to give the title compound. MS (m/e): 508.6 (MH+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:26](=[O:37])[C:27]#[C:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)/[C:27](=[C:28](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])/[C:26]2=[O:37])[CH:13]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2OC)c2ccccc2)c1
Reactant: Clc1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(Cl)cc3)c3ccccc3OC)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-({[3-(2-methoxy-phenyl)-propynoyl]-phenyl-amino}-methyl)-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 7.99 (s, 1H), 7.92 (d, 1H), 7.26-7.49 (m, 7H), 6.93-7.15 (m, 4H), 6.72 (t, 1H), 6.61-6.64 (m, 2H), 4.93 (dd, 2H), 3.90 (s, 3H), 3.63 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[S:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([Cl:13])[N:12]=1>CN1CCCC1=O>[Cl:13][C:11]1[N:12]=[C:8]([N:4]2[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]2)[S:9][C:10]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1cc[nH]n1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Solvent: CN1CCCC1=O
Product: Cc1ccn(-c2nc(Cl)c([N+](=O)[O-])s2)n1
Temperature: 0 °C
Reaction time: 96 h
Yield: 94.8 %

Procedure:
4.1 g (0.05 mol) of 3-methylpyrazole are added to a solution of 5.0 g (0.025 mol) of 2,4-dichloro-5-nitrothiazole in 50 ml of N-methyl-2-pyrrolidinone at room temperature. After the mixture has been left to stand at room temperature for four days, it is stirred into 500 ml of ice-water and the precipitate is filtered off, washed with water and dried. 5.8 g (94.9% of theory) of 4-chloro-2-(3-methyl-1-pyrazolyl)-5-nitrothiazole of melting point 153° C. are obtained.