Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=CC=1C(=O)[S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:8][CH:7]=1.CCOC(C)=O.[OH-].[Na+]>O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([SH:5])=[CH:7][CH:8]=1)=[O:21]
Reactant: O=C(Nc1ccc(SC(=O)c2ccccc2Cl)cc1)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(S)cc1)c1ccccc1Cl
Temperature: 70 °C
Yield: 86.8 %

Procedure:
S-4-(2-chlorobenzamido)phenyl 2-chlorobenzothioate (305 g, 0.76 mol), EtOAc (325 mL), and water (65 mL) are charged to a flask fitted with reflux condenser. A solution of NaOH (3 eq., 50% aq.) is added and the mixture heated to 70° C. for 30-40 minutes. EtOAc was removed by distillation at 100 mm Hg and the mixture cooled to 5° C. The mixture was acidified with 6N HCl to pH 2. The solid is collected by vacuum filtration and washed with water (390 mL). The solid is taken up in CH2Cl2 (520 mL) and washed with saturated aqueous NaHCO3. The organic layer is dried over Na2SO4, filtered, and concentrated to give the desired material (174 g, 87%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C@:13]3([CH3:22])[C:18]([F:20])([F:19])[CH2:17][O:16][C:15]([NH2:21])=[N:14]3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(CC)CC)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:19][C:18]1([F:20])[CH2:17][O:16][C:15]([NH2:21])=[N:14][C@:13]1([CH3:22])[C:11]1[CH:10]=[N:9][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:3]=2)[CH:12]=1
Reactant: C#C[Si](C)(C)C
Reactant: C[C@]1(c2cnn(-c3cccc(Br)c3)c2)N=C(N)OCC1(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@]1(c2cnn(-c3cccc(C#C[Si](C)(C)C)c3)c2)N=C(N)OCC1(F)F
Temperature: 70 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
A solution of (R)-4-(1-(3-bromophenyl)-1H-pyrazol-4-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-1,3-oxazin-2-amine (227 mg, 612 μmol) (intermediate K7.1) in tetrahydrofuran (5 ml) was treated consecutively with ethynyltrimethylsilane (120 mg, 169 μl, 1.22 mmol), triphenylphosphine (4.81 mg, 18.3 μmol) and triethylamine (186 mg, 256 μl, 1.83 mmol). The mixture was degassed by bubbling argon through the solution, then copper(I) iodide (1.16 mg, 6.12 μmol) and bis(triphenylphosphine)palladium(II) chloride (21.5 mg, 30.6 μmol) were added. The reaction mixture was stirred at 70° C. in a sealed tube. In order to complete the reaction, ethynyltrimethylsilane (120 mg, 169 μl, 1.22 mmol) and bis(triphenylphosphine)palladium(II) chloride (21.5 mg, 30.6 μmol) were added again and stirring continued at 70° C. for 20 hours. Thereafter, the reaction mixture was evaporated and the residue purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (R)-5,5-difluoro-4-methyl-4-[1-(3-trimethylsilanylethynyl-phenyl)-1H-pyrazol-4-yl]-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (105 mg, 44% yield) was obtained as a brown, amorphous material. MS (ISP): m/z=389.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])=[O:13])(=[O:7])=[O:6].[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O>[N:36]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:37]=[N-:38]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)C1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COS(=O)(=O)CCCN=[N+]=[N-])[C@@H](OCc1ccccc1)C(=O)OCCOC(=O)C1CCCCC1
Yield: 67.9 %

Procedure:
Following the general procedure for the preparation of azides of Description 16, (cyclohexylcarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (44a) (1.6 g, 3.0 mmol) dissolved in 15 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.65 g (10.0 mmol) of sodium azide (NaN3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:4) as eluent to provide 1.1 g (65% yield) of the title compound (44b) as a colorless oil. Rf=0.30 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3, both diastereomers): δ=1.04-1.06 (m, 6H), 1.19-1.30 (br. m, 3H), 1.40-1.49 (br. m, 2H), 1.51 (d, J=5.6 Hz, 3H), 1.62-1.66 (br. m, 1H), 1.70-1.78 (br. m, 2H), 1.85-1.94 (br. m, 2H), 2.01-2.08 (m, 2H), 2.24-2.37 (m, 1H), 3.09-3.15 (m, 2H), 3.43-3.47 (m, 2H), 3.81-3.83 (2s, 1H), 3.93 (d, J=8.8 Hz, 1H), 4.17-4.22 (m, 1H), 4.32-4.36 (2d, J=11.6, 11.2 Hz, 1H), 4.56-4.65 (2d, J=11.6, 11.6 Hz, 1H), 6.91-6.95 (m, 1H), 7.32-7.37 (m, 5H) ppm. MS (ESI) m/z 562.13 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[C@@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]3[C@@H:11]([CH2:19][OH:20])[CH2:10]2)[CH:3]=1.[NH2:21][C@@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>C(Cl)Cl>[C@@H:22]1([NH:21][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]3[C@@H:13]4[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]4[C@@H:11]([CH2:19][OH:20])[CH2:10]3)[CH:3]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(Cl)ncn3)[C@@H]2O1
Solvent: ClCCl
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(N[C@H]4CCc5ccccc54)ncn3)[C@@H]2O1
Temperature: 180 °C
Yield: 82.4 %

Procedure:
A mixture of {(3aR,4R,6R,6aS)-6-[(6-chloropyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol (200 mg, 0.667 mmol) and (S)-(+)-1-aminoindan (0.188 mL, 1.47 mmol) were heated to 180° C. for 3 h in a sealed tube using MWI. The mixture was dissolved in DCM and the resulting suspension was washed with H2O followed by saturated ammonium chloride solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in EtOAc to afford the title compound as an amorphous solid (218 mg, 82.4%). LC/MS: Rt=1.44 min, ES+ 397 (AA standard).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:8][C:7](=[O:9])/[CH:6]=[CH:5]/[C:4]1[CH:10]=[CH:11][C:12]([F:13])=[C:2]([F:1])[CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)/C=C/c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of trans-3,4-difluorocinnamic acid (10 g, 54 mmol) in 300 mL methanol was added concentrated sulfuric acid (2 mL). The solution was stirred 48 h at ambient temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (2×100 mL), brine (1×100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide trans-3,4-difluorocinnamic acid methyl ester as a white solid.
Reaction SMILES: [CH3:1][CH:2]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].[CH3:21][C:22]1[S:23][C:24]([CH2:27]Cl)=[N:25][N:26]=1>CN(C=O)C>[CH3:21][C:22]1[S:23][C:24]([CH2:27][O:11][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([CH3:1])[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:10][CH:9]=2)=[N:25][N:26]=1
Reactant: CC(COc1ccc(O)cc1)Oc1ccccn1
Reactant: Cc1nnc(CCl)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nnc(COc2ccc(OCC(C)Oc3ccccn3)cc2)s1
Temperature: 80 °C
Yield: 44.6 %

Procedure:
A solution of 4.46 g (18.2 mmol) of 4-[2-methyl-2-(2-pyridinyloxy)ethoxy]phenol in 30 ml of DMF was added to a suspension of 0.6 g (1.1 eq.) of NaH (80% dispersion in mineral oil) in 30 ml of DMF at RT and the mixture was then heated at 80° C. for 1 h. A solution of 2.7 g (18.2 mmol) of 2-methyl-5-chloromethyl-1,3,4-thiadiazole in 20 ml of DMF was added and the mixture was then heated at 120° C. for 6 h. The solvent was stripped off in a rotary evaporator, the residue was taken up in ethyl acetate, and the solution was washed three times with water. Drying, removal of the solvent and purification of the crude product by chromatography (silica gel, cyclohexane/ethyl acetate 2:1) resulted in 2.9 g (45%) of colorless crystals; melting point 72°-78° C.
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.N[C:11]1[C:12]([Cl:21])=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([OH:16])=[O:15].N(O)=O.[ClH:25]>C(O)(=O)C>[Cl:21][C:12]1[C:11]([Cl:25])=[CH:19][C:18]([Cl:20])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: Cl
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Agent: O=NO
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)cc(Cl)c1Cl
Reaction time: 2 h

Procedure:
Powered sodium nitrite (37.0 g, 0.54M) was added portionwise to concentrated sulphuric acid (270 ml) which was stirred under an atmosphere of nitrogen. The temperature of the mixture was not allowed to rise above 70°. Meanwhile 3-amino-2,5-dichlorobenzoic acid (100 g, 0.45M) was dissolved in hot glacial acetic acid (1,200 ml), the resultant solution was cooled rapidly to room temperature and added dropwise to the above stirred and cooled nitrous acid mixture so that the internal temperature did not rise above 30°. The solution formed after the addition was left at room temperature for 2 hours then was slowly added to a stirred solution of cuprous chloride (97 g, 0.97M) in concentrated hydrochloric acid (970 ml). The resultant mixture was stirred until the nitrogen evolution had ceased and was then left overnight. The solid was filtered off, washed well with water and dried in vacuo. Yield 90.1 g (89%) m.p. 164°-165° C. (uncorrected).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.CC1N=C(N2CCN(CCCCC)C2=O)SC=1C(O)=O.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>>[CH3:18][C:16]1[N:17]=[C:13]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][CH2:2][CH2:7][CH2:6][CH3:5])[C:9]2=[O:22])[S:14][C:15]=1[C:19]([NH:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1)=[O:21]
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CCCCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Product: CCCCCN1CCN(c2nc(C)c(C(=O)NCc3cccnc3)s2)C1=O
Yield: 40 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-pentylimidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 40% yield: mp 102-103° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.54-8.43 (m, 2H), 7.63 (d, J=7.5 Hz, 1H), 7.21-7.17 (m, 1H), 6.50 (br s, 1H), 4.54 (J=5.8 Hz, 2H), 4.05-3.97 (m, 2H), 3.55-3.47 (m, 2H), 3.26-3.14 (m, 2H), 2.55 (s, 3H), 1.52-1.46 (m, 2H), 1.30-1.20 (m, 4H), 0.84 (t, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.4, 153.6, 149.2, 148.8, 135.5, 134.0, 123.6, 116.6, 43.8, 42.1, 42.0, 41.3, 28.8, 26.9, 22.3, 17.3, 14.0; MS (ES+) m/z 388.3 (M+1).
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.II.C(O[I:19](C1C=CC=CC=1)OC(=O)C)(=O)C.[Al]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[I:19][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:7]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: II
Solvent: CN(C)C=O
Product: O=C(O)C1(c2ccccc2I)CC1
Reaction time: 8 h

Procedure:
A solution of 1-phenyl-1-cyclopropanecarboxylic acid (2.00 g, 12.3 mmol), Pd(OAc)2 (0.138 g, 0.617 mmol), iodine (2.34 g, 9.24 mmol) and (diacetoxyiodo)benzene (2.97 g, 9.24 mmol) in DMF (10 mL) was stirred at 60° C. for 18 hours covered aluminium foil. Additional iodine (2.34 g, 9.24 mmol) and (diacetoxyiodo)benzene (2.97 g, 9.24 mmol) were added and stirring was continued at 60° C. for a further 8 hours. A final addition of iodine (2.34 g, 9.24 mmol) and (diacetoxyiodo)benzene (2.97 g, 9.24 mmol) was performed and stirring was continued at 60° C. for a further 16 hours. The resulting mixture was partitioned between EtOAc and water and the aqueous phase was extracted several times with EtOAc. The combined organic extracts were washed with a 10% aqueous solution of sodium metabisulfate (3×30 mL), 10% aqueous citric acid (2×30 mL), water, brine, dried (MgSO4), filtered and evaporated. The residue was purified using silica gel column chromatography (CombiFlash Rf, 80 g SiO2 Cartridge, 30-40% EtOAc in cyclohexane) to give the title compound I10 as a cream solid (3.11 g, 87%); 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=8.0 Hz, 1H), 7.28-7.35 (m 2H), 6.97-7.03 (m, 1H), 2.13 (brs, 2H), 1.30 (brs, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:7]=2[CH:18]=1.[C-:19]#[N:20].[Na+].[I-].[Na+].O>CN(C)C=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[C:7]3[CH:18]=[C:3]([CH2:2][C:19]#[N:20])[CH:4]=[CH:5][C:6]=3[O:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2noc3ccc(CBr)cc23)cc1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc2onc(-c3ccc(Cl)cc3)c2c1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
5-Bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole(6.5g.), sodium cyanide (1.1g) and dry sodium iodide (0.3g) were stirred together in dry dimethylformamide (50ml) for 20 hours at ambient temperature. The mixture was poured into water (500ml.), stirred for one hour and the brown solid filtered off, washed and dried (5.1g). This was recrystallised, with charcoaling, from 50% toluene/60-80 petrol ether (100ml.) To give the title compound as an off-white solid (3.4g) m.p. 118°C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:22][CH2:23][O:24][CH3:25])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[CH2:26][CH2:27][CH3:28])(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:39]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)=[CH2:40].Cl>O1CCOCC1.O>[F:16][C:14]([F:17])([F:15])[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([CH:39]=[CH2:40])[CH:46]=2)=[C:8]([CH2:26][CH2:27][CH3:28])[CH:9]=1)([O:22][CH2:23][O:24][CH3:25])[C:18]([F:20])([F:19])[F:21]
Reactant: C=Cc1cccc(B(O)O)c1
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cccc(-c2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)c1
Yield: 81.4 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenyl trifluoromethanesulfonate (238 mg, 497 μmol) in 1,4-dioxan, potassium phosphate (401 mg), 3-vinylphenylboronic acid (88 mg), and tetrakis triphenylphosphine palladium complex (57 mg) were added at room temperature under an argon atmosphere, and the resultant mixture was heated at 80° C. After completion of the reaction, the reaction solution was neutralized by adding water and 2 mol/L of hydrochloric acid, extracted with ethyl aceate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and the title compound (175 mg, yield 81%) was obtained as a colorless oil.
Reaction SMILES: [CH:1]1([N:4]([CH3:14])[C:5]([CH:7]2[CH2:9][CH:8]2[C:10](OC)=[O:11])=O)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1.C(Cl)Cl>[CH:1]1([N:4]([CH2:5][CH:7]2[CH2:9][CH:8]2[CH2:10][OH:11])[CH3:14])[CH2:2][CH2:3]1
Reactant: COC(=O)C1CC1C(=O)N(C)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CN(CC1CC1CO)C1CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
The crude methyl (1RS,2RS)-2-(cyclopropyl-methylcarbamoyl)-cyclopropanecarboxylate is dissolved in 9 ml of THF and added dropwise to a boiling suspension of 1.4 g of lithium aluminium hydride in 40 ml of THF. The reaction mixture is boiled for a further 24 hrs., then cooled to 0° C. and treated with 9 ml of water, dried, filtered and concentrated. The oil obtained is dissolved in methylene chloride, dried and concentrated to give 4.2 g of (1RS,2RS)-[2-[(cylcopropyl-methyl-amino)-methyl]-cyclopropyl]methanol, MS: m/e 156 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C[O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([Cl:39])[CH:33]=1.C([O-])(O)=O.[Na+].ClCCl>S(Cl)(Cl)=O>[Cl:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[NH:38][C:14](=[O:15])[CH:13]([N:12]1[C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:31]([OH:40])=[O:30]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)nc2)nc2cc(F)c(F)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)nc3)nc3cc(F)c(F)cc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared by heating [2-(6-chloro-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexylacetic acid (200 mg, 0.46 mmol) in 5 ml thionylchloride to 80° C. for 4 h. The solvent was evaporated and the residue taken up in dichloromethane. 4-Amino-3-chloro-benzoic acid methyl ester (85 mg, 0.46 mmol) were added and the reaction mixture stirred at rt overnight. The crude product was worked up by addition of a solution of 1 M NaHCO3 and extraction of the aqueous layer with dichloromethane. Organic layers were combined, dried over MgSO4 and evaporated to dryness. The residue was taken up in methanol (3 ml) and 1N NaOH (1 ml) added. The mixture was stirred at rt overnight, the solvent evaporated and the product isolated via preparative HPLC. MS (ES+): 560 (M+H).
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]#N)[CH2:30][CH2:29]2)=[CH:20][CH:19]=1.[Cl-].[NH4+].C[OH:46]>O1CCCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([CH:34]=[O:46])[CH2:30][CH2:29]2)=[CH:20][CH:19]=1
Reactant: CO
Reactant: N#CC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=CC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
1(a) 75 ml of a 1M hexane solution containing diisobutylaluminum hydride were added to 400 ml of tetrahydrofuran under a stream of nitrogen, and the mixture was cooled at -78° C. Whilst the mixture's internal temperature was -15° C., 20.25 g of 1-[2-bis(4-fluorophenyl)methoxyethyl]-4-piperidinecarbonitrile (prepared as described in Preparation 4) were added to the mixture over a period of 40 minutes, and the resulting mixture was stirred for 30 minutes at -15° C. The mixture was then allowed to stand overnight at room temperature. At the end of this time, the mixture was placed in an ice bath, and 15 ml of methanol, followed by 100 ml of a saturated aqueous solution of ammonium chloride, were added. The reaction mixture was then extracted with ethyl acetate. The extract was purified by silica gel column chromatography. Elution with 3% by volume methanol in methylene chloride afforded 14.67 g (yield 72%) of the title compound as an oily substance.
Reaction SMILES: [N+](C1C=CC=CC=1N=NC1C=C(C)C=CC=1O)([O-])=O.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[N:30][C:31]1[CH:36]=[C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])[CH:34]=[C:33]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[C:32]=1[OH:47])([O-])=O>>[OH:47][C:32]1[C:33]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])=[CH:34][C:35]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:36][C:31]=1[N:30]1[N:29]=[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]2=[N:20]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1

Procedure:
When in Example 6, the 2-nitro-2'-hydroxy-5'-methylazobenzene was replaced by an equivalent amount of 2-nitro-2'-hydroxy-3',5'-di-tert-amylazobenzene and a total of 4% catalyst was used, the above named product was prepared in very high yield.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([S:17]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])=[O:18])=[CH:12][N:11]=1.CCOCC>CN(C=O)C>[CH3:6][N:4]([CH:3]=[N:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([S:17]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:18])=[O:19])=[CH:12][N:11]=1)[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(N)nc1O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ncc(S(=O)(=O)NC(C)(C)C)c(O)n1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Dimethylformamide dimethyl acetal (304 mL, 2.28M) was added to a suspension of 2-amino-4-hydroxy-N-(1,1-dimethylethyl)-5-pyrimidinesulfonamide (304 g, 1.23M) in DMF (3000 mL). Stirring was continued for 1/2 hour after precipitate formation and then the reaction slurry was concentrated in vacuo. Trituration of the resulting white solid with ether afforded the desired compound (362 g, yield 97%, m.p. 258°-261° C.). The compound was dried in vacuo at 40° C. for 16 hours.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C1(C)C=CC=CC=1.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH2:10]([O:9][C:3](=[O:8])[CH:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5](=[O:6])[CH3:7])[CH3:11]
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a suspension of 36.08 g 60% sodium hydride in 1000 ml of toluene, 112.9 g ethyl acetoacetate was dropped in. The temperature rose to 60° C. and then the reaction mixture was stirred for 1 hour at room temperature. Then 17.54 g Aliquat 336 were added and the reaction mixture was heated to 84° C. Now a solution of 54.90 g benzyl chloride in 50 ml of toluene was dropped in. Then the mixture was stirred at 84° C. for 26 hours. After the mixture was cooled down to room temperature, it was acidified with 250 ml of 2N HCl and extracted with ether. The combined organic phase was washed with 5% sodium bicarbonate and brine, dried, filtered and evaporated to dryness. The resulting brown oil was purified by chromatography to yield 55.74 g of a colourless oil.