Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[Ir:10](Cl)(Cl)Cl.[C:14]1([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[Ir+3:10].[C:14]1([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:14]1([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=[O:8]
Reactant: Cl[Ir](Cl)Cl
Reactant: O=C(O)c1ccccn1
Agent: c1ccc(-c2nc3ccccc3o2)cc1
Solvent: ClCCl
Product: O=C([O-])c1ccccn1
Product: [Ir+3]
Temperature: 25 °C

Procedure:
0.52 mmol (0.064 g) of picolinic acid was added to a room-temperature solution of 0.14 mmol 2-phenylbenzoxazole Iridium chloride dimer (0.18 g) in 20 mL of dichloromethane. The mixture was heated to reflux under nitrogen in an oil bath overnight (17.5 hrs.). Reaction mixture was cooled to room temperature, and the yellow precipitate was filtered off via vacuum. The precipitate was dissolved in dichloromethane and transferred to a vial, and the solvent was removed. Emission spectrum is in FIG. 46.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:32]12[O:39][CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34][CH2:33]2.Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH:36]12[O:39][CH:32]([CH2:38][CH2:37]1)[CH2:33][N:34]([CH2:22][C@@H:21]([N:12]1[C@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:9][C@@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[C:11]1=[O:26])[CH2:24][CH3:25])[CH2:35]2
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C1CC2CNCC1O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC[C@@H](CN1CC2CCC(C1)O2)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (99 mg, 0.215 mmol; Example 210, Step A) in DCE (3 mL) was added 48.7 mg (0.43 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane (Connolly, T.; Considine, J.; Ding, Z.; Forsatz, B.; Jennings, M.; MacEwan, M.; McCoy, K.; Place, D.; Sharma, A.; Sutherland, K. Organic Process Research & Development. 2010, 14(2), 459-465. Note: reference is for the HCl Salt). Sodium triacetoxyborohydride (91 mg, 0.430 mmol) was added followed by acetic acid (1.2 μL, 0.022 mmol). After stirring overnight, the mixture was partitioned between 5% aq. HCl and ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated. The residue was purified by reversed phase preparatory HPLC (eluent: 0-100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes). Fractions containing the product were transferred to a separatory funnel and sat. aq. NaHCO3 and dichloromethane were added. The aqueous layer was back extracted with dichloromethane. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.N.[OH-].[Na+].C(OC(C)C)(C)C.O=C(C)C(=S)[NH2:37]>N.CCOC(C)=O>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:37])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC(=O)C(N)=S
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(=S)N1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(N)=N1
Temperature: 74 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 19 Step 3, 22.7 g, 57.7 mmol) and ammonia (7 M in MeOH, 180 mL, 1.26 mol) was put in a pressure reactor and heated to 74° C. overnight. The residue was allowed to reach r.t. and the mixture was concentrated. The residue was partitioned between 2 M citric acid (400 mL) and EtOAc (400 mL). Any insoluble material was filtered off and was determined is to be unreacted starting material. The organic phase (org 1) was concentrated in vacuo to give additional unreacted starting material. To the aqueous phase was EtOAc (300 mL) added and then 50% NaOH was added until pH ˜12, and the mixture was stirred for 10 min. The resulting organic phase (org 2) was saved. The residue from org 1, and the solid filtered off were combined and suspended in ammonia (7 M in MeOH, 180 mL, 1.26 mmol) and put in a pressure reactor and heated 100° C. overnight. The obtained solution was concentrated in vacuo. The residue was partitioned between 2 M citric acid (300 mL) and EtOAc (300 mL). To the aqueous phase was EtOAc (300 mL) added and then 50% NaOH was added until pH ˜12, and the mixture was stirred for 10 min. The organic phase was combined with org 2 from above. Activated charcoal was added to the organic phase and the mixture was stirred for 30 min before it was filtered through diatomaceous earth. The organic phase was concentrated and dried in vacuo overnight to give a solid. To the solid was diisopropyl ether (125 mL) added and the mixture was refluxed overnight. The mixture was allowed to reach r.t. and the solid was filtered off to give the title compound (equivalent to Example 19 Isomeric Mixture 2 above) (15 g, 69% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 0.93 (m, 1 H) 1.1-1.25 (m, 2 H) 1.35-1.45 (m, 3 H) 1.81 (br. d, 2 H) 2.16 (s, 3 H) 2.87-3.03 (m, 3 H) 3.18 (s, 3 H) 6.59 (br. s., 2 H), 6.64 (d, 1 H), 7.25 (d, 1 H), 7.34 (dd, 1 H); ES+) m/z 376 [M+H]+.
Reaction SMILES: Cl[N:2]1C(=O)CCC1=O.CN1CC[O:15][B:14]([C:18]2[CH:19]=[C:20]([S:24]([O-:26])=[O:25])[CH:21]=[N:22][CH:23]=2)[O:13]CC1.[Li+].[OH-].[NH4+]>C(Cl)Cl>[S:24]([C:20]1[CH:21]=[N:22][CH:23]=[C:18]([B:14]([OH:15])[OH:13])[CH:19]=1)(=[O:26])(=[O:25])[NH2:2]
Reactant: CN1CCOB(c2cncc(S(=O)[O-])c2)OCC1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li+]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cncc(B(O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
Step 3) N-Chlorosuccinimide (0.937 g, 7.01 mmol) was added to a suspension of the above prepared lithium 5-(6-methyl-[1,3,6,2]dioxazaborocan-2-yl)-pyridine-3-sulfinate (2 g, 7.24 mmol) in CH2Cl2 (14 mL) and the mixture was stirred for 2 h at rt.A solution of 25% ammonium hydroxide (1.00 mL, 13.4 mmol) was added and the mixture was stirred again for 2 h at rt, then completely evaporated to give the title compound as an off-white solid (1.28 g, 88%) (according to Bioorg. Med. Chem. 2005, 13, 2305-2312). MS (ISP) 201.4 [(M−H)−].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][NH:11][CH:10]3[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16]CN(C(C)C)C(C)C.CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH2:12][N:11]([CH3:16])[CH:10]3[CH3:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1NCC2CC21c1ccc(Cl)c(Cl)c1
Solvent: CI
Solvent: CN(C)C=O
Product: CC1N(C)CC2CC21c1ccc(Cl)c(Cl)c1

Procedure:
To a dried, 5 mL round-bottomed flask was added (±)-1-(3,4-dichlorophenyl)-(R/S)-2-methyl-3-aza-bicyclo[3.1.0]hexane, Hunig's Base, and DMF under Ar (g) with stirring. Methyl iodide was added drop wise with stirring over 5 min and the resulting solution stirred under ambient temperature overnight. The solution was concentrated under reduced pressure and purified after drying. The residue was purified by HPLC which failed to remove the impurities. This was further purified on a prep TLC plate eluting with 20/1 CHCl3/MeOH (v/v). The desired band was collected, extracted with CHCl3/MeOH, and concentrated after filtration to afford the desired free base. Yield: 0.005 g 15%; LCMS (+)ESI: m/z=256 [MH]+ (100); 258 [MH+2]+; (65); 1H NMR (300 MHz, CDCl3) δ□: 7.33 (d, H, J=12 Hz, ArH), 7.32 (d, 1H, J=2Hz, ArH), 7.08 (dd, 1H, J=9 Hz, J=2Hz, ArH), 3.31 (q, 1H, J=6Hz, CHNH2), 2.83 (s, 2H, CH2N), 2.32 (s, 3H, NCH3), 1.79 (m, 1H, CH2CH), 1.40 (t(br), 1H, ArCCH2), 0.73 (d, 3H, J=7 Hz, CHCH3), 0.60 (dd, 2H, J=8 Hz, 4Hz, ArCCH2); 13C NMR (75 MHz, CDCl3) δ□: 131.2, 130.1, 128.9, 61.1, 53.8, 36.5, 21.9, 18.4, 11.6.
Reaction SMILES: O[C:2]1([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]2=[O:10].CCN(CC)CC.S(Cl)(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]3[CH2:9][CH2:8][CH:6]([CH:7]=2)[C:5](=[O:10])[CH2:4]3)[CH:12]=1
Reactant: O=C1CC2CCC1CC2(O)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC2CCC1C=C2c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of 0.5 g of crude 5-hydroxy-5-pyridin-3-yl-bicyclo[2.2.2]octan-2-one (intermediate K3A.2) in 20 mL DCM were added 84 mg DMAP and 1.6 mL NEt3. The mixture was cooled to 0° C. before 0.53 mL of mesylchloride was added dropwise. The resulting suspension was stirred at 0° C. for 1 h and then overnight at rt. The reaction was quenched by the addition of sat. aq. NaHCO3 solution. The water phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by CC (EtOAc) yielded 0.27 g of rac-(1R*,4R*)-5-pyridin-3-yl-bicyclo[2.2.2]oct-5-en-2-one as yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br.Br[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(OCC)C>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccncc1
Reactant: CCOC(=O)c1cc2cc(C(C)(C)C)ccc2[nH]1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2cc(C(C)(C)C)ccc2n1Cc1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A solution of 1 g (4.08 mmol) of ethyl 5-t-butyl-1H-indole-2-carboxylate is added dropwise to a suspension of 0.33 g (8.15 mmol) of 60% sodium hydride in 10 ml of dimethylformamide, stirred at 0° C. under argon. The mixture is stirred for 30 minutes at 0° C. and then for 30 minutes at 20° C. The reaction mixture is cooled and 1.06 g (4.08 mmol) of 4-bromomethylpyridine hydrobromide are added portionwise. The mixture is stirred for 30 minutes at 0° C. and then for 30 minutes at 20° C. The reaction mixture is cooled again to 0° C. and a further 0.33 g (8.15 mmol) of 60% sodium hydride in 10 ml of dimethylformamide is added. After 30 minutes at 0° C., 1.06 g (4.08 mmol) of 4-bromomethylpyridine hydrobromide are added portionwise. The reaction mixture is then stirred for 20 hours at 20° C. After this time, the mixture is poured into a solution of 100 ml of ice-water and 70 ml of ethyl ether. The organic phase is separated out and the aqueous phase is re-extracted with 50 ml of ethyl ether. The organic phases are combined, washed with 50 ml of water and then dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane/acetone). 0.7 g of expected product is obtained in the form of an oil, which is used without further purification in the subsequent synthesis.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)#[N:2].C(Cl)(Cl)[Cl:13].[H][H]>C(O)C.[Pd]>[ClH:13].[NH2:2][CH2:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: [H][H]
Reactant: ClC(Cl)Cl
Agent: [Pd]
Solvent: CCO
Product: Cl
Product: NCc1ccc(C(=O)O)cn1

Procedure:
6-Cyano-nicotinic acid (1 g, 6.7 mmol) is dissolved in ethanol (100 mL) and chloroform (2 mL) and hydrogenated at 3 bar hydrogen pressure for 5 h using palladium on charcoal as catalyst. After filtration of the catalyst the product is isolated by evaporation of the solvent.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:8](=O)(=[O:11])([OH:10])[OH:9].Cl[SiH](Cl)Cl>>[OH2:9].[C:1]1([CH3:7])[C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccccc1
Agent: Cl[SiH](Cl)Cl
Product: Cc1ccccc1S(=O)(=O)O
Product: O
Reaction time: 0.5 h

Procedure:
Hydrogen silsesquioxane resin was prepared by the method taught in Japanese Patent Publication Number Sho 47-31838 [31,838/1972 ] as follows: Toluenesulfonic acid monohydrate was prepared by dripping 6 moles toluene over a period of 1 hour into a mixture of 3.75 moles sulfuric acid and 2.25 moles fuming sulfuric acid at a mixture temperature of 45° C. to 60° C. and then aging for an additional 30 minutes at 45° C. Into this product was then dripped the mixture of 1 mole trichlorosilane and 6.6 moles toluene over a period of 5 hours at 30° C. followed by ageing for 30 minutes at 45° C. After cooling and layer separation, the toluenesulfonic acid layer (lower layer) was removed. In order to remove the acid present in the upper layer, it was washed with suitable quantities of sulfuric acid/water (50/50 weight ratio), then sulfuric acid/water (25/75 weight ratio), and finally water. The water was then completely eliminated by azeotropic drying for 1 hour to afford a toluene solution. Removal of the toluene front this toluene solution by reduced pressure (vacuum pump) at 60° C. gave hydrogen silsesquioxane resin A. This hydrogen silsesquioxane resin A had a number-average molecular weight. (Mn) of 1,650, and the value of its weight-average molecular weight/number-average molecular weight ratio (Mw /Mn) was 19.4.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([SH:34])[CH2:32][CH3:33].C(OCC)(=O)C>C(#N)CCC>[CH3:17][O:16][C:14]([CH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:2]([S:34][CH2:31][CH2:32][CH3:33])=[C:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:4]=[N:5]2)=[CH:8][CH:9]=1)=[O:15]
Reactant: CCCS
Reactant: COC(=O)Cc1ccc(-n2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Solvent: CCOC(C)=O
Product: CCCSc1c(C(=O)OC(C)(C)C)cnn1-c1ccc(CC(=O)OC)cc1
Temperature: 90 °C

Procedure:
tert-butyl 5-chloro-1-[4-(methoxycarbonylmethyl)phenyl]pyrazole-4-carboxylate (Intermediate #37) (767 mg, 2.19 mmol) was dissolved in butyronitrile (10 mL). Potassium carbonate (906 mg, 6.57 mmol) and propanethiol (284 μL, 2.74 mmol) were added and the mixture heated at 90° C. for 18 h. The reaction mixture was cooled to ambient and ethyl acetate (50 mL) was added. The mixture was washed with water (4×25 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution gradient 0-25% EtOAc in isohexane) to afford tert-butyl 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylate as a yellow oil. (527 mg, 62%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[CH3:24]>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]([NH2:13])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:17][C:16]=1[CH3:24]
Reactant: Cc1cc(B(O)O)ccc1Cl
Reactant: COCCOc1ncc(N)cc1Br
Product: COCCOc1ncc(N)cc1-c1ccc(Cl)c(C)c1

Procedure:
The title compound was synthesized in analogy to Example E, using 5-bromo-6-(2-methoxy-ethoxy)-pyridin-3-ylamine (example 69 b) and B-(4-chloro-3-methylphenyl)-boronic acid (CAN 161950-10-3) as starting materials; GC/MS (FID/EI): 100%, 292 (M)+.
Reaction SMILES: [CH2:1](OCC)C.[OH-].[K+].CN(N=O)/C(/N)=N/[N+]([O-])=O.[O:18]=[C:19]([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>C(Cl)Cl>[CH3:1][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:18])[CH3:27]
Reactant: CC(=O)CCCCC(=O)O
Reactant: CCOCC
Agent: CN(N=O)/C(N)=N/[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)CCCCC(C)=O
Reaction time: 0.17 h

Procedure:
To a rapidly stirred mixture of diethyl ether (175 ml) and 40% KOH (52 ml) at 0° C. was added MNNG (15.4 g, 105 mmol). The mixture was stirred for 10 minutes. The ethereal layer was transferred to a solution of 6-oxo-heptanoic acid 1—1 (5.0 g, 34.68 mmol) and CH2Cl2 at 0° C. The solution was purged with argon for 30 minutes and then concentrated. Flash chromatography (silica, 30% to 50% EtOAc/hexanes) gave ester 1-2 as a clear oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][C:22](=O)C(F)(F)F)=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].CI>CS(C)=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][CH3:22])=[CH:20][C:13]=3[N:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(NC(=O)C(F)(F)F)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CI
Product: CNc1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Temperature: 35 °C
Reaction time: 4 h

Procedure:
11.2 g (30.0 mmol) of N-{2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-trifluoroacetamide, 10.5 g (76.0 mmol) of potassium carbonate and 2.0 mL of methyliodide were stirred for 3 hours in 80 mL of dimethylsulphoxide at 40-50° C. Then the mixture was diluted with 100 mL of ethyl acetate, poured onto water and extracted. The organic phase is again washed with water, dried and concentrated by evaporation. The residue is chromatographed on silica gel. The methylated trifluoroacetamide is taken up in MeOH, with 10 mL of conc. aqueous ammonia solution and stirred for 4 h at 30-40° C. The methanol is distilled off, the residue is taken up in 75 mL of ethyl acetate, washed with water, dried and evaporated down. The product is crystallised from diethylether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:14]([F:17])([F:16])[F:15])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2.CO.O.O[Li].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][CH:7]([C:14]([F:17])([F:15])[F:16])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(OC)cc2OC1C(F)(F)F
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
The ester from Step 2 (4 g, 12 mmole) was dissolved in a mixture of THF:MeOH:H2O and LiOH.H2O (4 g, 95 mmole) was added and the mixture was stirred for 2 h at room temperature and then concentrated in vacuo. The mixture was acidified with 10% HCl and extracted with EtOAc. The EtOAc layer was washed twice with H2O, aqueous NH4Cl solution, dried over Na2SO4 concentrated in vacuo and to give 1.3 g (36% yield) of the product: 1H NMR (CDCl3/300 MHz) 7.48 (s, 1), 7.09 (s, 1H), 6.47 (s, 1H), 5.56 (q, 1H, J=6.9 Hz), 3.79 (s, 3H); ESHRMS m/z 307.0012 (M−H, C12H7ClF3O4, Calc'd 306.9985).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C@@H:13]2[C@@H:20]3[C@@H:16]([CH2:17][NH:18][CH2:19]3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:30](=O)([O:38]C1C=CC([N+]([O-])=O)=CC=1)[O:31][CH2:32][C:33]1[N:34]=[CH:35][S:36][CH:37]=1.C1CCCCC1>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C@@H:13]2[C@@H:20]3[C@@H:16]([CH2:17][N:18]([C:30]([O:31][CH2:32][C:33]4[N:34]=[CH:35][S:36][CH:37]=4)=[O:38])[CH2:19]3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=C(OCc1cscn1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Clc1ccc(O[C@H]2CC[C@@H]3CNC[C@@H]32)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: O=C(OCc1cscn1)N1C[C@H]2CC[C@H](Oc3ccc(Cl)c4ccccc34)[C@H]2C1
Yield: 18.9 %

Procedure:
The process is performed according to the procedure described in Example 1, step 1.3. Starting with 0.059 g (0.21 mmol) of (3aR,4S,6aS)-4-[(4-chloro-1-naphthyl)oxy]-octahydrocyclopenta[c]pyrrole, obtained in step 13.3., 0.04 mL (0.25 mmol) of N,N-diisopropylethylamine and 0.066 g (0.23 mmol) of thiazol-4-ylmethyl 4-nitrophenyl carbonate (WO 2008/013 834), and after chromatography on silica gel, eluting with a 95/5 and then 90/10 mixture of cyclohexane and ethyl acetate, 0.017 g (19%) of expected product is obtained in the form of an oil.
Reaction SMILES: C(O[C:4]([Cl:6])=O)C.[CH2:7]([S:14][C:15]1[S:16][C:17](CN2CCOCC2)=[CH:18][N:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([S:14][C:15]1[S:16][C:17]([CH2:4][Cl:6])=[CH:18][N:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CSc2ncc(CN3CCOCC3)s2)cc1
Solvent: C1CCOC1
Product: ClCc1cnc(SCc2ccccc2)s1
Temperature: 25 °C

Procedure:
5.5 ml of chloroformic acid ethyl ester are added to 8.0 g of 4-(2-benzylsulfanyl-thiazol-5-ylmethyl)-morpholine in 60 ml of tetrahydrofuran, and the mixture is heated at reflux for 5 hours. The mixture is then cooled to room temperature, the solvent is removed by evaporation in vacuo and the residue is purified by chromatography on silica gel with ether-hexane 1:2. 2-Benzylsulfanyl-5-chloromethyl-thiazole having a melting point of 57-59° C. is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:26]4[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=4[O:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>ClCCl.C(OC(C)C)(C)C>[ClH:31].[Cl:31][C:28]1[CH:29]=[CH:30][C:25]2[O:24][N:23]=[C:22]([CH:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:17][CH2:18]3)[C:26]=2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(Cl)cc34)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(Cl)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trans-(4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester (1.35 g, 2.92 mmol) was dissolved in 2 ml dichloromethane and 4N HCl in dioxane (8.8 ml, 38.8 mmol) was added. The white suspension was stirred for 4 hours at room temperature, diluted with diisopropylether and filtered. The crystals were washed with diisopropylether and dried for 2 hours at 50° C. and <20 mbar, to get the desired salt as a white solid (1.65 g, quant.) [MS: m/e=362.2 (M+H+)].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[N:3]=1.[S-2:19].[Na+].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[C:5]([CH:9]=[O:10])=[C:6]([SH:19])[N:7]=1
Reactant: [S-2]
Reactant: Cc1ccc(-c2nc(N)nc(Cl)c2C=O)c(C)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc(N)nc(S)c2C=O)c(C)c1
Reaction time: 1 h

Procedure:
2-Amino-4-chloro-6-(2,4-dimethylphenyl)-pyrimidine-5-carbaldehyde was added to a suspension of sodium sulphide (5 eq.) in DMF and the mixture stirred for ˜60 mins, to give a yellow suspension. The suspension was poured into water, and the solution filtered. The filtrate was acidified with acetic acid, to give a yellow precipitate. The solids were removed by filtration and washed with water and hexane, dried in vacuo, to give a yellow powder.