Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][NH:13][C:14](=O)[CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][C:10]1[O:11][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]3)=[N:13][N:12]=1
Reactant: O=C(COc1ccc2[nH]c(=O)ccc2c1)NNC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: O=c1ccc2cc(OCc3nnc(Cc4ccc(Cl)c(Cl)c4)o3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a stirred solution of 2-(3,4-dichlorophenyl)-N′-(2-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)acetyl)acetohydrazide (0.2 g, 0.476 mmol) and TEA (0.265 mL, 1.904 mmol) in DCM (8 mL) at 0° C., Ts-Cl (0.181 g, 0.952 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated and dissolved in ethyl acetate, then washed with 10% NaHCO3 solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to a yellow gum, which was further washed with diethyl ether and chloroform to afford a brown solid. The crude product was purified by preparative HPLC on a C18 reverse phase column (ACN-NH4OAc method) to afford 6-((5-(3,4-dichlorobenzyl)-1,3,4-oxadiazol-2-yl)methoxy)quinolin-2(1H)-one (0.015 g, 8%). 1H NMR: 400 MHZ, DMSO-d6: δ 4.38 (s, 2H), 5.40 (s, 2H), 6.51 (dd, J=2.00, 9.60 Hz, 1H), 7.25 (d, J=2.40 Hz, 2H), 7.34 (dd, J=2.00, 8.00 Hz, 2H), 7.62 (d, J=8.00 Hz, 1H), 7.65 (d, J=2.00 Hz, 1H), 7.81 (d, J=9.60 Hz, 1H), 11.68 (s, 1H). LCMS: RT 1.61 min. LCMS (ES-API), m/z 403.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[C:3]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc(Nc2cc(OCC3CCNCC3)c(N)cn2)cn1

Procedure:
A solution of tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-yloxy)methyl)piperidine-1-carboxylate (16 mg, 0.038 mmol) in 10 mL dichloromethane (10 mL) was treated over 45 minutes with 2 mL trifluoroacetic acid. After concentration of the solution in vacuo, the required product was isolated by SPE using a MP-TsOH cartridge, eluting with 2N ammonia in methanol. Concentration of the eluent gave the required product as a yellow solid (10 mg).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][N:31]1[CH:36]2[CH2:37][CH2:38][CH:32]1[CH2:33][NH:34][CH2:35]2>>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:34]4[CH2:35][CH:36]5[N:31]([CH3:30])[CH:32]([CH2:38][CH2:37]5)[CH2:33]4)=[O:22])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CN1C2CCC1CNC2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C)cn3)nc2n1C1CCCC1
Yield: 60.3 %

Procedure:
Following general amide formation method 1, 6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (100 mg, 0.254 mmol, 1.0 eq) was combined with 8-Methyl-3,8-diaza-bicyclo[3.2.1]octane (55.5 mg, 0.279 mmol, 1.1 eq) which gave 7-cyclopentyl-2-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as solid (77 mg) in 60% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56-1.76 (m, 4H) 2.01 (br. s., 6H) 2.44 (br. s., 4H) 3.06 (br. s., 8H) 3.33 (br. s., 4H) 3.49 (br. s., 4H) 4.76 (quin, J=8.84 Hz, 1H) 6.66 (s, 1H) 7.82-7.88 (m, 1H) 8.33-8.41 (m, 2H) 8.85 (s, 1H) 10.05 (s, 1H)
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:26])[CH:12]=[CH:11][C:10]([S:13]([O:16][CH2:17][C@H:18]([OH:25])[CH2:19][CH2:20][C@@H:21]([CH3:24])[CH2:22][CH3:23])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>[C:7]1([CH3:26])[CH:8]=[CH:9][C:10]([S:13]([O:16][CH2:17][C@H:18]([O:25][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[CH2:19][CH2:20][C@@H:21]([CH3:24])[CH2:22][CH3:23])(=[O:14])=[O:15])=[CH:11][CH:12]=1
Reactant: CC[C@H](C)CC[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC[C@H](C)CC[C@H](COS(=O)(=O)c1ccc(C)cc1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
In a 50 ml egg-plant type flask were charged 1.7 g of 3,4-dihydro-2H-pyran, 30 ml of diethyl ether, 5.0 g of (2R, 5S)-2-hydroxy-5-methylheptyl p-toluenesulfonate, and 50 mg of p-toluenesulfonic acid, and the mixture was stirred at room temperature overnight. The resulting reaction mixture was neutralized with a saturated sodium hydrogencarbonate aqueous solution, and diethyl ether was distilled off under reduced pressure to obtain 6.5 g of a crude product.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13][CH2:14][CH:15](OCC)OCC)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N1C2C=C3C=CSC3=CC=2CC1)(=O)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:13][CH2:14][CH3:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(CSc1ccc2c(c1)CCN2C(C)=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(=O)N1CCc2cc3sccc3cc21
Solvent: ClCCl
Product: CCSc1ccc2c(c1)CCN2C(C)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of acetal (D5, 2.14 g, 6.9 mmol) in dry dichloromethane (80 ml) at -78° C. was added titanium tetrachloride (1.48 ml, 13.85 mmol) dropwise by syringe. The mixture was stirred for 2 h at -78° C., 2 h at 0° C. and then overnight at room temperature. The mixture was then washed with water, saturated sodium bicarbonate solution, then water again, dried and evaporated. The residue was taken up in hot dichloromethane and petrol was added to precipitate polar material as a gum. The liquor was decanted off and addition of petrol/decantation was repeated twice. The final liquor was evaporated to give a mixture of the title compound and 5-acetyl-6,7-dihydro-5H-thieno[2,3-f]indole (0.31 g), which was hydrolysed without separation.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[OH:12][CH2:13][C@@H:14]1[C@:23]2([CH3:24])[C@H:18]([C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22]2)[CH2:17][CH2:16][C@@:15]1([CH3:28])[OH:27].C([O-])([O-])=O.[Cs+].[Cs+].COCCOCCOC>CCOC(C)=O.[Cu]I.C1(C)C=CC=CC=1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([O:10][CH3:11])[CH:5]=1)[O:12][CH2:13][C@@H:14]1[C@:23]2([CH3:24])[C@H:18]([C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22]2)[CH2:17][CH2:16][C@@:15]1([CH3:28])[OH:27]
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Reactant: COc1cc(I)cc(OC)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: COCCOCCOC
Product: COc1cc(OC)cc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Temperature: 120 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
In a sealed tube purged with nitrogen, 1-iodo-3,5-dimethoxybenzene (36) (0.78 g, 3.0 mmol), (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (0.65 g, 2.68 mmol), Cs2CO3 (1.3 g, 4.0 mmol), 3,4,7,8-tetramethyl-[1,10]-phenylthroline (0.12 g, 0.50 mmol), CuI (0.05 g, 0.3 mmol), diglyme (2 mL) and toluene (10 mL) were added. The reaction mixture was stirred at 120° C. for 18 h. The reaction was cooled to room temperature, diluted with EtOAc (300 mL) and washed with water (100 mL). The organic layer was dried (Na2SO4) and concentrated. Purification by column chromatography on silica gel (Hexanes/EtOAc, 2:1) gave (1S,2R,4aS,8aS)-1-(3,5-dimethoxyphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (37) (0.71 g, 70%) as a colourless oil.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:20][OH:21]>CCO.CCOC(C)=O>[OH:21][NH:20][C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[NH:2]
Reactant: CNC(=O)c1ccc(C#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)c1ccc(C(=N)NO)cc1
Temperature: 80 °C
Reaction time: 25 h
Yield: 94.1 %

Procedure:
4-Cyano-N-methylbenzamide (200 mg, 1.249 mmol), potassium carbonate (1035 mg, 7.49 mmol) and hydroxylamine hydrochloride (521 mg, 7.49 mmol) were dissolved in EtOH (12.6 mL). The reaction mixture was stirred at 80° C. for 25 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (10 mL), water phase extracted with EtOAc (20 mL). Combined organic phases were washed with brine (10 mL) and dried over sodium sulfate. The solvent was removed to yield 227 mg of a white powdery solid. The crude material was used without further purification.
Reaction SMILES: [CH3:1][C:2]([S:30]([CH3:33])(=[O:32])=[O:31])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)[C:3]([NH:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)=[O:4].Br[C:35]1[CH:36]=[CH:37][C:38](=[C:41]2[C:46](=[O:47])OC(C)(C)OC2=O)NC=1.IC1C=CC=CC=1O.[F-].[Cs+]>C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[OH:47][C:46]1[CH:35]=[CH:36][CH:37]=[CH:38][C:41]=1[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][C:2]([CH3:1])([S:30]([CH3:33])(=[O:32])=[O:31])[C:3]([NH:5][O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[O:4])=[CH:20][CH:19]=1
Reactant: CC1(C)OB(c2ccc(CCC(C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)OC1(C)C
Reactant: CC1(C)OC(=O)C(=C2C=CC(Br)=CN2)C(=O)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Oc1ccccc1I
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(CCc1ccc(-c2ccccc2O)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 115 °C
Reaction time: 8 h

Procedure:
To a flask containing 2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanamide prepared as in Preparation Number 3 (150 mg, 0.312 mmol) was added 2-iodophenol (89.3 mg, 0.406 mmol), cesium fluoride (190 mg, 1.25 mmol), water (500 uL) and 1,4-dioxane (3 mL). To this mixture was added Palladium tetrakis (54.3 mg, 0.047 mmol) and the mixture was heated to 115° C. with stirring overnight. The mixture was diluted with ethyl acetate and water. The phases were separated and the crude organic extract was concentrated in vacuo to dryness. The crude material was purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford 4-(2′-hydroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as solid. 19.6 mg LCMS: (M−1) 446.3.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[CH:7][N:6]=2.[H-].[Na+].[CH3:15]I>CN(C)C=O>[CH3:15][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([CH3:12])=[C:10]2[N:11]=[C:3]1[CH2:2][OH:1]
Reactant: Cc1ccnc2[nH]c(CO)nc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccnc2c1nc(CO)n2C

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 5.00 g of 2-hydroxymethyl-7-methyl-3H-imidazo[5,4-b]pyridine, 1.34 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.0 ml of methyl iodide and 120 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 4.4 g of the title compound, melting at >300° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:13][CH2:14][O:15][CH3:16].O>CN(C)C=O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][CH2:13][CH2:14][O:15][CH3:16])=[CH:3][C:2]=1[F:1]
Reactant: Oc1ccc(F)c(F)c1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a solution of 3,4-difluoro-phenol (10 g, 76.9 mmol) (Aldrich) in N,N-dimethylformamide (100 mL) was added sodium hydride (4.6 g, 115 mmol) and 1-bromo-2-methoxy-ethane (12.8 g, 92.2 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 2 h, then heated at 80 ° C. for 16 h. The reaction mixture was cooled to room temperature and poured into water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over dried over MgSO4, filtered and concentrated. The residue was purified with chromatography (EtOAc:Hexane=1:10) to give 1,2-difluoro-4-(2-methoxy-ethoxy)-benzene as colorless oil (Yield 6.3 g, 44%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[OH:12])[CH2:2][CH3:3].[H-].[Na+].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[I-].[K+]>O.C(OCC)(=O)C.CN(C)P(N(C)C)(N(C)C)=O.O1CCCC1>[CH2:1]([C:4]1[C:9]([Cl:10])=[C:8]([Cl:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])[CH2:2][CH3:3]
Reactant: BrCCCCCBr
Reactant: CCCc1c(O)ccc(Cl)c1Cl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCCCBr)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.12 g. of 2-propyl-3,4dichlorophenol in 30 ml. of dry tetrahydrofuran and 30 ml. of dry hexamethylphosphoramide were added 0.72 g. of a 50% sodium hydride dispersion in oil. Two milliliters of 1,5-dibromopentane were then added followed by a catalytic amount of potassium iodide. The reaction was stirred overnight under a nitrogen atmosphere at 60°-70° C. The reaction was then cooled to room temperature, ethyl acetate and water were added, and the solution was evaporated to dryness. Ethyl acetate and water were added to the residue and the layers were separated. The ethyl acetate layer was washed with dilute acid to remove residual hexamethylphosphoramide. The ethyl acetate was then washed with a saturated sodium chloride solution, filtered through sodium sulfate, and evaporated to dryness. The residue was purified by high pressure liquid chromatography to provide 1.6 g. of the desired bromo intermediate. NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.Cl.[CH2:17]([O:19][NH2:20])[CH3:18].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([NH:20][O:19][CH2:17][CH3:18])[CH2:8]2
Reactant: COc1ccc2c(c1OC)CCC(=O)C2
Reactant: CCON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCONC1CCc2c(ccc(OC)c2OC)C1
Temperature: 10 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
5,6-Dimethoxy-3,4-dihydro-1H-naphthalen-2-one (1.5 g, 7.5 mmol), prepared as described in J Med. Chem. 1977, 20, 1111-1116, was dissolved in water (15 ml) and a solution of O-ethylhydroxylamine hydrochloride (1 g, 10 mmol) and Na2CO3 (0.53 g, 5 mmol) in water (10 ml) was added dropwise under stirring at 10° C. The reaction was left at room temperature overnight and then extracted with diethyl ether. The ether solution was evaporated to dryness under vacuum. The residue was dissolved in 20 ml of ethanol and concentrated hydrochloric acid (1 ml) and hydrogenated at 3,6×106 Pa (50 psi) using PtO2 as catalyst. The solvent was removed under reduced pressure, water was added and the aqueous phase was treated with NaHCO3 and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated to dryness under vacuum. The crude residue was purified by chromatography, to afford 0.85 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[N:17]([CH3:18])[CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[N:25][CH:26]=1)#[CH:20]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:20]=[CH:19]\[C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:6]1[CH2:11][C@H:12]3[N:17]([CH3:18])[C@@H:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: C#Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1C
Product: Cc1ccc2c(c1)c1c(n2/C=C\c2ccc(C)nc2)C[C@@H]2CCC[C@H]1N2C

Procedure:
The coupling of 2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.458 mmol; Example 114A) and 5-ethynyl-2-methylpyridine (107 mg, 0.915 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to give the racemic mixture of the title compound as the major of two alkene isomers. The individual enantiomers from this racemic mixture were separated by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine) to afford the title compound as the second-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 1.18-1.41 (m, 2H), 1.48 (dd, J=13, 2 Hz, 1H), 1.65-1.75 (m, 1H), 1.83-2.08 (m, 2H), 2.26 (d, J=17 Hz, 1H), 2.28 (s, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 2.90 (dd, J=18, 7 Hz, 1H), 3.17 (t, J=5 Hz, 1H), 4.13 (s, 1H), 6.64 (d, J=8 Hz, 1H), 6.84-6.91 (m, 1H), 6.92-7.10 (m, 3H), 7.15-7.23 (m, 2H), 7.96 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [Na].[SH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>C(O)C=C>[CH2:7]([O:6][C:4]([CH2:3][S:2][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[O:5])[CH3:8]
Reactant: CCOC(=O)CS
Reactant: C=CCOC(=O)CCCCl
Agent: [Na]
Solvent: C=CCO
Product: C=CCOC(=O)CCCSCC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Sodium (9.06 g; 0.39 mole) was decomposed in allyl alcohol (380 ml). The obtained solution was treated by dropwise adding of first ethyl mercaptoacetate (42.7 ml; 0.39 mole) at the temperature of 0° C. and then of allyl 4-chlorobutyrate (58.3 g; 0.36 mole) prepared according to the process disclosed in Example 2a. The obtained mixture was stirred for three hours at room temperature and then for 1 hour at reflux temperature. The mixture was concentrated by evaporation and poured into a mixture of diethylether (200 ml) and of an ice/water mixture (100 g). The obtained solution was acidified with 1M hydrochloric acid solution to achieve a pH value of the medium between 3 and 6. The ether phase was separated and the obtained aqueous phase was extracted with diethyl ether (200 ml). The combined ether fractions were washed with water (200 ml) and 4% aqueous sodium hydrogencarbonate solution (200 ml) and dried with magnesium sulfate. After the removal of the drying agent and evaporation of ether, the title compound (78.1 g; 84%) was obtained, which was used in the crude form in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[O:5].[C:23](Cl)(Cl)=[S:24].C(N(CC)CC)C>C1(C)C=CC=CC=1.COC(C)(C)C>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]1[O:5][C:23](=[S:24])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])[N:6]=1
Reactant: O=C(NNc1ccccc1C(F)(F)F)c1c(F)cccc1F
Reactant: S=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: Fc1cccc(F)c1-c1nn(-c2ccccc2C(F)(F)F)c(=S)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.79 g (15 mmol) of 2,6-difluoro-N'-(α,α,α-trifluoro-o-tolyl)-benzhydrazide in 30 ml of toluene are treated with 1.98 g (17 mmol) of thiophosgene and the reaction mixture is heated at the reflux temperature for 5 hours. 4.8 ml (35 mmol) of triethylamine are then added dropwise at 45° C. while cooling and, after cooling, the mixture is stirred at room temperature for about 1 hour. The mixture is subsequently taken up in 100 ml of tert.butyl methyl ether and the solution is washed in each case once with dilute, ice-cold sodium hydroxide solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is purified by chromatography using acetone/n-hexane (1:4) as the eluent and crystallized from diisopropyl ether/n-hexane. In this manner there is obtained 5-(2,6-difluorophenyl)-3-(α,α,α-trifluoro-o-tolyl)-1,3,4-oxadiazole-2(3H) -thione as a white crystallizate, m.p. 128°-130° C.; mass spectrum: 358(58), 298(15 ), 289(17), 159(100).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH:12]1([NH:15]C)CC1>>[CH3:12][NH:15][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=1
Reactant: CNC1CC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Product: CNc1ccc([N+](=O)[O-])c(C)n1

Procedure:
6-Chloro-2-methyl-3-nitro-pyridine (0.5 g) was treated with cyclopropyl-methylamine according to General Procedure U to give methyl-(6-methyl-5-nitro-pyridin-2-yl)-amine. LCMS (m/z): 208. This was reduced under hydrogen atmosphere according to General Procedure Z to give N*2*-cyclopropylmethyl-6-methyl-pyridine-2,5-diamine (0.35 g), LCMS (m/z): 178. This was converted to 6-(cyclopropylmethyl-amino)-2-methyl-pyridine-3-sulfonyl chloride according to General Procedure AA. LCMS (m/z): 261.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:12])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10]Cl)[N:9]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:10][C:8]3[N:9]=[C:5]([NH:4][C:3]([NH:2][CH3:1])=[O:12])[S:6][CH:7]=3)[CH2:14][CH2:15]2)=[CH:20]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: CNC(=O)Nc1nc(CCl)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Yield: 30.1 %

Procedure:
In a stream of nitrogen gas, a mixture of 2-(3-methylureido)-4-chloromethylthiazole (1.0 g), 3-(4-piperidyl)indole (0.98 g), sodium hydrogen carbonate (0.45 g) and N,N-dimethylformamide (5 ml) was heated at 80° to 90° C. The reaction mixture was then concentrated and the residue was subjected to column chromatography on silica gel. Elution was carried out with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the desired compound were collected and concentrated under reduced pressure. The residue was precipitated with n-hexane to give 4-[4-(3-indolyl)piperidinomethyl]-2-(3-methylureido)thiazole (540 mg).