Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:7][CH:8]=1.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:20]=[CH:21][C:22]=1[Cl:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:3][C:4]4[N:5]=[C:6]([CH2:9][N:10]5[CH2:15][CH2:14][O:13][CH2:12][CH2:11]5)[S:7][CH:8]=4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: ClCc1csc(CN2CCOCC2)n1
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(CN2CCOCC2)n1
Temperature: 70 °C
Reaction time: 21 h
Yield: 55.1 %

Procedure:
4-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}morpholine hydrochloride (0.024 g, 0.089 mmol) and 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (0.030 g, 0.089 mmol) were suspended in DMF (2 mL) and potassium carbonate (0.062 g, 0.449 mmol) was added. The mixture was stirred at 70° C. for 21 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC to afford the title compound as a colorless solid (0.026 g, 0.049 mmol, 54% yield). 1H NMR (400 MHz; CDCl3): 2.50 (br s, 1H); 2.57-2.64 (m, 4H); 3.75 (t, 4H); 3.84 (s, 2H); 3.96 (s, 3H); 5.28 (s, 2H); 7.09 (s, 1H); 7.31 (s, 1H); 7.37 (s, 1H); 7.43 (d, 1H); 7.60 (dd, 1H); 7.97 (d, 1H); 8.61 (s, 1H); MS (EI) for C24H23Cl2N5O3S: 532 (MH+).
Reaction SMILES: Cl[C:2]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]([C:5]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=2[F:12])O1.[NH2:18][C:19]([NH2:21])=[S:20].C([O-])([O-])=O.[K+].[K+]>CCO>[NH2:21][C:19]1[S:20][C:4]([C:5]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=2[F:12])=[C:2]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:18]=1
Reactant: CCOC(=O)C1(Cl)OC1c1c(F)cccc1F
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1nc(N)sc1-c1c(F)cccc1F
Temperature: 0 °C

Procedure:
To a solution of ethyl 2-chloro-3-(2,6-difluorophenyl)oxirane-2-carboxylate in EtOH was added thiourea, followed by heating under reflux for 4 hours. To the reaction mixture was added ice-water, followed by addition of K2CO3 to make it basic. The solid precipitated was collected by filtration and washed with water to obtain ethyl 2-amino-5-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C:25]1([CH:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH:42]4[CH2:47][CH2:46][CH:45](O)[CH2:44][CH2:43]4)[CH:37]=3)[O:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:25]1([CH:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH:42]4[CH2:47][CH2:46][CH:45]([O:5][C:4](=[O:6])[C:3]5[CH:7]=[CH:8][N:9]=[CH:10][C:2]=5[F:1])[CH2:44][CH2:43]4)[CH:37]=3)[O:32]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccncc1F
Reactant: OC1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1)c1ccncc1F
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 158 mg of 3-fluoroisonicotinic acid (1.12 mmol) and 156 μl of triethylamine (1.12 mmol) in 16 ml of dichloromethane at 15° C. 138 μl of pivaloyl chloride (1.12 mmol) were added dropwise. The solution was stirred for 30 min. A solution of 110 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanol (0.34 mmol) in 4 ml of dichloromethane was added and 82 mg of 4-dimethylamino-pyridine (0.68 mmol) were added in one portion. Stirring at room temperature was continued for 16 h. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered, and the solvent removed by evaporation. The resulting oil was purified by reversed phase HPLC. 104 mg of the title compound were isolated as solid (69%).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[N:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1>>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:16][C:13]2[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1ccncc1
Product: Cc1ccc(C=Cc2ccncc2)cc1

Procedure:
By the procedure described in Ex. 1 4-tolualdehyde (12.6 g) and 4-picoline (9.3 g) were reacted to obtain 4-(4-methylstyryl)pyridine.
Reaction SMILES: [C:1]([SH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH2:11]>C(Cl)(Cl)(Cl)Cl>[C:1]([S:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:11])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(OC)cc1
Reactant: S=C(S)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(C)SC(=S)c2ccccc2)cc1
Temperature: 70 °C
Yield: 53 %

Procedure:
A mixture of dithiobenzoic acid (3.6 g), 4-vinylanisole (2.9 g) and carbon tetrachloride (20 mL) were heated at 70° C. overnight. The solvent was evaporated and the residue subjected to column chromatography (aluminium oxide (activity III) column, 2% diethyl ether in n-hexane eluent) which gave the title compound (53% yield). 1H-nmr (CDCl3) d (ppm): 1.80 (d, 3H, SCHCH3); 3.80 (s, 3H, OCH3); 5.22 (q, 1H, SCHCH3) and 6.88-7.97 (m, 9H, ArH).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].F[C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:14]=1[C:15]#[N:16].O>CN(C)C=O>[C:2](=[N:4][O:5][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][O:23][CH3:24])[C:14]=1[C:15]#[N:16])([CH3:3])[CH3:1]
Reactant: CC(C)=NO
Reactant: COCOc1cccc(F)c1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cccc(ON=C(C)C)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
Acetone oxime (11.14 g, 0.1524 mole) was dissolved in 300 ml of dry dimethyl formamide (DMF) and then potassium t-butoxide (17.0 g, 0.152 mole) was added portionwise. The reaction mixture was allowed to stir for 30 minutes at room temperature and the 2-fluoro-6-methoxymethoxybenzonitrile of Example 1(b) (23.0 g, 0.127 mole) was added in 150 ml of DMF. After 30 minutes the reaction mixture was poured into 1000 ml of water and stirred well as the product crystallized. The product was filtered off, washed well with water, and then taken up in CH2Cl2 and dried with magnesium sulfate. Concentration and recrystallization from methanol-water gave 20.5 g (69%) of 2-[(isopropylideneamino)oxy]-6-methoxymethoxybenzonitrile as fine needles, mp 62°-64° C.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[F:13][C:14]([F:43])([F:42])[C:15](Cl)([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][CH:33]=1)[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1.C([SnH](CCCC)CCCC)CCC.O>C1(C)C=CC=CC=1>[F:13][C:14]([F:42])([F:43])[CH:15]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH3:40])=[CH:36][CH:37]=1)[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1
Reactant: CCOc1ccc(C(Cl)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc(C(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Yield: 90.2 %

Procedure:
A few crystals of α,α-azoisobutyronitrile (AIBN) were added to a solution of 1,1,1-trifluoro-2-chloro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.36 g) in toluene (15 cm3), and the mixture was cooled in an ice bath whilst tri-n-butyl tin hydride (0.25 cm3) was added. The reaction mixture was heated at the reflux temperature for 1.5 hours under an atmosphere of nitrogen. Analysis by gas liquid chromatography at this time showed no trace of the starting chloro compound. The mixture was cooled, poured I into water (50 cm3), and extracted with diethyl ether (4×30 cm3). The combined organic layers were dried over anhydrous sodium sulphate and the residual oil after evaporation of the solvent under reduced pressure was purified by column chromatography on a silica gel support, eluting with n-hexane containing 6% by volume diethyl ether, to give 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)-propane (0.3 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:29]([C@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:37]4[C@@H:36]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:40][O:39][C:38]4=[O:41])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN4C(=O)OC[C@@H]4Cc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (S)-4-benzyl-oxazolidin-2-one.
Reaction SMILES: [NH2:1][C:2]([C:14]1[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)=[N:16][C:17]([S:21][CH3:22])=[N:18][C:19]=1[NH2:20])=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6]CC)=O.CCCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[N:16][C:17]([S:21][CH3:22])=[N:18][C:19]=2[N:20]=[C:4]([OH:6])[C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C(=O)OCC)=C(N)c1c(N)nc(SC)nc1-c1cccc([N+](=O)[O-])c1
Solvent: CCCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c(O)nc2nc(SC)nc(-c3cccc([N+](=O)[O-])c3)c2c1N
Temperature: 240 °C

Procedure:
A suspension of diethyl 2-(amino-[6-amino-2-methylthio-4-(3-nitrophenyl)-pyrimidin-5-yl]-methylene)-malonate (example 30b, 1.34 g) in diphenyl ether (30 ml) was heated under a stream of nitrogen to 240° C. for 2 h. After the mixture was cooled to room temperature, heptane was added (200 ml) and the solids were collected by filtration. The title compound was purified by chromatography on silica gel using CH2Cl2/acetone=1/0 to 4/1 (v/v) as eluent.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=O>>[CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH:19][CH2:20][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=Cc1nccs1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Product: c1csc(CNc2ccc3c(c2)COC(NC2CCCCCC2)=N3)n1
Yield: 38.8 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (188 mg, 0.73 mmol) and 2-formylthiazole (90 mg, 0.80 mmol) according to the procedure described for example 88. Obtained the title compound as a yellow foam (101 mg, 39%), MS (ISP) m/e=357.3 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][OH:14])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH:11]([OH:16])[C:12](=[NH:15])[NH:13][O:14][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:9][CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(O)C(=N)NO
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NC(=O)OC(C)(C)C)C(O)C(=N)NOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
A solution of {1-[hydroxy-(N-hydroxycarbamimidoyl)-methyl]-propyl}-carbamic acid tert-butyl ester (2) (2.5 g, 10 mmol) in dichloromethane (125 ml) was treated with benzoic acid (1.36 g, 11 mmol), EDCI (2.14 g, 11 mmol), HOBT (1.37 g, 10 mmol) and triethylamine (1.35 ml, 11 mmol) and stirred at room temperature overnight. Reaction mixture was washed with saturated sodium bicarbonate solution and then water and dried over Na2SO4. Solvent evaporated under reduced pressure, crude purified by mplc eluting with 1% triethylamine in 2:3 v/v ethyl acetate and heptane mixture to give yellow solid (850 mg); MS: MH+ 352.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[N:3]=1.[C:13]([C:15]1([NH:24][C:25](=[O:35])[CH:26]([NH2:34])[CH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]1)#[N:14].CN1CCOCC1>C(#N)C>[C:13]([C:15]1([NH:24][C:25](=[O:35])[CH:26]([NH:34][C:2]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4](=[O:12])[N:3]=2)[CH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH3:23])[CH2:19][CH2:20]1)#[N:14]
Reactant: O=c1nc(Cl)c2ccccc2o1
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CCC(C)(C)CC)CC1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCCN1CCC(C#N)(NC(=O)C(CCC(C)(C)CC)Nc2nc(=O)oc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A suspension of 4-chloro-benzo[e][1,3]oxazin-2-one (620 mg, 3.41 mmol, 2.0 eq), 2-amino-5,5-dimethyl-heptanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide (675 mg, 1.71 mmol, 1.00 eq), and 4-methylmorpholine (NMM) (0.56 mL, 5.09 mmol, 3.00 eq) in acetonitrile (9.0 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated, resuspended in ethyl acetate (50 mL) and washed with saturated Na2CO3 solution. The organic phase was dried (MgSO4) and concentrated and the resulting residue was chromatographed over silica gel using a gradient of methanol in dichloromethane as the eluant to provide 124 mg (16% yield) of the title compound; m/z calculated for C26H37N5O3 467.6, found 468.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][C@@H:7]1[CH3:13])=[O:5])[CH3:2].[S:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.[Li]CCCC.CO>C1COCC1.O.CCOC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([OH:12])([C:15]2[S:14][CH:18]=[CH:17][N:16]=2)[CH2:8][CH:7]1[CH3:13])=[O:5])[CH3:2]
Reactant: c1cscn1
Reactant: CCOC(=O)[C@@H]1CCC(=O)C[C@@H]1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(O)(c2nccs2)CC1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a cooled (−78° C.) solution of cis-2-methyl-4-oxo-cyclohexanecarboxylic acid ethyl ester (22 g, 119 mmol) and thiazole (16.9 mL, 239 mmol) in THF (154 mL) was added nBuLi (1.6 M in Hex, 74.6 mL, 119 mmol) dropwise at such a rate that the internal temperature was maintained <−65° C. The reaction mixture was stirred for 30 min, MeOH (4.83 mL, 119 mmol) was introduced, and the reaction warmed to room temperature where it was diluted with water and EtOAc. The layers were separated, the organic layer dried with MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography to afford 4-hydroxy-2-methyl-4-thiazol-2-yl-cyclohexanecarboxylic acid ethyl ester (21 g, 78 mmol).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:27]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc(N2CCCC2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(N2CCCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 3-(pyrrolidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions I): tR=1.48 min.; [M+H]+: 409.18 g/mol.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:23]1[S:24][C:25]([CH2:28][CH:29]2[CH2:33][CH2:32][O:31][CH2:30]2)=[CH:26][CH:27]=1)[NH:6][C:7](=[O:22])[CH:8]([CH2:17][S:18]C(=O)C)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.CO.C(Cl)(Cl)Cl>ClCCl>[O:31]1[CH2:32][CH2:33][CH:29]([CH2:28][C:25]2[S:24][C:23]([CH:5]([C:4]([OH:34])=[O:3])[NH:6][C:7](=[O:22])[CH:8]([CH2:17][SH:18])[CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:27][CH:26]=2)[CH2:30]1
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(CC2CCOC2)s1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(NC(C(=O)O)c1ccc(CC2CCOC2)s1)C(CS)CCc1ccccc1

Procedure:
The title compound was prepared from 2-[5-(tetrahydrofuran-3-ylmethyl)thien-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester (Description 47) by the procedure described in Example 24 except that the eluent used was 10% methanol in dichloromethane. vmax (CHCl3) 3409, 3293, 1648 and 1603 cm-1. δ (CD3SOCD3) 1.44-1.61 (1H, m), 1.70-1.82 (1H, m), 1.85-2.03 (1H, m), 2.30-2.80 (8H, m), 3.29-3.40 (2H, m), 3.53-3.76 (3H, m), 5.13 and 5.25 (1H, two d's, J 6.55 Hz), 5.70 and 5.77 (1H, two s's), 6.64 (1H, d, J 3.23 Hz), 6.74-6.84 (1H, m), 7.11-7.31 (5H, m), 7.87 and 8.12 (1H, two d's, J 6.68 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](I)=[CH:11][C:10]([NH2:14])=[N:9]2)=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:19]=[C:20]([CH2:22][O:23][C@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:18]3[CH:19]=[C:20]([CH2:22][O:23][C@H:24]([CH3:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=[C:16]([F:15])[CH:17]=3)=[CH:11][C:10]([NH2:14])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1)C(F)(F)F
Reactant: Nc1cc(I)n(-c2ccc(F)cc2)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: C[C@@H](OCc1cc(F)cc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F

Procedure:
To a solution of 1-(4-fluorophenyl)-5-iodo-1H-pyrazol-3-ylamine (38 mg) prepared in Preparation 18 in 1,4-dioxane (0.4 ml) were sequentially added 2-[3-fluoro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (52 mg) prepared according to the same procedures as Preparation 15, palladium (II) acetate (3 mg), tricyclohexylphosphine (7 mg) and a 2M aqueous solution of potassium carbonate (0.2 ml) at room temperature, and the mixture was stirred at 105° C. for 4 hours. After removing an aqueous layer of the reaction mixture, an organic layer was filtered through silica gel (5 g), and subjected to elution with ethyl acetate. The filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel thin-layer chromatography (eluent: n-hexane/ethyl acetate=1/1) to give the titled compound.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: [H][H]
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(O)cc1
Reaction time: 4 h
Yield: 109.9 %

Procedure:
3.00 g of {2-hydroxy-2-[4-(phenylmethoxy)phenyl]propyl}[(methylethyl)sulfonyl]amine (prepared in example 32) and 3.10 g. of 10% Pd/C in ethyl acetate (300 mL) were subjected to a hydrogen atmosphere while shaking at 60 psi's for 4 hours. Solution was filtered through a Celite mat and the resulting filtrate was concentrated under reduced vacuum to yield intermediate title compound (2.48 g, 100%) as a foam. This material slowly crystallized and was used without further purification. Ion spray M.S. 272.1 (M*−1).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=[CH:16][C:3]1=2.S(Cl)([Cl:22])=O>>[Cl:22][C:17]([C:14]1[CH:15]=[CH:16][C:3]2[C:2](=[O:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=1)=[O:19]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2=O
Product: O=C(Cl)c1ccc2c(c1)Sc1ccccc1CC2=O

Procedure:
Heat a solution of 5 g. of 10,11-dihydro-11-oxodibenzo[b,f]thiepin-3-carboxylic acid and 40 ml. of thionyl chloride under reflux for 20 minutes. Evaporate the reaction mixture under vacuum to dryness. Repeat the evaporation with two 30 ml. portions of carbon tetrachloride. Crystallize the residue from diisopropyl ether to obtain the title product.
Reaction SMILES: C(N[C:5](=[CH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([Cl:18])=[C:13]([CH3:19])[CH:12]=1)[C:6]([O:8]C)=[O:7])(=O)C.Cl.[OH2:21]>CN1CCCC1=O>[Cl:18][C:14]1[C:15]([CH3:17])=[CH:16][C:11]([CH2:10][C:5](=[O:21])[C:6]([OH:8])=[O:7])=[CH:12][C:13]=1[CH3:19]
Reactant: O
Reactant: COC(=O)C(=Cc1cc(C)c(Cl)c(C)c1)NC(C)=O
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc(CC(=O)C(=O)O)cc(C)c1Cl
Reaction time: 6 h

Procedure:
29.4 g (105 mmol) methyl 2-acetylamino-3-(4-chloro-3,5-dimethylphenyl)-acrylate in 330 mL N-methyl-2-pyrrolidinone were combined with 500 mL cooled 4 M HCl, stirred for 6 h at reflux temperature and for 16 h at RT. After the reaction had ended the reaction mixture was poured onto 1650 mL water, stirred for 1 h, suction filtered and the crystals were dried at 50° C. in the vacuum drying cupboard. The product was recrystallised from toluene.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([CH3:21])([O:16][Si](C)(C)C)[C:12]([F:15])([F:14])[F:13])=[N:9][CH:10]=1.Cl>C1COCC1>[F:15][C:12]([F:13])([F:14])[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][N:9]=1)([OH:16])[CH3:21]
Reactant: COCOc1ccc(C(C)(O[Si](C)(C)C)C(F)(F)F)nc1
Agent: Cl
Solvent: C1CCOC1
Product: COCOc1ccc(C(C)(O)C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
A mixture of 1.48 g (4.58 mmol) 5-methoxymethoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-pyridine and 5 ml (10 mmol) 2N HCl in 15 ml THF was stirred at room temperature for 2 h. After that the reaction mixture was poured on water and a pH of 1-2 was adjusted by the addition of 2N HCl. The reaction mixture was extracted 2 times with EtOAc. The combinded organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo to afford 1.06 g of the title compound as an oil (88% pure), which was used in the next step without purification. LCMS (method L): tR=0.88 min, M+H=252.