Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:14]([CH3:25])=[C:13]([CH3:26])[N:12]=1>O1CCCC1>[CH3:26][C:13]1[C:14]([CH3:25])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCO)c1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCO)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Sodium hydride (7.80 g of a 60% dispersion in mineral oil, 195 mmol) was added in portions to a chilled (0° C.) solution of phenol (18.36 g, 195 mmol) in tetrahydrofuran (200 mL). After the addition was completed the reaction mixture was allowed to stir at ambient temperature for 30 minutes. Solid 3-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]propan-1-ol (16.89 g, 65.0 mmol) was added and the reaction mixture was heated at reflux for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (400 mL) and water (100 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by flash chromatography (500 mL silica gel eluting with a gradient of 30–75% ethyl acetate in hexanes) and then heated under high vacuum until it melted. The melt solidified to provide 11.54 g of 3-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]propan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([C:22]1C=CC=C[CH:23]=1)[C:18]([F:21])([F:20])[F:19].ClC1C=C2C(=CC=1)NC(=O)N(CC(F)(F)F)C2(O)C(F)(F)F.C([Mg]Br)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH2:22][CH3:23])[C:18]([F:20])([F:21])[F:19]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)(C(F)(F)F)N1CC(F)(F)F
Agent: CC[Mg]Br
Agent: O=C1Nc2ccc(Cl)cc2C(O)(C(F)(F)F)N1CC(F)(F)F
Product: CCC1(C(F)(F)F)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F

Procedure:
Utilizing the general procedure outlined for 6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one, 6-chloro-4-hydroxy-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one (227 mg, 0.65 mmol) was reacted with 3.0M ethyl magnesium bromide (0.9 ml, 2.6 mmol) to afford 6-chloro-4-ethyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin2(1H)-one as a white solid. 1H NMR (d6-DMSO, 400 MHz) δ 7.41 (s, 1H), 7.35 (dd, J=2.4 and 8.6 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 4.52 (m, 1H), 4.26 (m, 1H), 2.55 (m, 1H), 2.36 (m, 1H), 0.9 (t, J=6.8 Hz, 3H). Exact Mass (Electrospray, M+H) Calc'd, 361.0537; Found, 361.0532.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH:8]([CH:13]=[N:14][OH:15])[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:26])[C:20]([CH3:25])([CH3:24])[CH2:21][C:22]#[CH:23]>>[CH3:17][O:18][C:19](=[O:26])[C:20]([CH3:25])([CH3:24])[CH2:21][C:22]1[O:15][N:14]=[C:13]([CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:16])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:23]=1
Reactant: CC(C)CC(C=NO)NC(=O)OC(C)(C)C
Reactant: C#CCC(C)(C)C(=O)OC
Product: COC(=O)C(C)(C)Cc1cc(C(CC(C)C)NC(=O)OC(C)(C)C)no1

Procedure:
Prepared from [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid tert-butyl ester (71) and 2,2-dimethyl-pent-4-ynoic acid methyl ester according to the procedure outlined in example 6A. MS (Cl) m/z: 313.2 (M-tBu), 269.3 (M−99)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][NH:14][OH:15].C(N(CC)CC)C.[CH3:23][O:24][C:25]([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])=[O:26].S([O-])(O)(=O)=O.[K+]>C1COCC1.O.C(OCC)(=O)C.CCCCCC>[OH:15][N:14]([CH2:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[O:2][CH3:1])[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:25]([O:24][CH3:23])=[O:26]
Reactant: COc1c(CNO)ccc2ccccc12
Reactant: COC(=O)CCCC(=O)O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CCCC(=O)N(O)Cc1ccc2ccccc2c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Into a solution of 267 mg (1.33 mmol) of 1-methoxy-2-naphthylmethylhydroxylamine and 185 μl (1.33 mmol) of triethylamine in THF (15 ml) and water (3 ml) was added under 0° C. a solution of 219 mg (1.33 mmol) of acid chloride of 4-methoxycarbonylbutanoic acid in THF (3 ml), followed by stirring at 0° C. for one hour and at room temperature for one hour. After the reaction, an aqueous potassium hydrogen sulfate was added, and the mixture extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The crude product obtained was subjected to silica gel column chromatography (hexane: ethyl acetate=1:1) to give 279 mg (64%) of the desired product.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.C(Br)C.[Br:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:28])[C:16]=2[CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[Br:13][C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:3]3[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]3)([OH:28])[C:16]=2[CH:15]=1
Reactant: O=c1c2ccccc2sc2ccc(Br)cc12
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccccc3Sc3ccc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 1.2 l g. (0.05 mol) of magnesium turnings covered by tetrahydrofuran in an Argon atmosphere is added about 0.5 g. of 4-chloro-N-methylpiperidine (from 8.5 g., 0.025 mol of the hydrochloride salt) and a small amount of ethyl bromide. The mixture is heated until the reaction is initiated, the remainder of the chloro compound in about 20 ml. of tetrahydrofuran is added and the mixture is refluxed for four hours. 2-Bromothioxanthone (7.3 g., 0.025 mol) is added and the mixture is refluxed for five hours, and then stirred at room temperature 3 days. The reaction mixture is poured into aqueous ammonium chloride and filtered to give 2-bromo-9(1-methyl-4-piperidyl)thioxanthene-9-ol, m.p. 225.5°-226° C.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]2=[CH:15][S:16][CH:17]=[C:6]2[C:5]1=O)[CH2:2][CH3:3].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]2=[CH:15][S:16][CH:17]=[C:6]2[CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1C(=O)c2cscc2Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCN1Cc2cscc2Nc2ccccc21

Procedure:
A 5 g. portion of 4,9-dihydro-9-propyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of dried tetrahydrofuran is added dropwise with stirring under nitrogen to a suspension of 3.1 g. of lithium aluminum hydride in 100 ml. of tetrahydrofuran. The reaction mixture is stirred for 18 hours under reflux, then cooled in an ice bath and treated under nitrogen, with stirring, with 3 ml. of water, 3 ml. of 15% sodium hydroxide and finally with 9 ml. of water. The complex is filtered and washed thoroughly with ether. The combined filtrate and washings are dried over sodium sulfate and filtered. The filtrate is concentrated to a dark blue oil. A 50 ml. portion of hexane:ether (10:1) is added and the mixture is stored in a chill room overnight. The solid is filtered, washed with hexane and dried. A second crop is obtained from the filtrate and is washed with hexane and dried. The two crops are combined, heated to solution in 100 ml. of hexane, filtered and cooled giving blue crystals which are collected, washed with hexane and dried, mp. 78°-79° C.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[NH:5][CH:4]=1.Cl[CH2:13][C:14]1[CH:15]=[C:16]2[S:22][C:21]([S:23][CH3:24])=[N:20][C:17]2=[N:18][CH:19]=1>CN(C=O)C>[N:3]1[C:7]2[C:6](=[N:11][CH:10]=[CH:9][CH:8]=2)[N:5]([CH2:13][C:14]2[CH:15]=[C:16]3[S:22][C:21]([S:23][CH3:24])=[N:20][C:17]3=[N:18][CH:19]=2)[CH:4]=1
Reactant: CSc1nc2ncc(CCl)cc2s1
Reactant: c1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2ncc(Cn3cnc4cccnc43)cc2s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 36.5 %

Procedure:
To a stirred mixture of DMF (5 mL) and sodium hydride (60% in mineral oil, 64 mg, 1.6 mmol) at 0° C. under argon, was added 4-azabenzimidazole (204 mg, 1.1 mmol) in one portion. The mixture was stirred for 5 min at 0° C. followed by dropwise addition of a solution of 6-(chloromethyl)-2-(methylthio)thiazolo[4,5-b]pyridine (497 mg, 2.2 mmol) in DMF (2 mL). The mixture was warmed slowly to rt then heated at 70° C. for 18 h. The mixture was cooled to rt, then partitioned between EtOAc (150 mL) and 0.5 M aq Na2CO3 (50 mL). The organic layer was separated and washed with water (50 mL), then brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% CH2Cl2 to 5% MeOH in DCM to afford 6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)thiazolo[4,5-b]pyridine (126 mg, 35%) as a yellow solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, DMSO-d6) δ 8.64-8.74 (m, 2H), 8.46 (d, J=2.1 Hz, 1H), 8.38 (dd, J=1.1, 4.7 Hz, 1H), 8.12 (dd, J=1.3, 8.1 Hz, 1H), 7.31 (dd, J=4.7, 8.1 Hz, 1H), 5.67 (s, 2H), 2.80 (s, 3H); LCMS (ESI) m/z 314 (M+H)+.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([I:15])=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH2:16][CH3:17])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:5]2[C:14]([I:15])=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH2:16][CH3:17])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1cc(C2CCC2)c(I)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1cc(C2CCC2)c(I)cc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a round-bottom flask, was added a solution of methyl 4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 10.3 g, 30.0 mmol, 1.00 equiv) in methanol (100 mL). A solution of sodium hydroxide (3.60 g, 3.00 equiv) in water (10 mL) was added dropwise to the stirred reaction mixture. The resulting mixture was stirred for 2 h at 60° C. After cooling to ambient temperature, the volatiles were removed under reduced pressure. The pH of the remaining aqueous mixture was adjusted to ˜4 using HCl (aq., 1 M). The resulting precipitate was collected by filtration and dried to yield 9.00 g (91%) of 4-cyclobutyl-2-ethyl-5-iodobenzoic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C@H:13]([OH:21])[C@H:14]([NH2:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:4]1.CN(C1C=CC=CN=1)C.[CH2:31]([O:38][C:39](ON1C(=O)CCC1=O)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:11])([CH3:12])[O:10][C@@H:6]2[C@@H:5]([C@H:13]([OH:21])[C@@H:14]([NH:20][C:39]([O:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:4]1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOC(=O)[C@@H](N)[C@@H](O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]12
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@H](NC(=O)OCc1ccccc1)[C@@H](O)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.5 %

Procedure:
A solution of ethyl (2R,3R)-3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-amino-3-hydroxypropanoate (3.05 g, 9.99 mmole, obtained from Reference Example 38), dimethylaminopyridine (250 mg, 2.1 mmole) and N-(benzyloxy)carbonyloxy succinimid (2.49 g, 10 mmole) in anhydrous methylene chloride (40 ml) was cooled at 0° C. under argon. Triethylamine (1.394 ml, 10 mmole) was introduced to this solution. The resulting mixture was warmed to room temperature and stirred at room temperature for 15 hours under argon, and the mixture was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (silica gel, methylene chloride:ether:methanol=93:5:2), to give ethyl (2R,3R)-3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-{[(benzyloxy)carbonyl]amino}-3-hydroxypropanoate as a white solid (2.92 g, 66%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C>[N:37]([C:23]1[N:22]=[C:21]([C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=1)=[N+:38]=[N-:39]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(S(C)(=O)=O)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(N2CCOCC2)nc(N=[N+]=[N-])n1
Temperature: 25 °C

Procedure:
A solution of N-(4-methyl-3-(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)phenyl)-3-(trifluoromethyl)benzamide (1.0 equiv.) and Sodium azide in DMF (0.2 M) was heated at 90° C. for 3 hours. The reaction mixture was then cooled to room temperature and quenched with water then the aqueous layer was separated and extracted with EtOAc (×2). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford N-(3-(2-azido-6-morpholinopyrimidin-4-yl)-4-methylphenyl)-3-(trifluoromethyl)benzamide. The compound was utilized in the subsequent reaction without further purification. LCMS (m/z) (M+H)=484.0/485.1, Rt=0.96 min.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].C(N(CC)CC)C.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](Cl)=[O:23]>ClCCl.C(OCC)(=O)C>[CH2:1]([NH:4][C:22]([C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=1)=[O:23])[C:2]#[CH:3]
Reactant: C#CCN
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCNC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Propargylamine (0.80 mL) and triethylamine (1.67 mL) were added simultaneously to a solution of 2-naphthoyl chloride (2.22 g) in dichloromethane (25 mL) cooled in an ice bath. The mixture was held at 0° C. for 1 hour and allowed to warm to room temperature over 3 hours. The solution was diluted with ethyl acetate, washed in turn with water, 1N hydrochloric acid, 1N sodium hydroxide, and saturated brine. Evaporation of the dried (K2CO3) organic layer gave a residue which was crystallized from dichloromethanehexane to give 2.06 g of N-(2-propynyl)-2-naphthalenecarboxamide, mp 163°-165° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.Br[CH2:20][C:21]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:22]=1[O:23][CH2:24][CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([N:8]([CH2:20][C:21]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:22]=2[O:23][CH2:24][CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:28]([CH3:30])[CH3:29])[CH:31]([CH3:33])[CH3:32])[C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: CC(=O)Nc1cc(F)ccc1Oc1ccccc1
Reactant: COc1ccc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c(CBr)c1
Product: COc1ccc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Yield: 56 %

Procedure:
The general procedure C was applied to N-(5-Fluoro-2-phenoxy-phenyl)-acetamide and 9b. The desired compound 9c was obtained in 56% yield (3.27 g; 5.61 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:32][CH2:31][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:24][C:20]=2[CH3:19])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: Cc1sc(-c2ccccc2)nc1CCO
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)sc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-(5-methyl-2-phenyl-thiazol-4-yl)-ethanol [PCT Int. Appl. (2002), WO 02/18355 A1] in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{3-fluoro-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-3-fluoro-4-[2-(5-methyl-2-phenyl-thiazol-4-yl)-ethoxy]-phenyl}-propionic acid as an off-white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[C:6]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:34]=[C:33](I)[CH:32]=[CH:31][N:30]=1>C([Mg]Cl)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:28][C:29]1[CH:34]=[C:33]([C:8]2[CH:7]=[C:6]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=3)[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)[CH:32]=[CH:31][N:30]=1
Reactant: O=S(=O)(Oc1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CC2)n1)C(F)(F)F
Reactant: Clc1cc(I)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: FC(F)(F)c1ccc(-c2cc(-c3ccnc(Cl)c3)nc(C3CC3)c2)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.34) (2.7 g, 7.0 mmol), commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (1.62 g, 6.8 mmol) and i-PrMgCl/ZnCl2 according to the general procedure IVc protocol a. Obtained as a white solid (0.75 g, 30%). MS (ISP) 375.2 [(M+H)+] and 377.1 [(M+2+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][OH:11].I[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:11][CH2:10][CH2:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:18]
Reactant: CCOC(=O)CI
Reactant: OCCc1c(F)cccc1Cl
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)COCCc1c(F)cccc1Cl

Procedure:
In analogy to the procedure described in example 78.1, 2-(2-chloro-6-fluoro-phenyl)-ethanol was reacted with ethyl iodoacetate in the presence of silver trifluoromethanesulfonate and 2,6-di-tert-butylpyridin to give [2-(2-chloro-6-fluoro-phenyl)-ethoxy]-acetic acid ethyl ester as colorless liquid. 1H NMR (CDCl3): 1.28 (t, J=7.1 Hz, 3H), 3.15 (t, J=7.1 Hz, 2H), 3.73 (t, J=7.3 Hz, 2H), 4.11 (s, 2H), 4.22 (q, J=7.1 Hz, 2H), 6.96 (m, 1H), 7.09-7.19 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]([CH3:26])[CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:18][CH2:17][CH2:16][N:15]([CH2:14][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:10]=[CH:11][CH:12]=1)[CH3:26]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1ccnn1-c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN)Cc1ccnn1-c1ccc(C#N)cc1
Yield: 85 %

Procedure:
A solution of tert-butyl N-[2-([[1-(4-cyanophenyl)-1H-pyrazol-5-yl]methyl](methyl)amino)ethyl]carbamate (100 mg, 0.28 mmol, 1.00 equiv) in dichloromethane (5 mL) and trifluoroacetic acid (3 mL) was stirred at 25° C. for 30 min. The resulting mixture was concentrated under vacuum to give 196.2 mg (85%) of 4-(5-(((2-aminoethyl)(methyl)amino)methyl)-1H-pyrazol-1-yl)benzonitrile trifluoroacetate as a colorless oil. 1H-NMR (300 MHz, D2O): δ 7.94-7.91 (m, 2H), 7.80 (d, J=2.7 Hz, 1H), 7.61-7.58 (m, 2H), 6.78 (d, J=1.8 Hz, 1H), 4.52 (s, 2H), 3.30-3.18 (m, 4H), 2.57 (s, 3H) ppm. LCMS (method R, ESI): RT=1.18 min, m/z=256.1 [M+H]+.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C@H:7]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([O:28]CC2C=CC=CC=2)=[O:27])[C:21]2[CH:36]=[CH:37][CH:38]=[CH:39][C:20]=2[O:19][CH2:18]1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3]>C(O)C.[C].[Pd]>[ClH:1].[CH2:2]([O:4][C:5]([C@H:7]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:36]=[CH:37][CH:38]=[CH:39][C:20]=2[O:19][CH2:18]1)[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Yield: 90.5 %

Procedure:
In 100 ml of ethanol is dissolved 0.7 g of benzyl 3(S)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate hydrochloride obtained in Example 16, and catalytic reduction is conducted at ordinary temperature and under atmospheric pressure using 0.5 g 10% palladium-carbon (containing 50% moisture) as a catalyst, when the absorption of hydrogen stops, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. Petroleum ether is added to the residue to give 0.53 g of 3(S)-[1(R)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid hydrochloride as a colorless powder.