Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.CN(C)CCN(C)C.[CH3:20][Si:21]([CH3:36])([CH3:35])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[CH:28]=[CH:27]1.[CH:37]1([CH2:42][C:43]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38]1>O1CCCC1>[CH:37]1([CH2:42][C:43]([C:45]2[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=2)([C:27]2[N:26]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:36])([CH3:35])[CH3:20])[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:29]3[CH:28]=2)[OH:44])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)CCOCn1ccc2cccnc21
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[Si](C)(C)CCOCn1c(C(O)(CC2CCCC2)c2ccc(Cl)c(Cl)c2)cc2cccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
A solution of n-butyl lithium in hexane (2.5 M, 4.5 mL, 11.2 mmol) was treated with N,N,N′,N′-tetramethylethylenediamine (1.69 mL, 11.2 mmol) dropwise, which resulted in a slight exotherm. The resulting yellow mixture was then stirred at room temperature for 15 min. After this time, the mixture was treated with 1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 138, 3.48 g, 14.0 mmol) dropwise. The resulting mixture was then stirred at room temperature for 30 min and then treated with a solution of 2-cyclopentyl-1-(3,4-dichloro-phenyl)-ethanone (1.8 g, 7.0 mmol) in tetrahydrofuran (8 mL) and then stirred at room temperature for 6 h. After this time, the reaction mixture was quenched by the addition of a saturated aqueous ammonium chloride solution (25 mL) and it was then stirred over the weekend. The reaction mixture was then extracted with ethyl acetate (2×100 mL) and the combined organic layers were then dried over magnesium sulfate, filtered and the filterate concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 10% ethyl acetate/hexanes) afforded 2-cyclopentyl-1-(3,4-dichloro-phenyl)-1-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-ethanol (1.13 g, 32%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([Cl:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([Cl:19])[CH:13]=2)=[N:28][OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1cc(Cl)ncc1F)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(CC(=NO)c1cc(Cl)ncc1F)c1ccc(Br)cc1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-1-(2-chloro-5-fluoro-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (1.6:1) as a colorless oil, MS (ESI+): m/z=447.733 ([M+H]+).
Reaction SMILES: [CH:1]1([C:11]([O:13]CC)=O)[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](OCC)=[O:7].[NH3:16]>>[C:6]1(=[O:7])[CH:2]2[CH2:3][CH2:4][CH2:5][CH:1]2[C:11](=[O:13])[NH:16]1
Reactant: CCOC(=O)C1CCCC1C(=O)OCC
Reactant: N
Product: O=C1NC(=O)C2CCCC12
Temperature: 130 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Load 1 kg of diethyl 1,2-cyclopentanedicarboxylate and 1.02 kg of 27% ammonia into an autoclave. The reaction mixture is heated in the autoclave at a temperature of 130° C. for a minimum of 4 hours. After cooling to 60° C. and depressurisation, evaporation of the solvent is carried out. The residue is then subjected to pyrolysis at 280° C. for 1 hour. The imide is purified by distillation in vacuo (4-12 mbars) at a temperature of 200° C. After isolation, the title product is obtained in a yield of 96%.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(CBr)cc1

Procedure:
A stirred mixture of 4-methylbenzophenone (15.02 g, 76.6 mmol) and N-bromosuccinimide (14.2 g, 79.8 mmol) in CHCl3 (100 cm3) was heated under gentle reflux for 18 h with a 100 W bulb shining 2 cm from the flask. The reaction mixture was washed with water, dried (MgSO4) and solvent was removed in vacuo). The resulting solid was then washed with Et2O to remove any starting material to leave the product as a white solid (15.07 g, 71.5%, mp 110–112° C. (lit. 110–111°); δH (200 MHz; CDCl3) 4.55 (2 H, s, CH2Br), 7.46–7.70 (5 H, m, ArH), 7.80–7.9 (4 H, m, ArH o- to C═O); m/z 277 ([M81Br+H]+, 25%) and 275 ([M79Br+H]−, 25%), 197 (100%).
Reaction SMILES: Cl[CH2:2]I.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:22][CH:23]=[CH2:24])[C:12]2([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH:25][C:26](=[O:41])[C@H:27]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30]>[Zn].[Cu].C(OCC)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:22][CH:23]2[CH2:2][CH2:24]2)[C:12]2([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:14][CH2:13]2)=[CH:7][C:6]=1[NH:25][C:26](=[O:41])[C@H:27]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C@@H:28]([CH3:33])[C:29]([F:32])([F:31])[F:30]
Reactant: ClCI
Reactant: C=COC(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1(C(=O)OC(C)(C)C)CC1
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Product: C[C@H]([C@H](C(=O)Nc1cc(C(OC2CC2)C2(C(=O)OC(C)(C)C)CC2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 8 h

Procedure:
68 mg (0.52 mmol) of zinc/copper pair were taken up in 5 ml of abs. diethyl ether, and 41 μl (0.56 mmol) of chloroiodomethane were added at room temperature. A solution of 200 mg (0.35 mmol) of tert-butyl 1-[(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]-amino}phenyl)(vinyloxy)methyl]cyclopropanecarboxylate (as diastereomer mixture) in 10 ml of abs. diethyl ether was then added dropwise to the reaction mixture. The reaction solution was then heated to reflux and stirred overnight. After cooling, the solution was filtered through kieselguhr and the kieselguhr was washed repeatedly with diethyl ether. The filtrate obtained was washed with saturated aqueous sodium bicarbonate solution and with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue was purified by preparative RP-HPLC (mobile phase methanol/water 80:20, isocratic). This gave 54 mg (27% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[NH:15][N:16]=2)[N:13]=1.[F:25][C:26]([F:31])([F:30])[CH2:27][CH2:28]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[CH:10][C:11]2[N:12]([C:14](=[O:17])[N:15]([CH2:28][CH2:27][C:26]([F:31])([F:30])[F:25])[N:16]=2)[N:13]=1
Reactant: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: FC(F)(F)CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=c1n(CCC(F)(F)F)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (36 mg, 0.1 mmol), 1,1,1-trifluoro-3-iodopropane (67 mg, 0.3 mmol) and solid K2CO3 (42 mg, 0.3 mmol) in anhydrous DMF (0.6 mL) was stirred at room temperature for 2 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional 1,1,1-trifluoro-3-iodopropane (67 mg, 0.3 mmol) was added, the reaction was allowed to continue at room temperature for 16 h, then at 45° C. for 30 min. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The separated EtOAc layer was washed with water, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-60%) in hexanes to yield a yellow oily product, which was lyophilized in acetonitrile to afford 38 mg (84%) of the title compound as a yellow powder. LC/MS (method A): retention time=3.69 min, (M+H)+=453. 1H NMR (CDCl3, 400 MHz): δ 7.44 (m, 2H), 7.35 (m, 2H), 7.25 (m, 1H), 7.21 (d,J=8.8 Hz, 2H), 7.05 (d,J=8.8 Hz, 2H), 4.36 (m, 2H), 2.76 (m, 2H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1([Mg]Br)C=CC=CC=1.[Cl:17][C:18]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:19]=1[C:20](=[O:23])[CH2:21][Cl:22].Cl>CCOCC>[C:3]1([C:20]([C:19]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:18]=2[Cl:17])([OH:23])[CH2:21][Cl:22])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: Brc1ccccc1
Agent: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: OC(CCl)(c1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
Into a 1 liter three-necked flask are placed 5.35 g (0.22 m) of magnesium turning and 50 ml of anhydrous ether. Bromobenzene (34.5 g, 0.22 m) in 100 ml of ether is then added dropwise under nitrogen. When the reaction started, the rate of addition is controlled so that ether remained refluxing gently. After the addition, the mixture is stirred for 10 minutes at room temperature and then cooled to 10° with an ice bath. To this phenyl magnesium bromide solution is added 44.7 g (0.2 m) of 2,4-dichlorophenacyl chloride dissolved in 100 ml of ether dropwise. The reaction mixture is stirred at room temperature for 1/2 hour followed by slow addition of dilute HCl solution (300 ml). The phases are then separated and the ether layer is washed with saturated sodium bicarbonate solution and dried over MgSO4. Solvent is evaporated to give 56 g of a yellow oil. Vacuum distillation (156°/0.1 mm) affords 40 g of pure product.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].C1COCC1.[CH3:10][N:11]([CH3:26])[C:12]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][C:13]=1[CH:23]([CH3:25])[CH3:24]>>[CH3:10][N:11]([CH3:26])[C:12]1[C:19]([CH:20]([CH3:21])[CH3:22])=[CH:18][C:15]([CH:16]([OH:17])[C:1]#[CH:2])=[CH:14][C:13]=1[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1N(C)C
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1cc(C(C)C)c(N(C)C)c(C(C)C)c1
Yield: 192.8 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 28 ml (14 mmol) of 0.5M ethynylmagnesium bromide/THF with 1.2 g (5 mmol) of 4-dimethylamino-3,5-diisopropylbenzaldehyde. 2.5 g of 1-(4-dimethylamino-3,5-diisopropylphenyl)prop-2-yn-1-ol are obtained in the form of a whitish solid (yield=90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH:7]=[CH:8][N:9]3[C:14](S(C)(=O)=O)=[N:13][N:12]=[C:10]3[CH2:11][C:5]=2[CH:4]=1.[CH3:21][O-:22].[Na+]>>[CH3:21][O:22][C:14]1[N:9]2[C:10]([CH2:11][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=3[CH:7]=[CH:8]2)=[N:12][N:13]=1
Reactant: COc1ccc2c(c1)Cc1nnc(S(C)(=O)=O)n1C=C2
Reactant: C[O-]
Agent: [Na+]
Product: COc1ccc2c(c1)Cc1nnc(OC)n1C=C2

Procedure:
The reaction of 9-methoxy-3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine with sodium methoxide yielded 3,9-dimethoxy-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from aqueous acetone), melting point: 176°-177° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[OH:20].C([O-])([O-])=O.[Na+].[Na+].CC(O)=O>N1C=CC=CC=1.O>[OH:20][C:19]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH:13][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1cnccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cnccc1O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 61.5 %

Procedure:
A solution of p-nitrobenzoyl chloride (4.8 g, 25.7 mmol) in pyridine (77.0 mL) was added dropwise to a solution of 3-amino-4-hydroxypyridine (3.4 g, 30.9 mmol) in pyridine (51.0 mL) at 10° C. and stirred overnight. A solution of Na2CO3 (1.7 g) in water (65 mL) was added and the resultant mixture was stirred for 1 h. The reaction mixture was neutralized with 10% AcOH. The precipitate was collected by filtration, washed with 10% AcOH, and dried in vacuo (50° C.) to afford N-(4-hydroxypyridin-3-yl)-4-nitrobenzamide as a light green powder (4.1 g, Yield: 62%). 1HNMR (400 MHz, DMSO-d6) δ: 11.64 (1H, br s), 9.57 (1H, s), 9.07 (1H, s), 8.75 (1H, d, J=4.4 Hz), 8.36 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=8.8 Hz), 7.74 (1H, d, J=4.4 Hz), 6.33 (1H, s); MS (ESI) calcd for C12H9N3O (m/z): 211, found: 212 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:15]C(=O)CC2C=CC=CC=2)[CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]>Cl>[NH2:15][C@H:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)C[C@H](NC(=O)Cc1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: N[C@@H](CC(=O)O)c1cccc([N+](=O)[O-])c1

Procedure:
(S)-3-(3-nitrophenyl)-3-phenylacetylaminopropionic acid is treated with 10 ml of 6N HCl solution. (S)-3-amino-3-(3-nitrophenyl)propionic acid is obtained and is reacted further in analogy to the R enantiomer. This gives (S)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-nitrophenyl)propionic acid, (S)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-nitrophenyl propionic acid sodium salt, (S)-3-{2-[4-(4-methylpyridin-2-ylamino)butyrylamino]acetylamino}-3-(3-nitrophenyl)propionic acid trifluoroacetate, RT* 16.89 min, FAB-MS (M+H)+ 444.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16]C(C#CC3C=CC(C(OCC)=O)=CC=3)=C[CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:3]([C:2]1[CH:7]=[CH:13][C:12]([C:9]2([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][CH2:11]2)=[C:17]([CH3:16])[CH:1]=1)#[CH:4]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane (Intermediate 75, 300.0 mg, 0.95 mmols) in methanol (6 mL) was treated with potassium carbonate (120.0 mg, 0.87 mmol) and stirred overnight at ambient temperature. The crude alkyne (185 mg, 79%) was used directly in the next reaction.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:27][C:11]2[N:12]([CH2:21][C:22]3[CH:26]=[CH:25][S:24][N:23]=3)[C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][C:18]=3[C:10]=2[CH2:9]1)(C)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[ClH:29].[NH2:7][C@H:8]1[CH2:27][C:11]2[N:12]([CH2:21][C:22]3[CH:26]=[CH:25][S:24][N:23]=3)[C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][C:18]=3[C:10]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2c(n(Cc3ccsn3)c3ccc(C#N)cc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)c1c(n2Cc2ccsn2)C[C@H](N)C1

Procedure:
Stir a suspension of (R)-(7-cyano-4-isothiazol-3-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid tert-butyl ester (1.16 g, 3.19 mmol) in 4M HCl in dioxane (20 mL) for 2 h at room temperature, then concentrate in vacuo. Dry the residue under vacuum overnight at 40° C. MS (m/z): 295 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]1.Cl[CH2:20][C:21]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:22]=1[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>>[F:16][CH:15]([F:17])[N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:22]=3[O:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:7][C:2]=2[F:1])[N:10]=[C:11]1[CH3:18]
Reactant: Cc1nn(-c2ccc(O)cc2F)c(=O)n1C(F)F
Reactant: COC(=O)COc1cc(C)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)COc1cc(C)ccc1COc1ccc(-n2nc(C)n(C(F)F)c2=O)c(F)c1
Yield: 79.1 %

Procedure:
By the method of Example 1, Step I, 2.0 g (0.0077 mole) of 1-(2-fluoro-4-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (Example 1, Step E) and 3.53 g (0.0151 mole) of methyl (2-chloromethyl-5-methylphenoxy)acetate were reacted in the presence of 1.60 g (0.0116 mole) of anhydrous potassium carbonate in 40 mL of N,N-dimethyl/-formamide, yielding 2.75 g of methyl [2-[4-(4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-on-1-yl)-3-fluorophenoxymethyl]-5-methylphenoxy]acetate. The NMR spectrum was consistent with the proposed structure. NMR: 2.30 (s, 3H); 2.44 (s, 3H); 3.78 (s, 3H); 4.70 (s, 2H); 5.18 (s, 2H); 6.60-7.36 (m, 7H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[C:6]2[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=12.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([F:29])[CH:28]=1)[NH2:25]>>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:6]3[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=23)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: Cc1cn(C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Reactant: Nc1cc(F)cc(F)c1
Product: Cc1cn(C)c2c(Nc3cc(F)cc(F)c3)ncc(C(=O)N3CCOCC3)c12
Yield: 25.1 %

Procedure:
Prepared in a similar manner to Example 4(d) from 1-(7-chloro-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-morpholin-4-yl-methanone (100 mg) and using 3,5-difluoroaniline (88 mg) instead of 3-bromoaniline and heating for 15 rather than 30 minutes to give 1-[7-(3,5-difluoro-phenylamino)-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-morpholin-4-yl-methanone (33 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[CH:11][C:10]([O:13][C@@H:14]([CH3:20])[C:15](OCC)=[O:16])=[CH:9][CH:8]=1>O1CCCC1>[C:7]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:8]=[CH:9][C:10]([O:13][C@@H:14]([CH3:20])[CH2:15][OH:16])=[CH:11][CH:12]=1
Reactant: CCOC(=O)[C@H](C)Oc1ccc(-c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CO)Oc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 1b) from lithium aluminium hydride (41.9 ml, 1.0M solution in ether) and solution (2S)-2-(biphenyl-4-yloxy)propanoic acid, ethyl ester (11.3 g, Example 2a)) in dry tetrahydrofuran (200 ml) at 0° C. The sub-title compound obtained after work-up was used directly without further purification (9.52 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2)(=[O:27])=[O:26]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: O=S(=O)(Cl)c1ccccc1F
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1S(=O)(=O)c1ccccc1F

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-fluorobenzenesulfonyl chloride were used for a similar reaction and treatment as Example 169, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:18](/[N:25]=[CH:16]\[C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)=[CH:11][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(-c2ccc(/C=N\Cc3ccccc3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
A mixture of 3′-bromo-4′-methoxy-1,1′-biphenyl-4-carbaldehyde (19.4 g, 69 mmol), prepared in step 3 of Example 6, benzylamine (38 mL, 345 mmol) and 60 g of anhydrous MgSO4 in 400 mL of methylene chloride was stirred under nitrogen at room temperature for 18 h. The reaction was filtered and the filtrate concentrated under reduced pressure to give an off-white solid. The solid was triturated with hexane and dried under reduced pressure to give N-benzyl-N-[(1Z)-(3′-bromo-4′-methoxy-1,1′-biphenyl-4-yl)methylidene]amine (23.6 g, 88%) as an off-white solid, MS KESI) m/z 380 [M+H]+. Elemental analysis for C21H18BrNO: Calc'd: C, 66.33; H, 4.77; N, 3.68; Found: C, 63.22; H, 4.85; N, 4.17
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH:27]([F:29])[F:28])[CH:23]=[CH:22][N:21]=1>>[F:29][CH:27]([F:28])[O:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])[CH:25]=1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: FC(F)Oc1ccnc(CBr)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc(OC(F)F)ccn1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 2-(bromomethyl)-4-(difluoromethoxy)pyridine. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 393.12 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10](=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[N:11][C:10](=[O:13])[N:9]2[CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1ncn(-c2ccc(Br)cc2)[nH]1
Product: C[Si](C)(C)CCOCn1c(=O)ncn1-c1ccc(Br)cc1
Yield: 58 %

Procedure:
Compound 11b (30.0 g, 125 mmol) was treated with SEMCl using the reaction conditions described in Example 10, Step C to obtain compound 11c as a white solid (30.0 g, 58% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H20BrN3O2S: 370.1 (M+H). Found 370.2.
Reaction SMILES: F[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[Cl:10][C:9]1[C:2]2[S:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cccc(Cl)c1F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cccc(Cl)c2s1

Procedure:
Using 1.0 g (6.31 mmol) of 2-fluoro-3-chlorobenzaldehyde, 0.38 g (9.46 mmol) of sodium hydride (60% pure) and 0.74 g (6.94 mmol) of methyl mercaptoacetate, 1.04 g (72.3% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2Br)[CH:6]=1)[CH3:2].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])=[C:24](B(O)O)[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]2[CH2:16][CH2:15][CH2:14][C:13]=2[C:22]2[CH:21]=[C:20]([Cl:19])[CH:25]=[CH:24][C:23]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C)cc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(F)cc1F
Product: CCOC(=O)c1cc(C)cc(C2=C(c3cc(Cl)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using 3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester and using [5-chloro-2-(2,4-di-fluorobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid.