Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])=[O:8])=[N:4][CH:3]=1.[Cl-].[Li+].C[Sn](C)C.C[Sn](C)C.Cl[C:26]1[N:35]=[C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:27]=1>O1CCOCC1>[C:11]([NH:10][S:7]([C:5]1[S:6][C:2]([C:26]2[N:35]=[C:34]([NH:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:27]=2)=[CH:3][N:4]=1)(=[O:9])=[O:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: CC(C)(C)NS(=O)(=O)c1ncc(Br)s1
Agent: C[Sn](C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1ncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)s1
Temperature: 90 °C
Yield: 4.5 %

Procedure:
To a stirring suspension of 5-bromo-N-tert-butylthiazole-2-sulfonamide (0.50 g, 1.67 mmol) in 1,4-dioxane (10 mL) was added lithium chloride (0.210 g, 5.03 mmol), followed by hexamethylditin (0.820 g, 2.50 mmol). After degassing with nitrogen, Pd(TPP)4 (0.19 g, 0.16 mmol) was added. The resultant suspension was stirred for over night at RT. 2-Chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.46 g, 1.33 mmol) was dissolved in 1,4-dioxane (3 mL) and then added to the reaction mixture. Upon completion of addition, the reaction mixture was heated at 90° C. for 24 h. After this time, the solvent was evaporated, water was added and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by recrystallization with ethyl acetate and further purified by preparative HPLC (method H) to provide N-tert-butyl-5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)thiazole-2-sulfonamide (32 mg, 4.2%) as a yellow solid. LCMS Method V: Rt 2.47 min; [M+1]=531.2; HPLC Method A1: purity 97.3%, retention time=10.89 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([O:23][CH2:24][CH3:25])[C@@H:5]([C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][C:8]=1[CH3:22])O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([O:23][CH2:24][CH3:25])[CH2:5][C:7]1[C:8]([CH3:22])=[CH:9][C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:12]=1[CH3:13]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1c(C)cc(OCc2ccccc2)cc1C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](Cc1c(C)cc(OCc2ccccc2)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 c], (2S,3R)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester was treated with triethylsilane in trifluoroacetic acid to yield (2S)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-ethoxy-propionic acid methyl ester as colorless liquid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]2[N:22]([CH3:23])[CH:21]=[N:20][N:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.N#N.[CH:26]1([C:29]#[CH:30])[CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>C1COCC1.CCOC(C)=O.[Cu](I)I.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>[CH:26]1([C:29]#[C:30][C:2]2[N:7]=[C:6]([CH2:8][O:9][N:10]=[C:11]([C:18]3[N:22]([CH3:23])[CH:21]=[N:20][N:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:28][CH2:27]1
Reactant: C#CC1CC1
Reactant: Cn1cnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1cnnc1C(=NOCc1cccc(C#CC2CC2)n1)c1ccccc1
Reaction time: 0.05 h
Yield: 190.3 %

Procedure:
To a stirred solution of N-[(6-bromopyridin-2-yl)methoxy]-1-(4-methyl-4H-1,2,4-triazol-3-yl)-1-phenylmethanimine (0.125 g, 0.33 mmol, 1 eq.) in 3 ml dry THF “degassed” with N2, was added Cyclopropylacetylene (0.95 g, 0.1 mmol, 3 eq.) followed by N-ethyldiisopropylamine (0.216 g, 1.67 mmol, 5 eq.), Copper Iodide (0.012 g, 0.06 mmol, 0.2 eq.) and Tetrakis(triphenylphosphine)palladium (0.077 g, 0.06 mmol, 0.2 eq.). The reaction was microwaved 120° C./normal/fixed hold/pre stir 100 s for 180 s. The reaction was diluted with EtOAc and filtered through a “celite” plug. The solvent was evaporated and the residue purified by chromatography on silica gel to give N-{[6-(cyclopropylethynyl)pyridin-2-yl]methoxy}-1-(4-methyl-4H-1,2,4-triazol-3-yl)-1-phenylmethanimine (0.068 g, 56% yield) as a yellow viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1[CH:24]=[CH:25][C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.Cl.CN(C)CCCN=C=NCC.C1(C(N)C)CC1>CN(C=O)C>[CH:26]1([CH:27]([NH:29][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH3:28])[CH2:25][CH2:24]1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: On1nnc2ccccc21
Agent: CC(N)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC(C)C4CC4)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 1-cyclopropylethylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(1-cyclopropylethyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[S:23]1[CH:27]=[C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=2)[N:25]=[N:24]1.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]([C:5]1[N:33]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:26]3[N:25]=[N:24][S:23][CH:27]=3)=[CH:35][CH:34]=2)[C:7](=[O:6])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: NCc1ccc(-c2csnn2)cc1
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(-c2csnn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 15 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid methyl ester (359 mg) in methanol (20 ml) were added 4-[1,2,3]thiadiazol-4-ylbenzylamine (956 mg) and triethylamine (1.4 ml) and the mixture was stirred at room temperature for 72 hrs. The solvent was evaporated under reduced pressure, and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, 4N hydrochloric acid ethyl acetate solution (5 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1→1/1) to give the title compound (80 mg, 15%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21]CC3C=CC=CC=3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.[H][H].[ClH:31]>C(O)C.CO.CCOCC.[Pd]>[ClH:31].[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[CH:14]=[CH:13]1
Reactant: [H][H]
Reactant: Fc1cnccc1CCCNn1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: CCO
Product: Oc1ccc2c(ccn2NCCCc2ccncc2F)c1

Procedure:
In a 500 ml Parr hydrogenation bottle, 10% Pd/C (1.5 g) was suspended in 50 ml ethanol, and to this was added a solution of 1-[(3-fluoro-4-pyridinyl)propylamino]-5-phenylmethoxy-1H-indole (15.0 g) in 200 ml ethanol. The mixture was shaken under 50 psi hydrogen gas for three hours at 50° C. Upon cooling, the mixture was filtered, and the filtrate was concentrated to give a solid, 11.4 g. This material was eluted on a silica gel column with ethyl acetate/dichloromethane (1:3) via HPLC, and the desired fractions were concentrated to give a solid, 8.5 g, m.p. 90°-95° C. A 2.0 g sample of this material was dissolved in 50 ml methanol, the pH was adjusted to 1 with ethereal HCl, and the solution was diluted with 200 ml ether. The resultant precipitate was collected and dried to give 2.1 g of the product, m.p. 218° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:9]=2[CH3:26])[CH:5]=[CH:6][CH:7]=1.[O:27]1[C:31](B(O)O)=[CH:30][C:29]2[CH:35]=[CH:36][CH:37]=[CH:38][C:28]1=2>>[O:27]1[C:28]2[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=2[CH:30]=[C:31]1[C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:8]1[N:12]([CH3:13])[N:11]=[C:10]([C:14]([N:16]2[CH2:20][CH2:19][CH:18]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH2:17]2)=[O:15])[C:9]=1[CH3:26]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3ccccc3-c3cc4ccccc4o3)c2C)C1
Yield: 39 %

Procedure:
In analogy to the procedure described in Example 14C], [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and benzo[b]furan-2-boronic acid gave the title compound in 39% yield as light brown foam. MS: 457.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([CH2:16][C@@H:17]2[C@H:20]([N:21](CC3C=CC(OC)=CC=3)C(=O)OCC3C=CC=CC=3)[C:19](=[O:41])[NH:18]2)[N:13]=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O>CO.[Pd]>[NH2:21][C@@H:20]1[C:19](=[O:41])[NH:18][C@@H:17]1[CH2:16][C:14]1[N:13]=[N:12][N:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:15]=1
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N[C@@H]2Cc2cn(CCNC(=O)OC(C)(C)C)nn2)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)OC(=O)NCCn1cc(C[C@H]2NC(=O)[C@H]2N)nn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a slurry of benzyl ((2R,3S)-2-((1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-4-oxoazetidin-3-yl)(4-methoxybenzyl)carbamate (20.2 mg, 0.036 mmol) in MeOH (0.68 mL) was added Pd black (19 mg, 0.018 mmol) and formic acid (31 μl, 0.711 mmol). After stirring at rt for 3 h, more Pd black (9.7 mg) was added. After stirring at rt for additional 5.5 h, the reaction mixture was filtered through cellulose with MeOH eluent, and the filtrate was concentrated in vacuo. It was used in step 6 without further purification. LCMS: Rt=0.396 min, m/z=311.1 (M+1). Method 2m_acidic.
Reaction SMILES: Cl[B:2]([Cl:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1>ClCCCl>[CH3:10][N:11]([B:2]([Cl:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1
Reactant: CNc1cccc(OC)c1
Reactant: ClB(Cl)c1ccccc1
Solvent: ClCCCl
Product: COc1cccc(N(C)B(Cl)c2ccccc2)c1

Procedure:
N-methyl-3-methoxyanilinochlorophenylborane was prepared by adding dichlorophenylborane (100 mmol) to a solution of N-methy-3-methoxyaniline (100 mmol) in 1,2-dichloroethane (100 mL) at 0° C. The resulting mixture was refluxed for 2 h under a rapid stream of nitrogen to remove the HCl formed. The mixture was cooled to give a 0.8 M cloudy solution of the title compound which could be stored at 0°C. for more than 6 weeks without deterioration.
Reaction SMILES: [Rh:1].[C:2]([OH:5])(=[O:4])[CH3:3]>C(O)C>[CH3:3][C:2]([O-:5])=[O:4].[CH3:3][C:2]([O-:5])=[O:4].[CH3:3][C:2]([O-:5])=[O:4].[CH3:3][C:2]([O-:5])=[O:4].[Rh+2:1].[Rh+2:1]
Reactant: CC(=O)O
Reactant: [Rh]
Solvent: CCO
Product: CC(=O)[O-]
Product: [Rh+2]

Procedure:
A mixture of 1.72 g. of rhodium hydrous oxide (Rh[OH]3.H2O), 6 ml. of glacial acetic acid and 15 ml. of ethanol is heated under reflux for 24 hours. The reaction mixture is cooled, and the volatile components are removed by evaporation in vacuo to give the crude product. The crude product is purified by dissolving it in acetone, allowing the solvent to evaporate slowly and then filtering off the solid which precipitates.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:17]=1)[C:5]2([CH3:25])[CH3:24].[C:26](Cl)(=[O:28])[CH3:27].O>C(Cl)Cl>[C:26]([N:21]1[CH2:22][CH2:23][N:18]([C:16]2[CH:17]=[C:12]([N:6]3[C:5]([CH3:25])([CH3:24])[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[C:7]3=[O:11])[CH:13]=[N:14][CH:15]=2)[CH2:19][CH2:20]1)(=[O:28])[CH3:27]
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(N2CCNCC2)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCN(c2cncc(N3C(=O)c4ccc(Cl)cc4C3(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of 5-chloro-3,3-dimethyl-2-(5-piperazin-1-yl-pyridin-3-yl)-2,3-dihydro-isoindol-1-one (52 mg, 0.146 mmol) and TEA (29.5 mg, 0.292 mmol) in DCM (5 mL) was added acetyl chloride (17.2 mg, 0.219 mmol) dropwise at 0° C. After stirring for 1 hour at room temperature, the mixture was treated with water and extracted with DCM. The organic layer was dried over anhy. Na2SO4. After removal of solvent, the residue was purified by preparative HPLC to afford the title compound as a white solid (23 mg, 40%). MS: 399.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[NH:22][C@@:16]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][CH2:18]3)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[Br:38][CH2:39][C:40](Br)=[O:41].O>C1COCC1>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([CH2:13][O:14][C@@H:15]2[CH2:21][CH2:20][C@@H:19]3[N:22]([C:40](=[O:41])[CH2:39][Br:38])[C@@:16]2([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18]3)[CH:4]=[C:3]([C:2]([F:29])([F:1])[F:30])[CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CBr)N1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(1R*,2R*,5R*)-2-{[3,5-Bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 60; 162 mg, 0.38 mmol) was dissolved in THF (3 ml) and triethylamine (0.059 ml, 0.42 mmol) added. The reaction mixture was cooled to 0° C. then bromoacetyl bromide (0.037 ml, 0.42 mmol) added, then the mixture warmed to room temperature. A further 1.1 equivalents of triethylamine (0.059 ml), and bromoacetyl bromide (0.037 ml) were added and the reaction mixture stirred at room temperature for 15 minutes. The reaction mixture was poured into water, extracted with ethyl acetate (×3), dried (MgSO4), and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[F:16][C:17]([F:26])([CH2:23][CH:24]=[CH2:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)Cl>[CH:24]1([CH2:23][C:17]([F:26])([F:16])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:1][CH2:25]1
Reactant: CC[Zn]CC
Reactant: C=CCC(F)(F)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)CC1CC1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A solution of diethyl zinc (500 mL, 1.0 M in hexanes) in methylene chloride (700 mL) was chilled to −10° C. under nitrogen in a cooling bath. A solution of trifluoroacetic acid (57 g, 0.5 mol) in methylene chloride (50 mL) was added dropwise over 1 hour 45 minutes. The mixture was stirred for 30 minutes at −5° C. A solution of diiodomethane (133.9 g, 0.5 mol) in methylene chloride (50 mL) was added to the mixture over a period of 20 minutes. The mixture became homogenous upon stirring for 30 minutes at 0° C. A solution of ethyl 2,2-difluoropent-4-enoate (40 g, 0.244 mol) in methylene chloride (50 mL) was added dropwise over a period of 25 minutes and the cooling bath was removed. The mixture was stirred for 1 hour at room temperature and then for 15 hours at reflux. The reaction was quenched by addition of saturated aqueous ammonium chloride (500 mL) and stirring for 30 minutes. The biphasic mixture was poured into 500 mL of saturated aqueous ammonium chloride and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3×300 mL) and the combined organic extracts were dried over magnesium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure to afford ethyl 3-cyclopropyl-2,2-difluoropropanoate (43.5 g, quant), as light yellow oil, which was used in the Example 4 without further purification. 1H-NMR (400 MHz, CDCl3): δ=0.12-0.22 (m, 2H), 0.49-0.59 (m, 2H), 0.75-0.91 (m, 1H), 1.37 (t, J=8 Hz, 3H), 1.95-2.05 (m, 2H), 4.34 (q, J=8 Hz, 2H).
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:22])[CH:11]=2)[N:6]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CO>[CH3:22][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([S:4][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:13]2=[O:21]
Reactant: ClCc1ccccn1
Reactant: Cc1ccc2nc(S)n(-c3ccccc3)c(=O)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2nc(SCc3ccccn3)n(-c3ccccc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
9.5 ml Of 28% methanolic solution of sodium methoxide were added to a solution of 6.0 g of 2-mercapto-6-methyl-3-phenyl-4(3H)-quinazolinone and 4.0 g of 2-chloromethylpyridine hydrochloride in methanol, the mixture was stirred at room temperature for 2 hours and allowed to stand overnight. Crystals precipitated were collected by filtration and recrystallized from ethyl acetate to give 4.2 g (52.2%) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[F:21].B(Br)(Br)Br>>[F:21][C:4]1[C:5]2[C:10](=[CH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[OH:2]
Reactant: COc1ccc(-c2ccc3c(F)c(OC)ccc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3c(F)c(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 2-methoxy-6-(4-methoxyphenyl)-1-fluoronaphthalene (0.250 g, 0.886 mmol) with boron tribromide (2.7 mL of 1 N solution, 2.7 mmol) according to method D to yield 0.13 g (15%) of a white solid: mp 219-224° C.;
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:16]3[N:15]4[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:14]4=[CH:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][CH2:27][CH2:28]Br.[H-].[Na+]>>[CH3:25][O:26][CH2:27][CH2:28][N:22]1[CH2:21][CH2:20][CH2:19][N:15]2[C:16]3[CH:17]=[CH:18][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][C:12]=3[CH:13]=[C:14]2[C:23]1=[O:24]
Reactant: COCCBr
Reactant: O=C1NCCCn2c1cc1cc(OCCCN3CCCC3)ccc12
Agent: [H-]
Agent: [Na+]
Product: COCCN1CCCn2c(cc3cc(OCCCN4CCCC4)ccc32)C1=O
Yield: 15 %

Procedure:
The title compound was synthesized in analogy to example 17, from 9-(3-pyrrolidin-1-yl-propoxy)-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (example 16), 2-bromoethyl methyl ether and sodium hydride, to give the desired product as a colorless oil (15%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[NH:11][N:10]=1.S(OC)(O[CH3:22])(=O)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:13]=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:22])[N:10]=1
Reactant: COS(=O)(=O)OC
Reactant: FC(F)Oc1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Cl)cc2Cl)cc1OC(F)F
Reaction time: 1 h
Yield: 78.7 %

Procedure:
457.2 g of 3-(2,4-dichlorophenyl)-5-difluoromethoxy-1H-pyrazole from Example 3.2 were initially charged in 2300 ml of toluene. 227.3 g of dimethyl sulfate were added dropwise, and the mixture was heated at reflux for 3 h. After cooling, 500 ml of saturated aqueous NH4Cl solution were added, the mixture was stirred for 1 h and the organic phase was separated off and washed with water until neutral. Drying over Na2SO4 and concentration gave 377.8 g of 3-(2,4-dichlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole of a purity of 92.9% (GC). Yield: 73.1%. M.p.: 35° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[CH2:23]1[O:33][C:32]2[C:25](=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH:27]=O)[O:24]1>>[O:33]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:26]([CH2:27][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:22][CH2:21][C:19]5[O:20][C:16]([CH3:15])=[CH:17][CH:18]=5)=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)[C:25]=2[O:24][CH2:23]1
Reactant: O=Cc1cccc2c1OCO2
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NCc4cccc5c4OCO5)cccc3n2)o1

Procedure:
The title compound, MS: m/e=388.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 2,3-(methylenedioxy)benzaldehyde as described in example 26.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=2[C:9]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:35][CH2:36][C:37](Cl)=[O:38]>O1CCCC1>[Cl:35][CH2:36][C:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=2[C:9]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:38]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3N)c(C3CCCCC3)c2s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cc2[nH]c(-c3ccccc3NC(=O)CCl)c(C3CCCCC3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of methyl 5-(2-aminophenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate obtained in Step 9, sodium acetate (2.4 g, 29 mmol) and acetic acid (1.7 ml, 29 mmol) in tetrahydrofuran (70 ml) was added chloroacetyl chloride (2.3 ml, 29 mmol) under ice-cooling. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure. Water (100 ml) was added to the obtained solid. The solid was collected by filtration, washed with diethyl ether (20 ml×2), and dried under reduced pressure to give methyl 5-[2-(2-chloroacetylamino)phenyl]-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate (5 g, yield after 2 steps from Step 9: 58%).