Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].[Br:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][CH:17]2[CH2:20][N:19](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:18]2)=[CH:14][CH:13]=1>C(Cl)Cl>[Br:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][CH:17]2[CH2:18][N:19]([C:1]([Cl:4])=[O:2])[CH2:20]2)=[CH:14][CH:13]=1
Reactant: Brc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A stirred solution of 18.8 g (0.192 mole) of phosgene in 100 ml of methylene chloride was cooled to 15° C. in a water bath, then treated with 26.5 g (0.192 mole) of potassium carbonate. After stirring for 30 min, 63 g (0.16 mole) of 3-(4-bromophenoxy)-1-diphenylmethylazetidine in 180 ml of methylene chloride was added dropwise and stirring continued for 18 hr. The reaction mixture was diluted with ice water to dissolve the inorganic salts, the aqueous portion was separated and the organic phase washed with 25 ml of ice water. After separation, the methylene chloride solution was dried with magnesium sulfate, then concentrated in vacuo to a viscous yellow oil. Trituration of the residue with 30/60 petroleum ether yielded a crystalline product, 76.9 g, which was recrystallized from isopropyl ether-ligroin (50-50) to yield 34.8 g (74.8%) of white granular crystals, m.p. 77°-78° C.
Reaction SMILES: [Cl:1][C:2]([F:16])([F:15])[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1.[Br-]>O.CCCCCCC>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][C:2]([Cl:1])([F:16])[F:15])=[CH:20][CH:19]=1
Reactant: FC(F)(Cl)C=CCCCCCCCCCBr
Reactant: Oc1ccc(Cl)cc1
Agent: [Br-]
Solvent: CCCCCCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: FC(F)(Cl)C=CCCCCCCCCCOc1ccc(Cl)cc1
Yield: 30.7 %

Procedure:
A mixture of 1.6 grams (0.005 mole) of 12-chloro-12,12-difluoro-10-dodecenyl bromide and 0.65 gram (0.005 mole) of 4-chlorophenol was stirred, and 0.75 ml (0.005 mole) of DBU was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. Gas chromatographic analysis of the reaction mixture indicated the presence of the bromide starting material. An additional 0.5 ml of DBU was added, and the reaction mixture was stirred for 18 hours more. After this time the reaction mixture was shaken with heptane and water. The heptane layer was washed with several portions of water and then with two portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using in succession heptane, 20% ethyl acetate in heptane, and 5% ethanol in heptane. The appropriate fractions were combined and concentrated under reduced pressure yielding 0.56 gram of 12-chloro-12,12-difluoro-10-dodecenyl 4-chlorophenyl ether. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: O1C2C(=CC=CC=2)[C@H](N[C:12]([C@@H:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C@H:24]4[CH2:28][C@@H:27]([C:29](=[O:41])[NH:30][C@H:31]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[CH2:34][CH2:33][CH2:32]5)[N:26]([C:42](=[O:55])[C@@H:43]([NH:48][C:49](=[O:54])[C@@H:50]([NH:52][CH3:53])[CH3:51])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:25]4)=[CH:20][CH:21]=3)[CH2:16][N:15]2[C:56](=[O:69])[C@@H:57]([NH:62][C:63](=[O:68])[C@@H:64]([NH:66][CH3:67])[CH3:65])[C:58]([CH3:61])([CH3:60])[CH3:59])=[O:13])CC1.[CH3:70][C:71]1[O:75][N:74]=[C:73]([C@@H:76]([NH2:84])[CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[N:72]=1.C(O)(C(F)(F)F)=O>>[CH3:61][C:58]([CH3:59])([CH3:60])[C@H:57]([NH:62][C:63](=[O:68])[C@@H:64]([NH:66][CH3:67])[CH3:65])[C:56]([N:15]1[C@H:14]([C:12]([NH:84][C@H:76]([C:73]2[N:72]=[C:71]([CH3:70])[O:75][N:74]=2)[CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)=[O:13])[CH2:23][C:22]2[C:17](=[CH:18][C:19]([C@H:24]3[CH2:28][C@@H:27]([C:29](=[O:41])[NH:30][C@H:31]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH2:34][CH2:33][CH2:32]4)[N:26]([C:42](=[O:55])[C@@H:43]([NH:48][C:49](=[O:54])[C@@H:50]([NH:52][CH3:53])[CH3:51])[C:44]([CH3:45])([CH3:46])[CH3:47])[CH2:25]3)=[CH:20][CH:21]=2)[CH2:16]1)=[O:69]
Reactant: CN[C@@H](C)C(=O)N[C@H](C(=O)N1C[C@@H](c2ccc3c(c2)CN(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)[C@H](C(=O)N[C@@H]2CCOc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Reactant: Cc1nc([C@@H](N)Cc2ccccc2)no1
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H](Cc1ccccc1)c1noc(C)n1)C(C)(C)C
Yield: 33 %

Procedure:
Following procedures analogous to those described for the preparation of Example 33, (S)-2-(tert-butoxycarbonyl)-7-((3R,5S)-1-(tert-butoxycarbonyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Compound F of Example 33, 60 mg, 0.10 mmol) and (S)-1-(5-methyl-1,2,4-oxadiazol-3-yl)-2-phenylethanamine, TFA (31 mg, 0.10 mmol) were converted to the title compound (34 mg, 33% over 6 steps). MS (ESI+) m/z 1001.7 (M+H)+.
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([CH3:16])[C:10]=1[CH3:17].[CH3:18][S:19]SC>[Cu]>[CH3:17][C:10]1[C:11]([CH3:16])=[C:12]([S:19][CH3:18])[CH:14]=[CH:15][C:9]=1[Br:8]
Reactant: Cc1c(N)ccc(Br)c1C
Reactant: CSSC
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1ccc(Br)c(C)c1C
Reaction time: 9 h

Procedure:
603 g (5.85 mol) of tert-butyl nitrite and 375 g of copper powder (5.9 mol) are initially charged in 3000 ml of dimethyl disulfide, and 761 g (3.75 mol) of 4-bromo-2,3-dimethylaniline are added dropwise at 50-58° C. The mixture is then stirred at 75-80 for 9 hours. For work-up, the mixture is cooled, the residue is filtered off and the filtrate is washed with saturated aqueous NaHCO3 solution. For purification of the product, the organic phase is separated by distillation. Initially, excess dimethyl disulfide is removed under atmospheric pressure. 1870 g of dimethyl disulfide (purity >97% according to GC) are recovered. The residue is then subjected to fractional distillation under reduced pressure (0.1 mbar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][CH2:21][S:22][CH3:23]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:12][CH2:20][CH2:21][S:22][CH3:23])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCSC)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 34.3 %

Procedure:
Step A To a solution of 3-methoxy-4-nitrophenol (0.5 g, 3 mmol) prepared in Example 132 Step A in anhydrous DMF (13 mL) were added K2CO3 (0.8 g, 5.9 mmol) and 1-Chloro-2-methylsulfanyl-ethane (Aldrich)(0.65 g, 5.9 mmol) sequentially. The reaction mixture was heated at 70° C. for 2 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (0-40% EtOAc in hexanes) to give 2-methoxy-4-(2-methylsulfanyl-ethoxy)-1-nitro-benzene as a white solid (0.25 g, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[CH:15]([CH3:17])[CH3:16]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([CH:15]([CH3:17])[CH3:16])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)Br
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C#N)C(C)C)c1
Yield: 79.8 %

Procedure:
By working in a way similar to that described in example 16 but using 3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles), anhydrous DMF (40 ml), NaH (55-65%, 1.44 g, 36.3 mmoles) and 2-bromo-propane (4.46 g, 36.3 mmoles), 4.53 g of the title compound were obtained (yield: 79.9%).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([NH:3][CH:4]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C(N)C(=O)O[C@H]2CN3CCC2CC3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC(=O)c2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-(4-methoxyphenyl)acetate dihydrochloride (I106) (325 mg, 0.89 mmol) in DCM (10 ml), were added triethylamine (374 μl, 2.68 mmol) and benzoyl chloride (125 μl, 1.07 mmol). The reaction was stirred at RT for 4 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-benzamido-2-(4-methoxyphenyl)acetate (145 mg; 41% yield). The product was used in the next step without any further purification.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)=O.[C:13](=[S:16])([S-:15])[NH2:14].[NH4+]>CO>[OH:12][C:7]1[CH:6]=[C:5]([C:3]2[N:14]=[C:13]([SH:16])[S:15][CH:2]=2)[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: NC(=S)[S-]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Agent: [NH4+]
Solvent: CO
Product: Oc1ccc(-c2csc(S)n2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
10.0 g (53.6 mmol) of 2-chloro-3'4'-dihydroxy-acetophenone was dissolved in 100 ml of methanol, and then 5.90 g (53.6 mmol) of ammonium dithiocarbamate was added thereto. The mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure. To the residue, water was added to adjust the mixture to pH2.0, and then the mixture was extracted twice with ethyl acetate. The extract was dried over anhydrous sodium sulfate and-then concentrated. The crystal residue was washed with diethyl ether to obtain 8.80 g (yield: 72.9%) of the above-identified compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH:4]=[CH2:5].[Cl-].[Cl-].[CH2:9]([Al+2])C.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15]C=1>[Cl-].[Cl-].C1([Ti+2]C2C=CC=C2)C=CC=C1.N12CCN(CC1)CC2>[CH2:3]([C:4]([CH2:13][CH2:18][CH2:17][CH:16]([CH3:15])[CH3:9])=[CH2:5])[CH:2]([CH3:6])[CH3:1]
Reactant: C=CCC(C)C
Reactant: Clc1ccccc1
Reactant: CC[Al+2]
Agent: C1=CC([Ti+2]C2C=CC=C2)C=C1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Product: C=C(CCCC(C)C)CC(C)C

Procedure:
To a 30 ml glass bottle, under an argon atmosphere, were added 7.2 milligrams (0.029 millimol) of di(cyclopentadienyl)titanium dichloride, 8 mg (0.072 millimol) of 1,4-diazabicyclo(2.2.2)octane, 5 ml (40.0 millimol) of 4-methyl-1-pentene, 7 ml of chlorobenzene, and 0.045 ml (0.44 millimol) of ethylaluminum dichloride. After a two hour reaction at 25° C., there had been formed 1.08 millimol of 2-isobutyl-6-methyl-1-heptene.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][C:10](=[O:11])[C:5]2=[C:4]([CH3:12])[C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[N:14]=1.[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1.CN([C:40]([O:44]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH3:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][C:10](=[O:11])[C:5]2=[C:4]([CH3:12])[C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:29][CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)=[O:26])=[CH:27][C:28]=2[O:44][CH3:40])[N:14]=1
Reactant: CN1CCC(N)CC1
Reactant: Cc1c(-c2ccnc(Nc3ccc(C(=O)O)cc3)n2)c(C)n2c1C(=O)NCC2
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1nccc(-c2c(C)c3n(c2C)CCNC3=O)n1

Procedure:
By reaction of Example I-26 4-[4-(6,8-dimethyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-7-yl)-pyrimidin-2-ylamino]-benzoic acid and 4-amino-1-methylpiperidine as described above but using TBTU as the coupling agent.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH3:31][N:28]1[CH2:27][CH2:26][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:30][CH2:29]1
Reactant: CN1CCN(c2nnc3ccc(F)cn23)CC1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of Intermediate A (125 mg, 0.766 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 62 mg, 1.54 mmol) and the mixture stirred at RT for 0.5 h. A solution of Intermediate 68a (180 mg, 0.766 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.75 h. The cooled mixture was diluted with water and extracted with DCM (5×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-20% [2M NH3 in MeOH] in DCM, to give the title compound as a pale brown gum (225 mg, 78%). LCMS (Method 3): Rt 0.44 min, m/z 379 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][C:38]1[CH:50]=[CH:49][CH:48]=[CH:47][C:39]=1[CH2:40][N:41]1[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29]([NH:46][CH:43]2[CH2:44][CH2:45][N:41]([CH2:40][C:39]3[CH:47]=[CH:48][CH:49]=[CH:50][C:38]=3[CH3:37])[CH2:42]2)=[O:35])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: Cc1ccccc1CN1CCC(N)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)NC1CCN(Cc2ccccc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) to prepare a solution. Triphosgene (99 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. 1-(2-Methylbenzyl)-3-pyrrolidinamine (87 mg) was then added thereto, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (58 mg, yield 35%).
Reaction SMILES: C[O-:2].[Na+].CO.[C:6]1([CH3:12])C=CC=CC=1.[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH2:21][C:22]#[N:23]>C(OCC)(=O)C.O>[C:6]([CH:21]([C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[Br:13])[C:22]#[N:23])(=[O:2])[CH3:12]
Reactant: C[O-]
Reactant: N#CCc1ccc(F)cc1Br
Reactant: Cc1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)C(C#N)c1ccc(F)cc1Br
Temperature: 70 °C

Procedure:
A solution of sodium methoxide in methanol (25%, 34 mL, 157 mmol) was combined with toluene (200 mL). The methanol was then distilled off at 90° C. using a Dean-Stark trap. After the solution was cooled to 70° C., 2-bromo-4-fluorobenzeneacetonitrile (21.4 g, 100 mmol) dissolved in ethyl acetate (40 mL) was added from a dropping funnel over 20 min with mechanical stirring. At this point additional toluene (150 mL) was added to facilitate stirring of a voluminous light pink precipitate. The reaction mixture was poured into water, and the organic phase was separated. The aqueous phase was acidified and extracted with ethyl acetate. The ethyl acetate phase was dried and concentrated under reduced pressure to provide the intermediate compound α-acetyl-2-bromo-4-fluorobenzeneacetonitrile as a crude oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](N)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[I-:19].[K+].II>COCCOC.[Cu]I>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([I:19])[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Nc1ccnc(Nc2ccc3c(c2)OCCO3)c1
Reactant: [I-]
Agent: [Cu]I
Agent: II
Agent: [K+]
Solvent: COCCOC
Product: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Temperature: 62.5 °C

Procedure:
Isopentyl nitrile (Aldrich Chemical Company) (3.9 mL, 29 mmol) was added to a mixture of N2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-pyridine-2,4-diamine (Example 2(a), 2.4 g, 9.8 mmol), potassium iodide (Aldrich Chemical Company) (1.6 g, 9.8 mmol), iodine (Aldrich Chemical Company) (1.2 g, 4.9 mmol) and copper (I) iodide (Aldrich Chemical Company) (1.9 g, 9.8 mmol) in 1,2-dimethoxyethane (60 mL). The reaction mixture was heated at 60-65° C. for 1 hr. After cooling to room temperature, the insoluble materials were removed by filtration and the filtrate was diluted with EtOAc, washed with 25% aqueous NH4OH, 5% aqueous sodium bisulfite and then brine. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was purified on a Biotage 40 M column (2.5:1 hexane:EtOAc) to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 355 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.[Mg].Br[CH:17]([CH3:21])[C:18]([O-:20])=[O:19].[Na+].S(=O)(=O)(O)O>O1CCCC1.O>[F:14][C:4]1[CH:3]=[C:2]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(Br)C(=O)[O-]
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1

Procedure:
A solution of 4-bromo-2-fluorobiphenyl (2.51g;0.01 mole) in dry tetrahydrofuran (15ml) was aded dropwise, with stirring, to magnesium turnings (0.25g;0.0103g. atom) under a nitrogen atomosphere. When the addition was complete, the mixture was stirred and boiled under reflux for 30 minutes. The mixture was then cooled and a suspension of sodium 2-bromopropionate (1.75g;0.01 mole) in dry tetrahydrofuran (20ml) was added. Frothing occurred and when this had subsided the mixture was boiled under reflux with stirring, for one hour. The mixture was then cooled in an ice-bath and water (15ml) was added, followed by sulphuric acid (20%;5ml). The mixture was stirred for 10-15 minutes, and extracted with ether. The extract was washed with water and then extracted with aqueous potassium carbonate (1N). This extract was washed with ether and then added to a mixture of concentrated hydrochloric acid (10ml) and water (20ml). The mixture was cooled overnight and the precipitate filtered, washed with water and dried in vacuo to give 2 -(2-fluoro-4-biphenylyl)propionic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[H-].[Na+].[CH3:12][O:13][CH2:14]Cl.O>CS(C)=O>[CH3:12][O:13][CH2:14][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]#[N:9]
Reactant: COCCl
Reactant: N#CCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCC(C#N)c1ccccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11.8 g. (0.1 mole) of 2-pyridylacetonitrile in dry dimethylsulfoxide at 10° C. is added 0.1 mole of sodium hydride (dispersed in mineral oil). After 20 minutes, 0.1 mole of chloromethyl methyl ether is added with cooling and the mixture is kept at 10° C. for 2 hours, then allowed to warm to room temperature overnight. The reaction mixture is poured into water and extracted with ether. The organic phase is washed with water, dried over anhydrous sodium sulfate, concentrated under vacuum and distilled to give 3-methoxy-2-(2-pyridyl)propionitrile.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[NH2:19][CH:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:21]>C(#N)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:17])[C:6](=[O:18])[C:5]=2[NH:19][CH:20]([CH3:21])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: CC(N)C(C)(C)C
Solvent: CC#N
Product: COc1ccc(-c2c(NC(C)C(C)(C)C)c(=O)c2=O)cc1
Yield: 79.9 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.300 g, 1.22 mmol) and 2-amino-3,3-dimethylbutane (0.18 mL, 1.34 mmol) in acetonitrile (7 mL) were converted to the title compound (0.28 g, 80%) m.p.: 179-181° C.; 1H NMR (DMSO-d6) δ8.56 (br d,1H), 8.06(ABq,2H), 7.09(ABq,2H), 4.31(m,1H), 3.83(s,3H), 1.24(d,3H), 0.91(s,9H); IR (KBr) 3200, 2980, 1780, 1720, 1620, 1420, 1310, 1270, 1190, 1120, 1040, 840 cm−1; MS (m/z) 287 [M+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:29][CH2:30][O:31][CH2:32][CH3:33])[CH3:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[CH2:32]([O:31][CH2:30][CH2:29][N:27]([C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH3:28])[CH3:33]
Reactant: CCOCCN(C)c1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.2 g), 4-[N-(2-ethoxyethyl)-N-methylamino]phenyl borate (0.17 g), potassium carbonate (0.2 g), water (1.1 ml), ethanol (1.1 ml) and toluene (10.7 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.03 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-[N-(2-ethoxyethyl)-N-methylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.22 g) as colorless amorphous.