Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:12][CH:11]=[CH:10]2.CN(C)[CH:28]=[O:29]>O1CCCC1>[CH:28]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:12][CH:11]=[CH:10]2)=[O:29]
Reactant: O=C(Nc1nccc2cc(Br)ccc12)c1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 29 mL of n-BuLi (1.6 M in hexane) in 40 mL of dry tetrahydrofuran under a nitrogen atmosphere at −78° C. was added dropwise a solution of 2.5 g of 1e in 60 mL of dry tetrahydrofuran over a period of 15 min. After stirring for 30 min a mixture of 34 mL of N,N-dimethylformamide and 20 mL of tetrahydrofuran was added fast. The cooling bath was removed, the reaction mixture was allowed to come to 0° C. and was poured into ice cold aqueous hydrochloric acid (60 mL, 0.5 N). The mixture was adjusted to pH 6, brine was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried (MgSO4) and concentrated under reduced pressure. Purification on silica gel (toluene/ethyl acetate: 3/1) gave 1.3 g of aldehyde 1f. 1H-NMR 200 MHz (CDCl3) δ: 7.12 (1H, d, J=7 Hz). 7.40-8.51 (9H, m), 9.26 (1H, d, J=8 Hz), 10.23 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4C=CC=C[CH:32]=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.C(=O)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][CH2:31][CH3:32])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Agent: [Na+]
Solvent: CCC=O
Product: CCCNc1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Yield: 46 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, intermediate 1j (100 mg, 0.234 mmol), propionaldehyde (15 mg, 0.258 mmol) and NaBH(OAc)3 (74.5 mg, 0.352 mmol) yielded 50.9 mg (46%) of intermediate 8a. MS (ESI) 469.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C-]#N.[K+].[C:15](#[N:17])[CH3:16]>C1OCCOCCOCCOCCOCCOC1>[C:15]([CH2:16][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:17]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [C-]#N
Agent: [K+]
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
To a solution of methyl 3-bromobenzoate (10.0 g, 44 mmol) in acetonitrile (100 mL) were added potassium cyanide (5.7 g, 87 mmol) and 18-crown-6 (1.0 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtrated, solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→30/70). The combined solution was concentrated under reduced pressure to give the title compound (7.0 g, 91%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:26]=[CH:25][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=1>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:46])([F:47])[F:48])[CH:40]=5)[CH2:20]4)=[O:16])=[CH:25][CH:26]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CCCNC4)cc3)oc12
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CCCN(Cc5cccc(C(F)(F)F)c5)C4)cc3)oc12
Reaction time: 1.5 h
Yield: 71 %

Procedure:
4-(5-Cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-[(3S)-piperidin-3-ylmethyl]benzamide (20 mg) was taken up in methanol (3 ml) and then potassium carbonate (14 mg) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (14 □l) were added. The mixture was stirred for 1.5 h and then added directly to a Biotage 40M samplet for purification via column chromatography on a Biotage Horizon 40M column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes to provide the title compound (20 mg, 71%). Mass spectrum (ESI) 561.4 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.31 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.59 (s, 1H), 7.55 (m, 3H), 7.41 (t, J=7.7 Hz, 2H), 6.43 (t, J=5.8 Hz, 1H), 3.47 (m, 3H), 2.72 (m, 3H), 2.34 (s, 3H), 2.03 (m, 2H), 1.90 (t, J=11.4 Hz, 2H), 1.47 (d, J=6.9 Hz, 6H), 1.31 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[S:28](=[O:30])(=[O:29])[N:27](CC[Si](C)(C)C)[C:26](=[O:37])[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][C:10]=1[N:24]1[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:37])[CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(OCCc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1CN(c2ccc(OCCc3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 25 °C

Procedure:
A solution of 5-(2-benzyloxy-4-phenethyloxyphenyl)-1 , 1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (47 mg, 0.087 mmol) and tetrabutylammonium fluoride (0.5M in THF, 0.35 mL, 0.175 mmol) in THF (5 mL) is refluxed for 1 h. The mixture is cooled to RT, concentrated, and extracted with EtOAc. The organic phase is washed with 1N HCl and is dried over magnesium sulfate. The solvent is removed under reduced pressure to afford the title compound: (M−1)−=437.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C@H:10]([OH:39])[CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([C:20]3[N:24]=[C:23]([C:25]4[CH:30]=[C:29]([CH3:31])[N:28]=[C:27]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[CH:26]=4)[O:22][N:21]=3)=[CH:15][C:14]=2[CH2:37][CH3:38])[CH2:6]1)=[O:4].C(O)=O>CO.C1COCC1.[Li+].[OH-]>[CH2:35]([N:32]([CH2:33][CH3:34])[C:27]1[CH:26]=[C:25]([C:23]2[O:22][N:21]=[C:20]([C:16]3[CH:17]=[C:18]([CH3:19])[C:13]([O:12][CH2:11][C@@H:10]([OH:39])[CH2:9][N:7]4[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]4)=[C:14]([CH2:37][CH3:38])[CH:15]=3)[N:24]=2)[CH:30]=[C:29]([CH3:31])[N:28]=1)[CH3:36]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CN1CC(C(=O)OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CN1CC(C(=O)O)C1
Yield: 11.8 %

Procedure:
A solution of 1-((S)-3-{4-[5-(2-diethylamino-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-2-hydroxy-propyl)-azetidine-3-carboxylic acid methyl ester (60 mg, 0.113 mmol) in methanol (2 mL), THF (2 mL) and 2 M aq. LiOH solution (1 mL) is stirred at rt for 2 h before the reaction mixture is neutralized by adding formic acid. The mixture is concentrated and the crude product is purified by prep. HPLC followed by precipitation of the product from EA/heptane to give the title compound (7 mg) as a pale yellow solid; LC-MS: tR=0.72 min; [M+1]+=524.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH2:37][CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[C:54]([C:58]1[CH:59]=[C:60]([NH2:65])[C:61]([NH2:64])=[CH:62][CH:63]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C)C=O>[NH2:65][C:60]1[CH:59]=[C:58]([C:54]([CH3:56])([CH3:55])[CH3:57])[CH:63]=[CH:62][C:61]=1[NH:64][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH2:37][CH3:38])[CH2:31]1
Reactant: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCC(=O)O)C1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCC(=O)Nc2ccc(C(C)(C)C)cc2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.84 g, 2.2 mmol) added to a solution 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(ethyl)amino)cyclobutyl)propanoic acid (0.89 g, 1.5 mmol) and N,N-Diisopropylethylamine (0.84 ml, 4.8 mmol) and 4-tert-butylbenzene-1,2-diamine (0.29 g, 1.8 mmol) in N,N-Dimethylformamide (9 ml). The reaction was stirred overnight at RT, partially concentrated to ca. 2 ml and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (DCM I 7N NH3 in MeOH 94:6) to give the desired compound (0.88 g) as a colorless solid. Retention time C, 3.363 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ccccc2)c(F)c1
Temperature: 90 °C

Procedure:
2,4-Difluorophenylboronic acid (15 g, 129 mmol) was added to a solution of bromobenzene (19.8 g, 126 mmol) in DME (500 mL). To this was added a solution of sodium carbonate (55.8 g, 520 mmol) in water (260 mL). The solution was degassed by bubbling argon through the mixture and then stirred under argon. Pd(dppf)Cl2 (1.5 g, 2.1 mmol) was added and the mixture heated overnight at 90° C. under argon. The mixture was cooled to room temperature and water (150 mL) and ethyl acetate (500 mL) were added. The layers were separated and the organic layer was washed with 2 M NaOH (100 mL), water (100 mL) and brine (100 mL). The black ethyl acetate layer was dried over MgSO4, charcoal was added, and the mixture was filtered through a short pad of silica. Evaporation of the solvents gave 2,4-difluorobiphenyl as a brown oil, which crystallised on standing (21.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][C:9]3[C:10]4[C:15]([C:14](=[O:16])[N:13]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:12](=[O:22])[C:11]=4[CH:23]=[CH:24][CH:25]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:26]1[O:34][C:33]2[CH:32]=[CH:31][C:30]([N:35]=[C:36]=[O:37])=[CH:29][C:28]=2[O:27]1>C(#N)C>[O:34]1[C:33]2[CH:32]=[CH:31][C:30]([NH:35][C:36]([NH:1][C:2]3[C:7]4=[CH:8][C:9]5[C:10]6[C:15]([C:14](=[O:16])[N:13]([CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])[C:12](=[O:22])[C:11]=6[CH:23]=[CH:24][CH:25]=5)=[C:6]4[CH:5]=[CH:4][CH:3]=3)=[O:37])=[CH:29][C:28]=2[O:27][CH2:26]1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4c(N)cccc4c(c23)C1=O
Reactant: O=C=Nc1ccc2c(c1)OCO2
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4c(NC(=O)Nc5ccc6c(c5)OCO6)cccc4c(c23)C1=O
Temperature: 20 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A solution of 100 mg (0.30 mmole) of 8-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 4) in 4 mL of acetonitrile was stirred at 20° C. 3,4-(methylenedioxy)phenyl isocyanate (4 molar equivalents) in 3 mL acetonitrile were added. The mixture was magnetically stirred at 20° C. during 24 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 95:5 volume ratio) to provide 76 mg (yield: 51%). of the desired product (formula below) as an orange powder
Reaction SMILES: C(OC(N1CCC(NCC2C=CC=CC=2)C(O)C1)=O)(C)(C)C.[C:23]([OH:32])(=[O:31])[C@H:24]([C@@H:26]([C:28]([OH:30])=[O:29])[OH:27])[OH:25]>C(#N)C.O>[C:23]([OH:32])(=[O:31])[CH:24]([CH:26]([C:28]([OH:30])=[O:29])[OH:27])[OH:25]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)C(O)C1
Solvent: O
Solvent: CC#N
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
Concentrate the mother liquor of Preparation 77 to obtain enantio enriched (3S,4S)-3-hydroxy-4-phenethyl-piperidine-1-carboxylic acid tert-butyl ester L-(+)-tartaric acid salt (0.0377 mol, 17.2 g). Add 4% aqueous potassium carbonate solution (500 mL) and stir for 30 min. Extract the free amine with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the free amine (11.0 g). Heat a mixture of 4-benzylamino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.0361 mol, 11.0 g) and D-(−)-tartaric acid (0.0397 mol, 5.97 g, 1.1 equiv.) in acetonitrile/water (20:1) (100 ml) at 75° C. for 4 h. Concentrate the reaction mixture under reduce pressure to obtain crude tartaric acid salt. Crystallize the residue from acetonitrile three times. Filter the crystals and dry under vacuum to obtain the title compound (14.8 g, 90%). HPLC (Column: Chiralcel OD-H (250 mm*4.6 mm); solvent system: isopropanol/0.1% triethylamine in hexanes (8:92); flow rate: 0.800 ml/min; wavelength: 258 nm): 96.4% ee. tR 8.714 min. tR for opposite enantiomer ((3R,4R)-3-Hydroxy-4-phenethyl-piperidine-1-carboxylic acid tert-butyl ester.L-(+)-tartaric acid salt) 9.502 min.
Reaction SMILES: C([C:3]1([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[S:7][CH:6]([C:8]([O-:10])=O)[N:5]=[C:4]1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])C.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].O>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:3]2[S:7][C:6]([C:8]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:10])=[N:5][C:4]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:20][CH:21]=1
Reactant: CCC1(c2ccc(Cl)cc2)SC(C(=O)[O-])N=C1c1ccc(Cl)cc1Cl
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
5-Ethyl-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)thiazole-2-carboxylate (1.65 gram, 4.0 mmol) is dissolved in anhydrous THF (25 mL) and aniline (0.37 mL, 4.0 mmol) is added. The resulting solution is cooled to 0° C. and sodium hexamethyidisilazide (4.4 mL of a 1M solution in THF) is added. The reaction mixture is stirred for 2 hours. Water is added and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is crystallised from diisopropyl ether to give 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-phenyl-thiazole-2-carboxamide (1.42 g, 77% yield). Melting point: 167-168° C.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1)#[N:2].Cl>C1COCC1>[O:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5][CH:4]1[CH2:3][CH2:1][NH2:2]
Reactant: N#CCC1COc2ccccc2O1
Agent: Cl
Solvent: C1CCOC1
Product: NCCC1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The 2-cyanomethyl-(2,3dihydrobenzo[1,4]dioxine) was dissolved in THF (50 mL) and 1 M BH3 in THF (80 mL, 80 mmol) was added and the reaction mixture refluxed for 5 h, then stirred at ambient temperature for 1 6h. With ice bath cooling, 2N HCl was added until pH=1.0 was achieved. The reaction mixture was then stirred for 1 h at room temperature and evaporated in vacuo to yield an oil. The oil was partitioned between 3N NaOH and diethyl ether, and the diethyl ether solution was washed with brine, dried (Na2SO4) and evaporated in vacuo to yield crude 2-(2,3 dihydrobenzo[1,4]dioxin-2-yl)ethylamine.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=2[C:4]#[N:5])=[C:14]([O:19][CH3:20])[CH:13]=1
Reactant: N#Cc1c(F)cccc1F
Reactant: COc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1Oc1cccc(F)c1C#N
Temperature: 70 °C
Yield: 72.5 %

Procedure:
To a solution of 2,6-difluorobenzonitrile (100 mg; 0.72 mmol) and 4-chloro-2-methoxyphenol (114 mg; 0.72 mmol) in anhydrous DMF (5 mL) is added potassium carbonate (50 mg; 0.36 mmol). The reaction mixture is heated to 70° C. overnight. After allowing to room temperature, the solvent is removed under vacuum and the resulting solid is partitioned between ethyl acetate and water. The organics are separated and dried over magnesium sulfate. The solvent is removed to give 145 milligrams of 2-(4-chloro-2-methoxyphenoxy)-6-fluorobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[C:11]=3[N:10]=[C:9]2[C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[NH2:41][C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][N:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:41][C:42]1[N:43]=[CH:44][C:45]([C:29]2[CH:30]=[CH:31][C:26]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]4[CH:15]=[N:16][N:17]([C:18]5[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=5)[C:21]#[N:22])[C:11]=4[N:10]=3)=[CH:27][CH:28]=2)=[CH:46][CH:47]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(C#N)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
A solution of 3-{5-(4-chloro-phenyl)-4-oxo-6-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl]-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl}-benzonitrile (2, 1.00 g, 1.81 mmol) in N,N-dimethylformamide (25 mL) is degassed with argon for 0.5 h. Then 2-amino-5-bromopyridine (0.47 g, 2.72 mmol), cesium carbonate (1.18 g, 3.62 mmol), Pd(dppf)2Cl2 (0.147 g, 0.181 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 2 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by preparative HPLC to afford 3-[6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile (3). LC-MS calculated for C29H18ClN7O (M+H+) 516.1, found 516.1.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH2:17][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: Oc1cccnc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccnc(COc2cccnc2Br)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-bromo-3-pyridinol (commercially available, e.g. from Aldrich) (2.9 g) and potassium carbonate (6.94 g) in DMF (25 ml) was stirred for 20 min before adding 2-(chloromethyl)-4-methylpyridine hydrochloride (for preparation see WO 2008/141011) (3 g). This was stirred at room temperature overnight. The reaction mixture was poured into ice/water and the solid formed was collected by filtration, washed with hexane and dried to give the title compound, 2.87 g (61%).
Reaction SMILES: Cl.[C:2]1(=[N:10]O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH2:12]>>[C:2]1(=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:10]1
Reactant: O
Reactant: ON=C1CCCCCCC1
Agent: Cl
Product: O=C1CCCCCCCN1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
Polyphosphoric acid (31.9 g) and water (3.75 g) were placed in a 100 mL round bottom flask equipped with a stir bar and a cold water condenser. The mixture was heated to 130 degrees C., and cyclooctanone oxime hydrochloride (5.9 g, 35 mmol, 1.0 eq) was added in small portions over 10 min. The oxime dissolved readily. The reaction mixture was stirred at 130 degrees C. for 1 hour, turned dark, was cooled to 100 degrees C., and poured into 100 mL of ice water. The aqueous mixture was extracted with chloroform (3×75 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The 2-azacyclononanone slowly crystallized into an off-white solid (4.69 g, 94%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:26])[C:20]=2[CH:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:17]1[C:25]2[C:20](=[C:21]([O:26][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Oc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cn2nc(Oc3cccc4[nH]ccc34)ccc2n1)C1CC1
Yield: 18.3 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (353 mg, 1.08 mmol), 1H-indole-4-ol (241 mg, 1.82 mmol), potassium carbonate (446 mg, 3.23 mmol) and N,N-dimethylformamide (4.0 mL) as starting materials and in the same manner as in Example 95, the title compound (66 mg, 18%) was obtained as a white powder.
Reaction SMILES: [Na].C[O-].[Na+].[Cl:5][C:6]1[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[N:9]=[C:8]([NH:16][CH2:17][CH2:18][SH:19])[N:7]=1.[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>CCOCC.CC(C)=O.CO>[Cl:5][C:6]1[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[N:9]=[C:8]([NH:16][CH2:17][CH2:18][S:19][C:22](=[O:23])[N:21]([CH3:25])[CH3:20])[N:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)Nc1nc(Cl)nc(NCCS)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(C)Nc1nc(Cl)nc(NCCSC(=O)N(C)C)n1
Temperature: 80 °C

Procedure:
A 0.46-g sample of sodium was added to 50 ml methanol in small pieces. To the resulting sodium methoxide solution was added 5 g of 2-chloro-4-isopropylamino-6-(2-mercaptoethylamino)-s-triazine, followed by 2.16 g dimethylcarbamyl chloride at 0° C. The reaction mixture was heated at 80° C. for 4 hours, cooled, filtered and evaporated under reduced pressure to give a yellow oil. The yellow oil was dissolved in 1:1 ether/acetone and filtered. The filtrate was evaporated to give the product as an oil. The elemental analysis on the product is tabulated in Table I.