Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:36]([OH:39])[C:37]#[CH:38]>O.[Cu]I.[Cu](I)I>[OH:39][CH2:36][C:37]#[C:38][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:11]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:12]=3[S:13][C:14]=2[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: C#CCO
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(I)cc2)cc1
Agent: I[Cu]I
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C#CCO)cc2)cc1
Reaction time: 3 h

Procedure:
The product from Step 1 (214 mg, 0.43 mmol) was combined with triethylamine (35 mL), copper (I) iodide (0.4 mg), propargyl alcohol (50 mL, 0.86 mmol), bis-triphenylphosphine palladium dichloride at room temperature. The copper iodide was added last. The reaction was stirred for 3 hours then diluted with water and extracted into methylene chloride. The combined organic layers was dried over anhydrous magnesium sulfate. After filtration, concentration and silica gel column chromatography with 1.5% methanol-methylene chloride (gravity column) as eluant the title compound (195 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:17]=[CH2:18])=[CH:8]2.B.[OH-:20].[Na+].OO>C1COCC1.O>[OH:20][CH2:18][CH2:17][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[CH:8]=1
Reactant: [OH-]
Reactant: C=Cc1ccc2c(OC)c(OC)c(OC)cc2c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2cc(CCO)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5,6,7-Trimethoxy-2-vinylnaphthalene (1.215 g) was dissolved in dry THF (10 mL) under an argon atmosphere, a 1 M THF solution (4.7 mL) of borane was added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for 2 hours. Water (4 mL) was added to the reaction mixture at 0° C., and a 4 M aqueous solution (1.2 mL) of sodium hydroxide was then added. 31% Aqueous hydrogen peroxide (0.5 mL) was added to the reaction mixture at 0° C., and the mixture was stirred at 50° C. for 50 minutes. The solvent was distilled off, and water was added to the residue to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:8) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
The process of claim 86 wherein the 2-chloro-5-nitrobenzoic acid is contacted with phosphorus pentachloride to form the 2-chloro-5-nitrobenzoyl chloride.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[C:52]([O:56][C:57]([N:59]1[CH2:63][CH2:62][CH2:61][C@H:60]1[C@H:64]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[C:65](O)=[O:66])=[O:58])([CH3:55])([CH3:54])[CH3:53]>C(Cl)Cl>[Cl:3][C:4]1[C:5]([N:13]2[CH2:14][CH2:15][N:16]([C:65](=[O:66])[C@H:64]([C@@H:60]3[CH2:61][CH2:62][CH2:63][N:59]3[C:57]([O:56][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:58])[C:68]3[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=3)[CH2:17][CH2:18]2)=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: Clc1cnc2[nH]ncc2c1N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(Cl)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1
Yield: 82.9 %

Procedure:
A solution of 5-chloro-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (75 mg, 0.205 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (“HATU”; 78.0 mg, 0.205 mmol), N-ethyl-N-isopropylpropan-2-amine (143 μL, 0.821 mmol), and (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (83.7 mg, 0.246 mmol, see Example C) in CH2Cl2 (5 mL) was stirred at room temperature for 1 hour. The solvent was removed, and the resulting residue was redissolved in EtOAc (20 mL) and washed with water. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude obtained was purified by C-18 reverse phase column chromatography (Biotage C-18 12M+) using 10-90% CHsCN/water gradient on Biotage SP4 unit. The fractions containing the product were pooled, and the solvents were removed and evaporated from CH3CN (3×10 mL). The residue was transferred to a 25 mL round bottom flask using EtOAc (about 5 to about 10 mL). The residue was concentrated in vacuo and dried under high vacuum for 2 hours to provide (S)-tert-butyl 2-((S)-2-(4-(5-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-1-(4-chlorophenyl)-2-oxoethyl)pyrrolidine-1-carboxylate (95 mg, 0.170 mmol, 82.7% yield) as a solid. LCMS (APCI+) m/z 459.1 [(M-Boc)+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:46][C:47]1[N:52]=[CH:51][CH:50]=[CH:49][N:48]=1>O1CCCC1>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][CH:10]1[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][S:46][C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[CH:8][CH:7]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: Sc1ncccn1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CSc3ncccn3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.9 %

Procedure:
To a solution of 100 mg (0.22 mmol) of tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 10 ml of tetrahydrofuran were added 68 mg (0.66 mmol) of triethylamine and thereafter dropwise at 0° C. 25 mg (0.26 mmol) of methanesulphonyl chloride. The reaction solution was stirred at room temperature for 90 minutes, thereafter 38 mg (0.33 mmol) of 2-mercaptopyrimidine were added and the mixture was stirred at room temperature for a further 18 hours. For the working-up, the reaction mixture was evaporated under reduced pressure, the residue was taken up in 20 ml of methylene chloride and then extracted with 10 ml of water. The organic phase was dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 5:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 100 mg (82% of theory) of tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(pyrimidin-2-ylsulphanylmethyl)-phenyl]-piperidine-1-carboxylate as a yellowish oil; MS: 542 (M+H)+.
Reaction SMILES: [Cl-].C[CH:3]=[N+:4]=[CH:5]C.[C:7]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:9])[CH3:8].[C:19](#N)C>>[C:7]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[CH2:3][N:4]([CH3:5])[CH3:19])=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:9])[CH3:8]
Reactant: CC=[N+]=CC
Reactant: CC#N
Reactant: CC(=O)c1cc2ccccc2[nH]1
Agent: [Cl-]
Product: CC(=O)c1[nH]c2ccccc2c1CN(C)C
Reaction time: 8 h

Procedure:
187 g (2 mols) N,N-dimethylmethyleneammonium chloride are suspended under an inert gas (nitrogen or argon) in 28 liters anhydrous acetonitrile. The stirred suspension is mixed with 159 g (1 mol) pulverized and dried 2-acetylindole, heated to the boil and, while stirring continuously, uniformly cooled over the course of 7 hours to 25° C. It is stirred overnight at 20°-25° C. The acetonitrile is substantially distilled off under vacuum and the remaining residue taken up in 20 liters of water and adjusted to pH 9-10 with concentrated ammonium hydroxide solution. This solution is stirred up three times with, in each case, 5 liters of dichloromethane. The organic phases are combined and washed with 5 liters of water. The organic phase is dried by the addition of anhydrous sodium sulphate, filtered and mixed with 5 liters tert-butyl methyl ether. The dichloromethane is substantially distilled off, the crystallization of the product thereby already commencing. This is completed by leaving to stand overnight at +4° C. The product is filtered off with suction, washed with n-hexane and dried under a vacuum. Yield: 141.7 g (65.6% of theory).
Reaction SMILES: C([N:4]([CH2:8]C)C(C)C)(C)C.FC(F)(F)C(O)=O.[NH2:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]2[N:24]([CH:28]([C:30]3[C:40]4[O:39][CH:38]([CH3:41])[CH2:37][N:36]([CH:42]5[CH2:45][CH:44]([C:46]([OH:48])=O)[CH2:43]5)[CH2:35][C:34]=4[C:33](F)=[C:32]([Cl:50])[CH:31]=3)[CH3:29])[N:25]=[C:26]([CH3:27])[C:19]=12.F[P-](F)(F)(F)(F)F.C[N+:59](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.N>CN(C)C=O.C(O)C>[NH2:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]2[N:24]([CH:28]([C:30]3[C:40]4[O:39][C@@H:38]([CH3:41])[CH2:37][N:36]([CH:42]5[CH2:43][CH:44]([C:46]([NH2:59])=[O:48])[CH2:45]5)[CH2:35][C:34]=4[C:33]([C:8]#[N:4])=[C:32]([Cl:50])[CH:31]=3)[CH3:29])[N:25]=[C:26]([CH3:27])[C:19]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OC(C)CN(C2CC(C(=O)O)C2)C3)c2ncnc(N)c12
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2O[C@@H](C)CN(C2CC(C(N)=O)C2)C3)c2ncnc(N)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N,N-Diisopropylethylamine (78 μl, 0.45 mmol) was added to a mixture of 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-fluoro-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutanecarboxylic acid trifluoroacetate (44 mg, 0.09 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (34 mg, 0.09 mmol) in N,N-dimethylformamide (2 mL) at room temperature. A solution of ammonia in ethanol (2.0 M, 130 μl) was added and the reaction was stirred at room temperature for 1.5 hrs. The reactions were purified by prep HPLC on C-18 column eluting water:acetonitrile gradient buffered pH 10 to give two diastereomers: Peak #1 (Example 43): LCMS calculated for C23H28ClFN7O2 (M+H)+: m/z=488.2; found: 488.2; Peak #2 (Example 44): LCMS calculated for C23H28ClFN7O2 (M+H)+: m/z=488.2; found: 488.2.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:16][O:15][C:14]2[C:5](=[CH:6][C:7]3[C:8]([C:21]([F:24])([F:23])[F:22])=[CH:9][C:10]([O:17][CH:18]([CH3:20])[CH3:19])=[N:11][C:12]=3[CH:13]=2)[N:4]1[CH2:25][C:26]([F:29])([F:28])[F:27].[H-].[Na+].I[CH2:33][CH2:34][CH3:35]>C1COCC1>[CH:18]([O:17][C:10]1[CH:9]=[C:8]([C:21]([F:22])([F:23])[F:24])[C:7]2[CH:6]=[C:5]3[N:4]([CH2:25][C:26]([F:28])([F:29])[F:27])[CH:3]([CH2:2][O:1][CH2:33][CH2:34][CH3:35])[CH2:16][O:15][C:14]3=[CH:13][C:12]=2[N:11]=1)([CH3:20])[CH3:19]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(CO)N3CC(F)(F)F
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCOCC1COc2cc3nc(OC(C)C)cc(C(F)(F)F)c3cc2N1CC(F)(F)F
Yield: 49.5 %

Procedure:
This compound was prepared according to General Method 16 (EXAMPLE 30) from (±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (EXAMPLE 28) (11 mg, 0.026 mmol), NaH (5.0 mg, 0.12 mmol) and 1-iodopropane (21 mg, 0.12 mmol) in 1.0 mL THF to afford 6 mg (50%) of (±)-2,3-dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a yellow oil, after flash chromatography (5:1 hexanes:EtOAc). Data for (±)-2,3-dihydro-7-isopropoxy-2-(1-propoxymethyl)-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: Rf0.57 (5:1 hexanes: EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 7.13 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.44 (dd, 1H, J=10.9, 1.8), 4.17 (dd, 1H, J=11.0, 2.5), 4.00-4.20 (m, 2H), 3.71 (broad t, 1H, J=6.8), 3.54-3.64 (m, 2H), 3.40 (broad t, 2H, J=6.6), 1.52-1.62 (m, 2H), 1.38 (d, 6H, J=6.2), 0.91 (t, 3H, J=7.4).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[N:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].[CH2:15]([CH2:17][NH2:18])[OH:16].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:18][CH2:17][CH2:15][OH:16])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2cccnc2c1O
Reactant: NCCO
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cccnc2c1NCCO
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A solution of 3-nitro[1,5]naphthyridin-4-ol (9.14 g, 43.7 mmol) dissolved in 300 mL of CH2Cl2 was treated with ethanolamine (7.9 mL, 130 mmol) and the mixture was stirred under N2. After 3 hours, the reaction mixture was concentrated to give a yellow solid. The yellow solid was treated with 200 mL of H2O and the suspension was heated to reflux, with stirring, for 10 minutes. The mixture was cooled in an ice bath. The resulting yellow solid was isolated by filtration, washed with cold H2O and dried with suction to give 2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol (10.02 g) as fine yellow crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH:9]=[CH:8]1)=[O:6].[O:16]1CCC[CH2:17]1>>[CH3:1][N:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[C:5](=[O:6])[N:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[C:17]1=[O:16]
Reactant: C1CCOC1
Reactant: CNc1ccccc1C(=O)N1C=CCC1
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 24.8 g. of racemic 1-(N-methylanthraniloyl)pyroline and 21 g. of dicyclohexylcarbonyl diimide in 300 ml. of tetrahydrofuran is stirred at room temperature for 24 hours and then heated on the steam bath for 4 hours. The reaction mixture is filtered to remove the insoluble dicyclohexyl urea and the mother liquid is concentrated to recover the desired product, which is further purified by recrystallization from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[NH2:14][CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18].C[Al](C)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([NH:14][CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:6]
Reactant: CCCC(N)CCC
Reactant: COC(=O)c1cc(Cl)cc(I)c1N
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCC(CCC)NC(=O)c1cc(Cl)cc(I)c1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 315.7 %

Procedure:
Added successively to a solution of 3 g of methyl 2-amino-5-chloro-3-iodobenzoate in 100 cm3 of toluene, under an inert atmosphere and at a temperature close to 20° C., are 2.2 g of 4-aminoheptane then 12 cm3 of a 2M solution of trimethylaluminum in toluene. The reaction mixture is heated, while stirring, for 16 h at 100° C., then it is cooled to 20° C. in order to then be poured over a mixture of 250 g of water/ice and 150 cm3 of ethyl acetate. The suspension obtained is filtered over a Celite 545 pellet. The aqueous phase is extracted with 3 lots of 100 cm3 of ethyl acetate. The organic phases are combined then washed with 100 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 12 g of crude product obtained are purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 100% dichloromethane). After concentrating the fractions under reduced pressure, 3.21 g of 2-amino-5-chloro-3-iodo-N-(1-propylbutyl)benzamide are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]#[N:17])[O:13][N:12]=2)[CH2:7][CH2:6]1.Cl.[NH+]1C=CC=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+].Cl>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]3[NH:32][N:31]=[N:30][N:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(N2CCC(Oc3cc(F)ccc3Br)CC2)no1
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1ccc(Br)c(OC2CCN(c3cc(-c4nnn[nH]4)on3)CC2)c1
Temperature: 130 °C

Procedure:
A mixture of 3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazole-5-carbonitrile (1.4 g, 3.82 mmol), pyridinium hydrochloride (0.9 g, 7.79 mmol) and sodium azide (1.3 g, 20.00 mmol) in NMP (12 mL) was stirred and heated at 130° C. bath for 2 h. After cooling, the mixture was diluted with water and acidified with 1N HCl (some precipitate appeared). The whole mixture was then extracted with EtOAc. The EtOAc extract was washed with water (3×), dried (Na2SO4) and concentrated. The residue was triturated with diethyl ether to give the title compound as a light brown powder.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([OH:23])=O)[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]([C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1)[NH2:25].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([NH:25][NH:24][C:26]2[N:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][N:27]=2)=[O:23])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[CH2:15][CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CCC(CN(C=O)OCc2ccccc2)(C(=O)O)CC1
Reactant: NNc1nccc(C(F)(F)F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)CCC(CN(C=O)OCc2ccccc2)(C(=O)NNc2nccc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a mixture of 1-[(benzyloxy-formyl-amino)-methyl]-4,4-dimethyl-cyclohexanecarboxylic acid (0.10 g, 0.31 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.067 g, 0.37 mmol), NMM (0.095 g, 0.93 mmol) and HOAt (0.05 g, 0.37 mmol) in DMF (1 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.072 g, 0.37 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.11 g, 74%). MH+480.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH2:22]>C(O)CCC>[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH:22][C:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH:11][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][C:6]=2[N:7]=1
Reactant: Cc1ccc2c(c1)NC(=S)c1ccccc1N2
Reactant: COC(CN)OC
Solvent: CCCCO
Product: COC(CNC1=Nc2cc(C)ccc2Nc2ccccc21)OC

Procedure:
In the manner given in Example 4, 8-methyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with amino acetaldehyde dimethyl acetal in n-butanol to give 8-methyl-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]-acetaldehyde dimethyl acetal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][O:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]#[CH:49])=[CH:44][CH:43]=1.C(N(CC)CC)C>ClCCl.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.[Cu]I>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:10]1[O:11][CH2:12][CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:49]#[C:48][C:45]3[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)cc2)CCO1
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(C#Cc2ccc(C3CCOC(c4c(F)cccc4F)=N3)cc2)cc1

Procedure:
In 2 mL of dichloromethane, the product of Step C (0.07 g) was combined with tetrakis(triphenylphosphine)palladium(0) (0.010 g), copper(I) iodide (0.006 g), triphenylphosphine (0.006 g), (4-fluorophenyl)acetylene (prepared by the method of A.D. Allen and C. D. Cook, Can. J. Chem. (1963), 41, 1084; 0.15 g), and triethylamine (2 mL) and the mixture heated at reflux until thin layer chromatographic analysis showed consumption of starting material. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the title product, a compound of this invention, as a solid melting at 95°-110° C. (material prepared on larger scale, identical by 1H NMR spectroscopy, was recrystallized from ethyl acetate/hexane to give a solid melting at 102°-104° C.). 1H NMR (CDCl3) δ2.0 (m, 1H), 2.4 (m, 1H), 4.3 (m, 1H), 4.5 (m, 1H), 4.8 (m, 1H), 6.9-7.1 (m,4H), 7.3-7.4 (m,3H), 7.5-7.6 (m,4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C(=CC=C(OC)C=2)[O:40][C:39]=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:40][CH3:39])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COc1ccc2oc(-c3ccccc3)c(I)c(=O)c2c1
Product: COc1ccc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2c1
Yield: 44 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-6-methoxy-2-phenyl-chromen-4-one (76 mg, 0.20 mmol) was reacted to give the title compound (42 mg, 44%). 1H NMR (400 MHz, CDCl3): δ 7.68-7.64 (d, 1H), 7.51-7.16 (m, 11H), 5.05 (s, 1H), 3.92 (s, 3H), 2.61-2.45 (m, 4H), 2.16-1.75 (m, 2H), 1.52-1.00 (m, 9H).
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5].[I-:17].[Na+]>CC(C)=O>[I:17]/[CH:2]=[CH:3]/[C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5]
Reactant: O=C(/C=C/Cl)C1CCC2(CCCCC2)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(/C=C/I)C1CCC2(CCCCC2)CC1
Yield: 70.9 %

Procedure:
In a procedure as described in Example 9H, 1-chloro-3-(spiro[5.5]undec-3-yl)-1E-propen-3-one was reacted with sodium iodide in acetone to yield 1-iodo-3-(spiro[5.5]undec-3-yl)-1E-propen-3-one (70.9%).