Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:23]1[CH:27]=[C:26]([C:28]2[C:29]3[CH:36]=[CH:35][N:34](COCC[Si](C)(C)C)[C:30]=3[N:31]=[CH:32][N:33]=2)[CH:25]=[N:24]1)[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=2)[C:16](O)=[O:17])[CH2:8][CH2:7]1)#[N:2].[CH2:45]([NH2:47])[CH3:46].C1COCC1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[C:1]([CH2:3][CH:4]([N:23]1[CH:27]=[C:26]([C:28]2[C:29]3[CH:36]=[CH:35][NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:25]=[N:24]1)[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=2)[C:16]([NH:47][CH2:45][CH3:46])=[O:17])[CH2:10][CH2:11]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCC(Oc5cc(F)cc(C(=O)O)c5)CC4)c3)ncnc21
Reactant: CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc(F)cc(OC2CCN(CC(CC#N)n3cc(-c4ncnc5[nH]ccc45)cn3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To a mixture of 3-[(1-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}piperidin-4-yl)oxy]-5-fluorobenzoic acid (18 mg, 0.029 mmol) and 2.0 M ethylamine in THF (21.8 μL, 0.0436 mmol) in methylene chloride (0.2 mL) and dimethylformamide (DMF) (50 μL) were added triethylamine (6.1 μL, 0.0436 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (19.3 mg, 0.0436 mmol). The resulting mixture was stirred overnight at room temperature and concentrated. To the residue was added saturated NaHCO3 solution then extracted with ethyl acetate (3×). The combined extracts were dried over MgSO4, filtered, and concentrated. The crude residue was dissolved in DCM (0.2 mL) and TFA (0.2 mL). The mixture was stirred for 2 hours then concentrated. To the reaction vial was added MeOH (0.5 mL) and ethylenediamine (EDA) (0.1 mL). After stirring for 1 hour, the mixture was diluted with acetonitrile and purified by preparative-LCMS (eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (2.7 mg, 18%). LCMS (M+H)+: 517.3.
Reaction SMILES: [OH-].[CH3:2][N+:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]=1SCCCS(O)(=O)=O.Cl.Cl.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]2[NH:27][N:28]=[N:29][C:25]=2[CH:24]=1.C([O-])(=O)C.[Na+]>O>[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[N:22][C:23]2[CH:31]=[CH:30][C:26]3[NH:27][N:28]=[N:29][C:25]=3[CH:24]=2)[CH2:4]1
Reactant: C[n+]1c(SCCCS(=O)(=O)O)sc2ccccc21
Reactant: Nc1ccc2[nH]nnc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1CS(=Nc2ccc3[nH]nnc3c2)c2ccccc21
Temperature: 50 °C
Yield: 98.7 %

Procedure:
175 g of anhydrous 3-methyl-2-(3-sulfopropylthio) benzothiazolium hydroxide was added to a mixture of 100 g of 5-aminobenzotriazole di-hydrochloride, 120 g of sodium acetate and 1000 ml of water under heating at 50° C with stirring in a 2000 ml flask. After stirring for 1 hour at 85° C the mixture was cooled (15° C) with water. The precipitate formed was collected by filtration, washed with water and then with acetonitrile to yield 135 g of crystals. These crystals were dissolved by heating (90° C) in 350 ml of dimethylformamide and the solution was treated with active carbon and filtered. By addition of 1400 ml of acetonitrile to the filtrate, crystals were formed. The crystals were collected to yield 121 g of the desired compound. The melting point was 240.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=O)=[CH:3][CH:2]=1.C([N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])(=O)C>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[C:20]2[CH2:21][CH2:22][NH:18][C:19]2=[O:23])=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1-c1ccncc1
Reactant: CC(=O)N1CCCC1=O
Product: O=C1NCCC1=Cc1ccccc1-c1ccncc1

Procedure:
The title compound was prepared via reaction between 2-pyridin-4-yl-benzaldehyde and N-acetylpyrrolidinone using General Aldol Procedure 1. 13C NMR (100 MHz, CDCl3) d 172.6, 149.9, 148.5, 140.0, 133.7, 132.8, 130.3, 128.9, 128.7, 128.4, 124.8, 40.0, 26.4; MS (AP/Cl) 252.1 (M+H)+.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].CC1(C)OC(=O)[CH:10]([C:14]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[C:9](=O)[O:8]1>C1(C)C=CC=CC=1>[C:1]([O:5][C:9](=[O:8])[CH2:10][C:14](=[O:15])[CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OC(=O)C(C(=O)C2CCOCC2)C(=O)O1
Reactant: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CC(=O)C1CCOCC1
Yield: 97.5 %

Procedure:
tert-Butanol (600 ul, 6 mmol) was added to a solution of 2,2-dimethyl-5-(tetrahydro-pyran-4-carbonyl)-[1,3]dioxane-4,6-dione (1.1 g, 4 mmol) in toluene (9.6 ml). The reaction mixture was heated under reflux conditions for 6 h and partitioned between ice water/brine 1/1 and iPrOAc. The layers were separated and the aqueous layer was extracted one more time with iPrOAc. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to give the title compound (891 mg, 3.9 mmol; 91%) as brown oil which was sufficiently pure to be used in the next reaction step. MS (EI): m/z=228 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([NH2:16])=[NH:15])=[N:6]1.[CH2:21]([C:28]([C:30]([F:33])([F:32])[F:31])=O)[C:22]([C:24]([F:27])([F:26])[F:25])=O>>[F:25][C:24]([F:26])([F:27])[C:22]1[CH:21]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:16]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)[N:15]=1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Product: Fc1ccccc1Cn1nc(-c2nc(C(F)(F)F)cc(C(F)(F)F)n2)c2cccnc21

Procedure:
At 110° C., 50 mg (19 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine from Example 25A and 42 mg (20 mmol) of 1,1,1,5,5,5-hexafluoroacetylacetone are heated for 5 h. Chromatography gives 33 mg (40.3% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2ccncc2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 1 from (R)-3′-(5-bromo-thiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-4-boronic acid. The title compound (34 mg) was obtained as a pale-yellow solid, m/z 342 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].C(N(C(C)C)CC)(C)C.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.O>CN(C)C=O>[CH3:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]([NH:25][CH:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]2)[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
1-Fluoro-5-methyl-2-nitro-4-(trifluoromethyl)benzene (D56) (4.9 mmol, 1.1 g) was dissolved in dry dimethylformamide (3 ml) and diisopropylethylamine (1 eq., 4.9 mmol, 0.460 ml), 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 4.9 mmol, 981 mg) were added at room temperature and the mixture was stirred at 80° C. for 3 hours. The crude mixture was then cooled to room temperature and water was added; the aqueous solution was extracted with ethyl acetate; organics were alternatively washed with brine and water. The organics were combined dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound that was purified by chromatography (ethyl acetate-n-hexane) to yield the title compound, 1.29 g, 65%, M+−H=402.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.4 %

Procedure:
Tert-butyl 4-(4-fluorophenyl)piperidine-1-carboxylate (46 mg, 0.165 mmol) was dissolved in MC (2 ml), followed by addition of trifluoroacetic acid (1 ml), and then the resulting mixture was stirred at room temperature for 4 hours. The resulting reaction liquid was neutralized by slow addition of a saturated aqueous NaHCO3 solution at 0° C., and then extracted with 5% MeOH/MC (10 ml×2). The organic layer was dried over anhydrous magnesium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 22 mg of colorless oil (74%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH:9]=2)=[CH:4][CH:3]=1>CO.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:10]([C:20]([O:22][CH3:23])=[O:21])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C=C(c2ccc(N)nc2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](c2ccc(N)nc2)CN1C(=O)OC(C)(C)C
Yield: 98.9 %

Procedure:
A degassed solution of (S)-1-tert-butyl 2-methyl 4-(6-aminopyridin-3-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (0.955 g, 2.99 mmol) in methanol (30 mL) was treated with 10% Pd/C (0.183 g, 0.172 mmol), then maintained under an atmosphere of hydrogen for 3 h. At completion, the reaction then filtered over a pad of Celite and concentrated to provide (2S,4R)-1-tert-butyl 2-methyl 4-(6-aminopyridin-3-yl)pyrrolidine-1,2-dicarboxylate (0.95 g. 99% yield). LCMS (m/z): 322.5 (MH+), 0.52 min.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[CH3:8][Si:9]([CH3:15])([CH3:14])[Si:10]([CH3:13])([CH3:12])Cl>[Zn].CN1CCCC1=O>[CH3:12][Si:10]([CH3:13])([CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])[Si:9]([CH3:15])([CH3:14])[CH3:8]
Reactant: O=C1OCCC1Br
Reactant: C[Si](C)(C)[Si](C)(C)Cl
Agent: [Zn]
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)[Si](C)(C)C1CCOC1=O
Temperature: 60 °C
Reaction time: 6 h

Procedure:
200 ml of N-methylpyrrolidone and 34.3 g of zinc dust are placed in a 1,000 ml three-neck flask fitted with internal thermometer, cold-drawn precision glass stirrer and dropping funnel. A mixture of 82.5 g of 2-bromo-γ-butyrolactone and 83.4 g of pentamethylchlorodisilane and 100 ml of N-methylpyrrolidone is added dropwise while stirring so that the internal temperature adjusts to 60° C. during the exothermic reaction. Stirring is continued for a further 6 h at this temperature and the reaction mixture is then poured onto 500 g of flaked ice. Once the ice has melted, the organic phase which separates is separated off and the aqueous phase is extracted with 200 ml of cyclohexane. The combined organic phases are distilled off using a rotary evaporator after drying over magnesium sulfate and the residue is distilled in vacuo.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]2=[O:14])([CH3:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[Br:15][C:6]1[CH:7]=[C:8]2[C:12](=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1)[NH:11][C:10](=[O:13])[C:9]2=[O:14]
Reactant: CC(C)c1cccc2c1NC(=O)C2=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)c1cc(Br)cc2c1NC(=O)C2=O
Temperature: 75 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
7-isopropylindoline-2,3-dione (23.8 g, 0.12 mol) was added to a stirred solution of glacial acetic acid (700 ml). To this solution was added, via additional funnel bromine (7.8 ml, 0.15 mol) in glacial acetic acid (300 ml) during 30 min. After the addition, the combined mixture was stirred at 75° C. for 3 hr, cooled, and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, and evaporated in vacuo; air dried to give (31.8 g, 94%) of crude product. 1H NMR (300 MHz, CDCl3) δ 8.04 (b, NH), 7.59 (dd 2H), 2.84 (m, 1H), 1.31 (d, 6H); ESI (+) MS m/e=269 (MH+), ESI (−) MS m/e=267 (MH−).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].Cl[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[CH2:34])=[CH:31][CH:30]=1>O>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([CH:33]=[CH2:34])=[CH:31][CH:30]=2)=[CH:10][CH:9]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: C=Cc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(CNc2ccc(Nc3ccccc3)cc2)cc1
Yield: 82.9 %

Procedure:
36.8 g (0.2 mole) of p-aminodiphenylamine was added to 200 ml of toluene, and 16.8 g of sodium hydrogen carbonate and 30 ml of water was added. With stirring, 30.5 g (0.2 mole) of p-chloromethylstyrene was added dropwise to the mixture at 60° C. After the addition, the mixture was stirred at less than 60° C. for 4 hours. The resulting precipitate was separated, and washed with water to afford 49.8 g (yield 83%) of 4-anilino-N-(4-vinylbenzyl)aniline having a melting point of 143° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[N+:12]([O-:15])([OH:14])=[O:13].[N:16]#[C:17][NH2:18]>C(O)C.O>[N+:12]([O-:15])([OH:14])=[O:13].[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17]([NH2:18])=[NH:16])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: N#CN
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: Cc1ccc(NC(=N)N)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 61.1 %

Procedure:
4-Methyl-3-nitroaniline (90 g, 0.592 mol) was dissolved in ethanol (250 ml) and 65% aqueous nitric acid solution (59 g, 0.592 mol) was added thereto. When the exothermic reaction is stopped, cyanamide (74.6 g) dissolved in water in a concentration of 50% was added. The brown mixture was reacted under reflux for 24 hours. The reaction mixture was cooled to 0° C., filtered, and washed with diethylether to give 4-methyl-3-nitrophenyl-guanidine nitrate (93 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:31]2[CH2:32][CH2:33][CH:28]([CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([C:18]4[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=4)[CH2:26][CH2:25]3)[CH2:29][CH2:30]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: c1cc(C2CCN(CC3CCNCC3)CC2)ccn1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC(CN2CCC(c3ccncc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A solution of 4-bromophenylsulphonyl chloride (411 mg) in methylene chloride (4 ml) was added dropwise over 15 minutes to a mixture of 4-[4-(4-pyridyl)-1-piperidylmethyl]piperidine trihydrochloride (545 mg) and triethylamine (1.07 ml) in dichloromethane (10 ml) at 0° C. The solution was stirred at ambient temperature for 18 hours. The solution was diluted with dichloromethane and washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 4% methanol in dichloromethane. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-bromophenylsulphonyl)-4-[4-(4-pyridyl)-1-piperidylmethyl]piperidine (410 mg), mp 163-164° C.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[NH:20]1[CH:24]=[C:23]([C:25]([OH:29])([C:27]#[CH:28])[CH3:26])[CH:22]=[N:21]1>>[F:19][C:3]1[C:2]([C:28]#[C:27][C:25]([OH:29])([C:23]2[CH:24]=[N:20][NH:21][CH:22]=2)[CH3:26])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1cn[nH]c1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cn[nH]c1
Yield: 19 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(1H-pyrazol-4-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (46.3 mg, 19%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N:12]1[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][OH:21])[CH:15]=[N:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:21][CH2:20][CH2:19][CH2:18][C:16]1[CH:17]=[N:12][CH:13]=[N:14][CH:15]=1)(=[O:3])=[O:2]
Reactant: OCCCc1cncnc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCc2cncnc2)cc1
Yield: 104.9 %

Procedure:
9.87 g (51.7 mmol) of tosyl chloride in 50 ml of dichloromethane are added dropwise at room temperature to a solution of 6.5 g (47 mmol) of 3-(pyrimidin-5-yl)propanol and 9 ml (64.6 mmol) of triethylamine in 100 ml dichloromethane that is being stirred under nitrogen. The mixture is stirred for 16 hours at room temperature, then washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation under reduced pressure. 14.42 g of 3-(pyrimidin-5-yl)propyl tosylate are obtained, which can be processed further without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1Cl.[BH4-].[Na+].[Cl-:13].[Li+]>[CH-]1[C-]=[C-][C-]=[C-]1.[CH-]1[C-]=[C-][C-]=[C-]1.Cl[Ti]Cl>[Cl:8][C:6]1[C:5]([Cl:9])=[C:4]([Cl:13])[CH:3]=[CH:2][CH:7]=1
Reactant: Clc1cc(Cl)c(Cl)cc1Cl
Reactant: [Cl-]
Agent: Cl[Ti]Cl
Agent: [BH4-]
Agent: [Li+]
Product: Clc1cccc(Cl)c1Cl
Temperature: 96 °C
Reaction time: 4.25 h

Procedure:
A flask equipped with a magnetic stir bar and a water cooled condenser with an oil bubbler was charged with 1,2,4,5-tetrachlorobenzene (648 mg, 3.0 mmol), sodium tetrahydridoborate (1135 mg, 30.0 mmol), bis(η5 -cyclopentadienyl)titanium dichloride (75 mg, 0.3 mmol) and 1-methyl-2pyrrolidine (NMP; 30.0 ml). The reaction mixture was heated at 96° C. in an oil bath. After 4.25 hours, lithium chloride (1.09 g, 30.0 mmol) was added. Aliquots were withdrawn by syringe, quenched with water, and extracted with diethyl ether. The ether layer was analyzed with the results shown in the following table. Only trichlorobenzene was produced.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=S)[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.[Cl-].[F:26][C:27]([F:34])([F:33])[CH2:28][CH:29]([OH:32])[CH2:30][NH3+:31].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@H:9]1[CH2:15][NH:14]/[C:13](=[N:31]\[CH2:30][CH:29]([OH:32])[CH2:28][C:27]([F:34])([F:33])[F:26])/[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2c(F)cccc2F)CNC1=S
Reactant: [NH3+]CC(O)CC(F)(F)F
Agent: Cl[Hg]Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2c(F)cccc2F)CN/C1=N\CC(O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mercury(II) chloride (538 mg, 1.98 mmol) was added to a solution of tert-butyl [(3R,6S)-6-(2,6-difluorophenyl)-2-thioxoazepan-3-yl]carbamate (353 mg, 0.99 mmol), 4,4,4-trifluoro-2-hydroxybutan-1-aminium chloride (498 mg, 2.77 mmol), and triethylamine (0.61 mL, 4.36 mmol) in ethanol (10 mL) at 55° C. After 2 h, the reaction was allowed to cool to ambient temperature. The mixture was filtered and concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound. MS 466.2 (M+1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([OH:31])=O)[CH:17]=2.C(=O)=O.[CH3:35][N:36]([CH3:41])[S:37]([NH2:40])(=[O:39])=[O:38].C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([NH:40][S:37]([N:36]([CH3:41])[CH3:35])(=[O:39])=[O:38])=[O:31])[CH:17]=2
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1,1′-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer was washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74%, >90% purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.28-1.49 (m, 3 H) 1.59-2.04 (m, 7 H) 2.74-2.82 (m, 1 H) 2.88 (s, 6 H) 7.57 (dd, J=8.42, 1.46 Hz, 1 H) 7.74 (d, J=8.78 Hz, 1 H) 7.91 (s, 1 H) 11.71 (s, 1 H) 12.08 (s, 1 H).
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[CH3:18][S:15]([C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([N:28]3[CH2:29][CH2:30][CH2:31][C@H:27]3[CH2:26][N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[CH3:20])=[O:19])=[CH:9][CH:8]=2)[N:11]=1)(=[O:16])=[O:17]
Reactant: COC(=O)c1ccc(-c2csc(S(C)(=O)=O)n2)cc1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2csc(S(C)(=O)=O)n2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure N and Procedure P starting from 4-(2-Methanesulfonyl-thiazol-4-yl)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 434.12.