Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([O:36][CH2:37][O:38][CH3:39])=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2[CH:32]=O)[CH3:21].O>CN(C)C=O>[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([O:36][CH2:37][O:38][CH3:39])=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2/[CH:32]=[CH:11]/[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])[CH3:21]
Reactant: CCOP(=O)(CC(=O)N1CCCCC1)OCC
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cccc2c(/C=C/C(=O)N3CCCCC3)cc(OC)c(OCOC)c12
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
0.15 g of 60% sodium hydride was suspended in 20 ml of N,N-dimethylformamide, to which 1.15 g of N-(diethoxyphosphoryl)acetylpiperidine was gradually added at room temperature. After stirring for 10 minutes, a solution of 800 mg of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde in N,N-dimethylformamide (10 ml) was gradually added. After stirring for 20 minutes, water was added, followed by extraction with ethyl acetate. The combined extracts were washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the resultant residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to obtain 1.1 g of the titled compound as pale yellow crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]Br.[C:13]1([C:23](Cl)=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCOCC>[C:13]1([C:23]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: O=C(c1cccc2ccccc12)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a cooled solution of indole (5.85 g, 50 mmol) in ether (50 ml) under nitrogen was added slowly a solution of methylmagnesium bromide (3M) in ether (17.5 ml). After addition, the reaction mixture was warmed up to room temperature and stirred for 2 h at room temperature. Then the mixture was cooled down again to 0° C., and to it was added slowly with stirring a solution of 1-naphthoylchloride (9.5 g, 50 mmol) in ether (50 ml). The resulting mixture was warmed up to room temperature and stirred for 2 h at room temperature followed by slow addition of saturated ammonium chloride solution (375 ml). The mixture was then stirred overnight at room temperature. A white solid was formed, filtered, washed by ether and dried under high vacuum to give 3-(1-naphthoyl)-1H-Indole 1 (12.3 g, 91%).
Reaction SMILES: [N+](C1O[C:7]([C:9]2[N:13]3NC(=COCC)[C:16]([NH2:18])=[CH:17][C:12]3=NN=2)=CC=1)([O-])=O.NO.Cl.NO.[Na].[N+:29]([C:32]1[O:36][C:35]([C:37]2[N:41]3[NH:42][C:43](=[CH:47][NH:48]O)[C:44]([NH2:46])=[CH:45][C:40]3=[N:39][N:38]=2)=[CH:34][CH:33]=1)([O-:31])=[O:30]>C(O)C.O1CCOCC1>[N+:29]([C:32]1[O:36][C:35]([C:37]2[N:41]3[NH:42][C:43](=[CH:47][NH:48][C:17]4[CH:16]=[N:18][C:9]([CH3:7])=[N:13][CH:12]=4)[C:44]([NH2:46])=[CH:45][C:40]3=[N:39][N:38]=2)=[CH:34][CH:33]=1)([O-:31])=[O:30]
Reactant: CCOC=C1Nn2c(nnc2-c2ccc([N+](=O)[O-])o2)C=C1N
Reactant: NC1=Cc2nnc(-c3ccc([N+](=O)[O-])o3)n2NC1=CNO
Agent: Cl
Agent: NO
Agent: [Na]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ncc(NC=C2Nn3c(nnc3-c3ccc([N+](=O)[O-])o3)C=C2N)cn1

Procedure:
In an analogous manner, from 0.6 g. 3-(5-nitro-2-furyl)-6-(ethoxy-methylene)-amino-s-triazolo[4,3-b]pyridazine in 12 ml. anhydrous dioxan and an ethanolic solution of hydroxylamine (prepared from 0.6 g. hydroxylamine hydrochloride in 15 ml. absolute ethanol by adding 0.14 g. sodium, dissolved in 5 ml. absolute ethanol, and filtering off with suction the precipitated sodium chloride) at 50° - 60°C., there was obtained, after a reaction period of 15 minutes and cooling of the reaction mixture, 0.55 g. 3-(5-nitro-2-furyl)-6-(hydroxylaminomethylene)-amino-s-triazolo[4,3-b]pyridazine, which melted, with foaming, at 251° - 253°C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[NH:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16]1[CH2:18][CH:17]1[CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.C(Cl)Cl>CC(O)C.O>[CH2:1]([N:8]1[CH2:14][CH:13]2[N:15]([CH2:18][CH:17]([OH:16])[CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: c1ccc(CN2CC3CCC(C2)N3)cc1
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(OCC(O)CN2C3CCC2CN(Cc2ccccc2)C3)cc1
Temperature: 60 °C
Reaction time: 22 h
Yield: 88.9 %

Procedure:
A mixture of 3-benzyl-3,8-diazabicyclo[3.2.1]octane (3.46 g, 17.1 mmol; from Preparation B, step (e) above) and 4-(2-oxiranylmethoxy)benzonitrile (3.00 g, 17.1 mmol; prepared as described in international patent application WO 99/31100) in 2-propanol (70 mL) and H2O (7 mL) was stirred at 60° C. for 22 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried (NaSO4), filtered and concentrated in vacuo to give the crude product. Flash chromatography on silica gel eluting with CH2Cl2:CMA (8:1) gave 5.74 g (89%) of the sub-title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:49]([O:53][CH2:54][CH3:55])(=[O:52])[C:50]#[CH:51]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1([N:13]([CH:51]=[CH:50][C:49]([O:53][CH2:54][CH3:55])=[O:52])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CC(=O)OCC
Reactant: CC(C)(C)OC(=O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=CN(C1(C(=O)OC(C)(C)C)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a mixture of 1-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-cyclopentanecarboxylic acid tert-butyl ester (1.0 g, 2.3 mmole) in 10 mL THF and 2.3 mL (2.3 mmole) 1M tetrabutylammonium fluoride in THF was added 0.23 mL (2.3 mmole) ethyl propiolate at ambient temperature. After stirring 1 hour the reaction was complete by HPLC and was stripped to dryness in vacuo. The residue was dissolved in 20 mL ethyl acetate and washed with 2×10 mL water and the organic solution stripped to an oil. This oil was chromatographed over silica gel, eluting with 10% ethyl acetate/hexane to yield 0.95 g (77% yield) 1-{(2-ethoxycarbonyl-vinyl)-[4-(4-fluoro-phenoxy)-benzenesulfonyl]-amino}-cyclopentanecarboxylic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3) indicated a 1.5:1 trans/cis ratio.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]23[CH2:19][CH2:18][C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([CH2:16][CH2:17]2)[CH2:14][CH2:13]3)(=O)=O)=CC=1.[C-:27]#[N:28].[Na+].O>CS(C)=O>[C:20]1([C:15]23[CH2:18][CH2:19][C:12]([CH2:11][C:27]#[N:28])([CH2:17][CH2:16]2)[CH2:13][CH2:14]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(c4ccccc4)(CC2)CC3)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCC12CCC(c3ccccc3)(CC1)CC2
Temperature: 100 °C
Yield: 92 %

Procedure:
A stirred mixture of 4-phenylbicyclo[2.2.2]oct-1-ylmethyl toluene-4-sulfonate (2.5 g, 6.75 mmol) and sodium cyanide (0.5 g, 10.20 mmol) in DMSO (20 mL) was heated at 100° C. under nitrogen for 5 h. After cooling overnight the mixture was poured into water (100 mL) then extracted with DCM (2×100 mL) then methyl t-butyl ether (3×100 mL). The DCM and methyl t-butyl ether phases were separately combined, washed with water (50 mL) and dried (MgSO4). The organic phases were then combined and the solvents evaporated to give the crude product which was purified by silica column chromatography (silica 40-63 micron) eluting with hexane:ethyl acetate 19:1 to give the title compound as a white solid (1.4 g; 93%).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([OH:25])=O)[CH:20]=[CH:19][S:18]2.[NH2:28][C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[N:33]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:38]([C:37]1[CH:36]=[CH:35][C:34]([C:32]2[N:33]=[C:29]([NH:28][C:23]([C:22]3[N:21]4[C:17]([S:18][CH:19]=[CH:20]4)=[N:16][C:15]=3/[CH:14]=[CH:13]/[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=3[O:4][CH2:3][C:2]([CH3:27])([CH3:1])[CH3:26])=[O:25])[S:30][CH:31]=2)=[CH:41][CH:40]=1)#[N:39]
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)(C)C
Reactant: N#Cc1ccc(-c2csc(N)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(-c3ccc(C#N)cc3)cs2)c1OCC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 3 (130 mg, 0.336 mmol) with 4-(2-amino-1,3-thiazol-4-yl)benzonitrile (81 mg, 0.403 mmol) in the presence of EDCI hydrochloride (128 mg, 0.672 mmol) and DMAP (61 mg, 0.504 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 27 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.02 (s, 9H), 3.57 (s, 2H), 3.80 (s, 3H), 7.00 (d, J=8.4 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.40-7.50 (m, 2H), 7.84 (s, 1H), 7.91-7.96 (m, 2H), 7.98-8.05 (m, 1H), 8.10-8.15 (m, 2H), 12.79 (br s, 1H); APCI-MS (m/z) 570.17 (MH)+.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:19][C:18](=[O:20])[N:17]([CH3:21])[C:16]=2[CH:22]=1)C1C=CC=CC=1>[Pd].CO.O1CCCC1>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:19][C:18](=[O:20])[N:17]([CH3:21])[C:16]=2[CH:22]=1
Reactant: Cn1c(=O)[nH]c2ccc(OCCOCc3ccccc3)cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2ccc(OCCO)cc21
Reaction time: 2 h
Yield: 95.6 %

Procedure:
A mixture of 6-(2-benzyloxy-ethoxy)-1-methyl-1,3-dihydro-benzoimidazol-2-one (0.69 g, 2.31 mmol) and 20% palladium on carbon (0.10 g) in methanol (10 ml) and tetrahydrofuran (10 ml) was stirred under a hydrogen atmosphere (1 atm) for 2 h. After removal of the catalyst, the catalyst was washed with boiling methanol (50 ml). The filtrate was evaporated to give 6-(2-hydroxy-ethoxy)-1-methyl-1,3-dihydro-benzoimidazol-2-one (0.46 g, 96%) as a solid. 1H NMR (DMSO) 10.54 (1H, s), 6.78 (1H, d, J=8.3), 6.70 (H, d, J=632.2), 6.50 (1H, dd, J=8.3, 2.4), 4.79 (1H, t, J=5.6), 3.90 (2H, t, J=5.0), 3.64 (2H, q, J=5.2), 3.18 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]([CH2:16][C:17]3[C:18]([NH2:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=3)[C:6]=2[CH:7]=1.[H-].[Na+].[NH:27]([C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][CH:32]=1)[C:28]([CH3:30])=[O:29]>C(O)=O>[NH2:23][C:20]1[N:19]=[C:18]([NH2:24])[C:17]([CH2:16][C:8]2[C:6]3[CH:7]=[C:3]([CH2:2][S:37][C:34]4[CH:33]=[CH:32][C:31]([NH:27][C:28](=[O:29])[CH3:30])=[CH:36][CH:35]=4)[O:4][C:5]=3[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:22][N:21]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: COc1cc(Cc2cnc(N)nc2N)c2cc(CCl)oc2c1OC
Agent: [H-]
Agent: [Na+]
Solvent: O=CO
Product: COc1cc(Cc2cnc(N)nc2N)c2cc(CSc3ccc(NC(C)=O)cc3)oc2c1OC

Procedure:
formic acid salt (20 mg) was obtained by reacting 5-(2-chloromethyl-6,7-dimethoxy-benzofuran-4-ylmethyl)-pyrimidine-2,4-diamine (52 mg, 0.151 mmol), NaH (12 mg, 0.303 mmol), and 4-acetaminothiophenol (56 mg, 0.303 mmol).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]=2[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=2)=[O:22])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][S:2]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[C:27]=2[CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=2)=[O:22])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: COc1cccc(CCc2c(CCNC(=O)CCCCC(=O)NCCc3ccc(N)cc3)ccc(OC)c2OC)c1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc(CCc2c(CCNC(=O)CCCCC(=O)NCCc3ccc(NS(C)(=O)=O)cc3)ccc(OC)c2OC)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methanesulphonylchloride (0.41 ml) was added to a stirred solution of the Intermediate (a) (2.74 g) and triethylamine (0.74 ml) in dry dimethylformamide. The solution was stirred at room temperature for 10 hours.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1([CH3:21])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[N:8]1.CI>CCCCCC.O1CCCC1>[CH3:6][C:7]1([CH3:21])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][C:13]=2[CH3:1])=[N:8]1
Reactant: CC(C)c1ccc(C2=NC(C)(C)CO2)cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: Cc1cc(C(C)C)ccc1C1=NC(C)(C)CO1
Reaction time: 2 h

Procedure:
n-Butyllithium (52.8 ml of a 2.5M solution in hexane) was added dropwise to a stirred solution of the product of step (i) (27.6 g) in tetrahydrofuran (100 ml) at -20° C. After 2 hours methyl iodide (85.3 g) was added and the mixture was stirred for 2 hours at this temperature then 0.5 hours at room temperature. The reaction mixture was partitioned between brine and ethyl acetate. The aqueous solution was extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 5% ethyl acetate in isohexane. Used directly in the next step.
Reaction SMILES: ClC(OCC)=O.[C:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.O.[BH4-].[Na+]>O1CCCC1>[C:7]([C:11]1[CH:19]=[CH:18][C:14]([CH2:15][OH:16])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1ccc(CO)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 93.1 %

Procedure:
10 ml of a tetrahydrofuran solution containing 3.12 g (28.8 mol) of ethyl chloroformate were added dropwise over a period of 10 minutes to 60 ml of a tetrahydrofuran solution containing 6.0 g (26.9 mmol) of 4-t-butyl-3-nitrobenzoic acid and 3.12 g (30.9 mmol) of triethylamine, whilst ice-cooling. The reaction solution was stirred for 45 minutes at this temperature, after which it was filtered using a Celite filter aid. The precipitate was washed with tetrahydrofuran, and the filtrate and the washings were combined. The combined solution was then added dropwise to a mixed solution which was composed of 40 ml of tetrahydrofuran and 40 ml of water containing 3.76 g (9.95 mmol) of sodium borohydride, over a period of 25 minutes, on an ice bath. The reaction mixture was then stirred for 2 hours at the temperature of the ice bath, after which it was condensed by evaporation under reduced pressure. As much as possible of the tetrahydrofuran was then removed by distillation under reduced pressure, and the residue was distributed between diethyl ether and water. The product was extracted from the aqueous layer with diethyl ether. The organic layers were combined and washed twice with water and then once with a saturated aqueous solution of sodium chloride. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 100 g of silica gel. Elution with mixtures of ethyl acetate and hexane ranging from 20:80 to 30:70 by volume afforded 5.24 g (yield 93%) of the title compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].C([NH+](CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]3[NH:33][N:32]=[N:31][N:22]=3)=[CH:18][CH:19]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=S(=O)(NCCc1ccc(Cc2nnn[nH]2)cc1)c1ccc(Cl)cc1

Procedure:
4.62 g. (13.8 mMol) 4-[2-(4-chlorobenzenesulphonamido)-ethyl]-phenylacetonitrile, 2.94 g. (21.3 mMol) triethylammonium chloride and 2.77 g. (42.6 mMol) sodium azide in 150 ml. 1-methylpyrrolidone are heated to 150° C. for 6 hours. The 1-methylpyrrolidone is subsequently distilled off in a high vacuum at 80° to 90° C., the residue is dissolved in dilute aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The aqueous phase is acidified with hydrochloric acid, also extracted three times with ethyl acetate, the extracts are dried over anhydrous sodium sulphate and, after treating with active charcoal, evaporated to dryness. The residue is taken up in an aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate and acidified, the product thereby crystallising out. There is obtained 1.5 g. (29% of theory) of the title compound in the form of colourless crystals; m.p. 168°-169° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH:14]4[CH2:15][CH2:16][O:17][C:5]34[C:4]=2[CH:3]=1.[H-].[Na+].[C:20]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CO>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:7](=[O:12])[CH:6]3[CH2:13][CH:14]4[CH2:15][CH2:16][O:17][C:5]34[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2C23OCCC2CC13
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCN1C(=O)C2CC3CCOC32c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 9-chloro-3,3a,4,4a-tetrahydro-2H-furo[2′,3′:2,3]cyclobuta[1,2-c]quinolin-5(6H)-one (200 mg, 0.801 mmol) in dimethylformamide (4 ml) at 0° C. was slowly added sodium hydride (19 mg, 0.801 mmol) over 15 minutes. The suspension was allowed to warm to room temperature. The mixture stirred for 45 minutes and 4-(Boc-amino)butyl bromide (202 mg, 0.801 mmol) was added. The solution was stirred for 15 hours, followed by addition of 0.25 mL methanol. Column chromatography provided the title compound.
Reaction SMILES: I[C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:20][C:21]3[C:26]([C:27]=2[CH:28]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:2]3[C:7]4[S:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:6]=4[CH:5]=[CH:4][CH:3]=3)[C:21]3[C:26]([C:27]=2[CH:28]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3
Reactant: Ic1cccc2c1sc1ccccc12
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Temperature: 160 °C
Yield: 57.9 %

Procedure:
A mixture of 10.9 g (35.1 mmol) 4-iododibenzo[b,d]thiophene, 8.6 g (35.1 mmol) of 3-bromo-9H-carbazole, 4.46 g (70.2 mmol) of Cu, 14.55 g (100.1 mmole) of K2CO3 was stirred in 100 ml dimethylformamide, the reaction mixture was then heat to 160° C. for about overnight under nitrogen. Then cooled to 100° C., the solution was filtered. To receive the filtrate, and most of the dimethylformamide was removed under reduced pressure from the filtrate. The distillation was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica(hexane-dichloromethane) to give product 8.7 g (58%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C@H:10]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=2)[O:2]1.[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:22]=1[NH2:23].C(N(CC)CC)C>C(Cl)Cl>[F:20][C:21]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:22]=1[NH:23][C:12](=[O:14])[CH2:11][C@H:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCC[C@H](CC(=O)O)c1cccc2c1OCO2
Reactant: Nc1c(F)cc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC[C@H](CC(=O)Nc1c(F)cc(F)cc1F)c1cccc2c1OCO2
Reaction time: 8 h
Yield: 86.8 %

Procedure:
In the same manner as in Example 1, 0.86 g (3.25 mmol) of (R)-3-(2, 3-methylenedioxyphenyl) octanoic acid was converted into its acid chloride. This acid chloride was dissolved in 5 ml of methylene chloride and added dropwise to a solution of 571 mg (3.88 mmol) of 2, 4, 6-trifluoroaniline and 0.54 ml (3.9 mmol) of triethylamine in 15 ml of methylene chloride. The reaction mixture was stirred overnight, washed with water, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/5) and recrystallized from a mixed solvent of hexane and a trace of ethyl acetate to give 1.11 g of (R)-N-(2, 4, 6-trifluorophenyl)-3-(2, 3-methylenedioxyphenyl) octanamide as white crystals. Yield, 87%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:35])[C:16]=2[N:17]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OCC3C=CC=CC=3)[CH2:19][CH2:18]2)=[O:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.C1CC=CCC=1>[Pd].C(O)C>[NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:35])[C:16]=2[N:17]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19][CH2:18]2)=[O:10])=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Cn1ncc(NC(=O)c2nc(Cl)ncc2N)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: Cn1ncc(NC(=O)c2ncncc2N)c1N1CCC[C@@H](N)CC1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
In a 40 mL sealed vial was added (R)-benzyl 1-(4-(5-amino-2-chloropyrimidine-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate (140 mg, 0.28 mmol), 1,4-cyclohexadiene (0.16 mL, 1.68 mmol) and ethanol (12 mL). 10% Pd/C (30 mg, 0.028 mmol) was added and the reaction vial was vacuum purged with nitrogen three times. The reaction mixture was then stirred at 95° C. under nitrogen for 2 h. LCMS indicated de-chlorinated product as the malor product. After cooling down to room temperature, the reaction mixture was filtered through Celite and rinsed thoroughly with methanol. The solvent was distilled off under reduced pressure to give the crude product which was purified via reverse phase HPLC to afford 326. 1H NMR (400 MHz, DMSO) δ 8.48 (s, 1H), 8.46 (s, 1H), 7.51 (s, 1H), 6.88 (s, 3H), 3.65 (s, 4H), 3.19-2.89 (m, 9H), 1.93-1.69 (m, 4H), 1.69-1.41 (m, 4H). MS (ESI) m/z: 331.2 [M+H+].