Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1>CCO.C(Cl)(Cl)Cl.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(/C=C/C#N)c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1cccc(CCCN)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A mixture of trans-3-(3-Methoxyphenyl)-2-propenenitrile (27.6 g, 173 mmol) and PtO2 (2.76 g) in 200 mL of EtOH and 30 mL of CHCl3 was shaken in a Parr apparatus under an atmosphere of 50-60 psi H2 overnight at RT. The reaction mixture was filtered through Celite and concentrated in vacuo to provide a brown solid which was then partitioned between CH2Cl2 and 1N NaOH. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (3×100 mL). The combined organic layers were then dried over MgSO4, filtered and concentrated in vacuo to provide 24.2 g of the desired product as a yellow oil (85% yield). 1H NMR (CDCl3) δ 7.15-7.22 (m, 1H), 6.70-6.80 (m, 3H), 3.80 (s, 3H), 2.72 (t, J=6.0 Hz, 2H), 2.58-2.65 (m, 2H), 1.70-1.85 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:25]1[O:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][O:5][C:25]1[O:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(Cl)o1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 59.8 g (0.2 mole) of 3,7,11,15-tetramethyl-1-hexadecanol and 19.2 g (0.4 mole) of sodium hydride (50% in oil) in 1 liter of toluene is refluxed with stirring for 2 hours then cooled to room temperature. To the mixture 29.3 g (0.2 mole) of 5-chloro-2-furoic acid is added and the mixture is refluxed with stirring for 24 hours. Upon cooling to room temperature the mixture is acidified with glacialacetic acid and water is added. The toluene layer is evaporated and allowed to crystallize to give 5-(3,7,11,15-tetramethylhexadecyloxy)-2-furoic acid.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)[C:8](Cl)=[O:9].[NH2:13][C:14]1[N:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=2)=[CH:16][CH:15]=1.O>ClCCCl.C1COCC1>[C:28]([NH:27][C:23]1[CH:22]=[C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:8]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[O:9])=[N:19][CH:18]=2)[CH:26]=[CH:25][N:24]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Reactant: CC(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCCl
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)C)nc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
A solution of isobutyramide (0.071 g, 0.819 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.104 g, 0.819 mmol), stirred at RT for 1 h, then heated at 75° C. for 1 h. The mixture was cooled to RT, treated with a solution of Example A2 (0.1 g, 0.409 mmol) and TEA (0.124 g, 1.228 mmol) in THF (3 mL) and stirred at RT for 1 h. The mixture was treated with water, extracted with 10% MeOH/DCM (1×), then DCM (1×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was treated with EtOAc, sonicated and the resulting solid collected via filtration. The solid was re-suspended in EtOAc, sonicated and again collected via filtration and dried to afford N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide (45 mg, 31%). 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.85 (s, 1H), 10.56 (s, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.18 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 6.68 (dd, J=5.7, 2.4 Hz, 1H), 2.68-2.66 (m, 1H), 2.03 (s, 3H), 1.09 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 358.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[N:18](C=O)CCOC3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:3]=1.B.[CH2:26]1[CH2:30][O:29][CH2:28][CH2:27]1>>[C:21]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][N:18]3[CH2:26][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:11][CH:12]=2)[N:5]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: C1CCOC1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C3COCCN3C=O)cc2)n1
Agent: B
Product: CC(C)(C)c1cc(N)n(-c2ccc(CN3CCOCC3)cc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 490 mg 5-[4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenyl]-morpholin-4-yl-methanone (1.49 mmol) in 13 mL THF, 3 mL (2.98 mmol) of borane (1M solution in THF) are added at rt. The reaction is stirred at rt for 12 h, concentrated, taken up in MeOH and concentrated again (3×). The residual crude product is purified by flash chromatography (SiO2, CH2Cl2/MeOH, gradient 0-5% MeOH) to give the title compound as a yellow solid. 1H-NMR (CDCl3): 7.50 (d, J=7.2 Hz, 2H), 7.40 (d, J=7.2 Hz, 2H), 5.52 (s, 1H), 3.73-3.70 (m, 5H), 3.51 (s, 2H), 2.47-2.44 (m, 3H), 1.32 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Reactant: COc1ccc(C(=O)Cl)cc1
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(OC)cc4)c3)csc12

Procedure:
3-[3-(4-Methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) and p-anisoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[CH:4]=[C:3]1[C:10]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:11].[CH3:21][N:22]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23]1[C:30](Cl)=[O:31]>CO.C(Cl)Cl.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:30]([C:23]2[N:22]([CH3:21])[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=2)=[O:31])[CH:4]=[C:3]1[C:10]([NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:11]
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)NCCN1CCOCC1
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)Cl
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)NCCN1CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-Methyl-N-[2-(4-morpholinyl)ethyl]-4-nitro-1H-pyrrole-2-carboxamide (1.42 g, 3.41 mmol; see step (iii) above) was dissolved in methanol (10 mL) and cooled to 0° C., Pd/C (0.055 g) was then added in small portions and the solution stirred under H2 for 3 h. The solution was then filtered and the solvent removed under reduced pressure. A solution of 1-methyl-4-nitro-1H-pyrrole-2-carbonyl chloride (0.642 g, 3.42 mmol) in DCM (10 mL) was added and the mixture allowed to stir for 1 h at RT. The solvent was then removed under reduced pressure and the crude product was separated on basified silica using a 1:1 solution of methanol ethyl acetate to yield the sub-title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:20])([CH3:19])[C:7](=[O:18])[CH:8](Br)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=[O:3])[CH3:2].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.C(=O)([O-])[O-].[K+].[K+].O.O.O.O.O.O.O.O.[C:40]1([S:54]([OH:57])(=[O:56])=[O:55])[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([S:50]([OH:53])(=[O:52])=[O:51])[C:44]=2[CH:43]=[CH:42][CH:41]=1>CC(C)=O>[C:40]1([S:54]([OH:57])(=[O:56])=[O:55])[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([S:50]([OH:53])(=[O:52])=[O:51])[C:44]=2[CH:43]=[CH:42][CH:41]=1.[C:1]([O:4][CH2:5][C:6]([CH3:20])([CH3:19])[C:7](=[O:18])[CH:8]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Yield: 70.3 %

Procedure:
A solution of 36.3 g (0.2 mol) of crude 4-acetoxy-1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-one in 50 ml of acetone was added dropwise, at the boil, to a suspension of 21 g (0.3 mol) of 1,2,4-triazole and 30g (0.2 mol) of potassium carbonate in 200 ml of acetone. After heating for 15 hours under reflux, the mixture was filtered and the filtrate was concentrated by distilling off the solvent in vacuo. The residue was taken up in 200 ml of methylene chloride and the solution was washed three times with 50 ml of water at a time, dried over sodium sulphate and concentrated. The residue was dissolved in 100 ml of acetone and 36 g (0.1 mol) of 1,5-naphthalenedisulphonic acid octahydrate in 100 ml of acetone were added. The crystalline precipitate which resulted was filtered off and dried. 45 g (45% of theory) of 4-acetoxy-1-(4-chloro-phenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one 1,5-naphthalenedisulphonate of melting point 155°-160° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[O:17][CH:16]([CH3:19])[C:15](=[O:20])[NH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].Br[CH:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[O:17][CH:16]([CH3:19])[C:15](=[O:20])[N:14]([CH:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(-c2cccc3c2OC(C)C(=O)N3)c(C)c1
Reactant: CCCC(Br)CCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCC)N1C(=O)C(C)Oc2c(-c3ccc(C)cc3C)cccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a solution of 8-(2,4-dimethylphenyl)-2-methyl-2H-1,4-benzoxazin-3(4H)-one (300 mg, 1.12 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydride (43 mg, 1.68 mmol). After the mixture was stirred at 80° C. for 30 min, 4-bromoheptane (804 mg, 4.49 mmol) was added. The mixture was stirred at 80° C. for 18 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 5% ethyl acetate/n-hexane to afford 186 mg (30%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][N:27]2[CH2:33][CH:32]3[O:34][CH:29]([CH2:30][CH2:31]3)[CH2:28]2)=[CH:8][CH:7]=1)([OH:5])[CH3:4].FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@H]2CN2CC3OC(CC3)C2)=CC=1)(O)C.FC(F)(F)[C@](C1C=CC(N2CCN(S(C3SC=CC=3)(=O)=O)C[C@@H]2CN2CC3OC(CC3)C2)=CC=1)(O)C.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:36][C:2]([F:1])([F:35])[C@@:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:20])[CH2:14][C@H:13]2[CH2:26][N:27]2[CH2:33][CH:32]3[O:34][CH:29]([CH2:30][CH2:31]3)[CH2:28]2)=[CH:10][CH:11]=1)([OH:5])[CH3:4]
Reactant: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CC3CCC(C2)O3)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CC3CCC(C2)O3)cc1)C(F)(F)F
Agent: C[C@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2CC3CCC(C2)O3)cc1)C(F)(F)F
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: C[C@@](O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@H]2CN2CC3CCC(C2)O3)cc1)C(F)(F)F

Procedure:
(2R)-1,1,1-trifluoro-2-(4-((2S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2R)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol; (2S)-1,1,1-trifluoro-2-(4-((2S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylmethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.91-7.89 (m, 1H), 7.68-7.66 (m, 1H), 7.47-7.45 (d, J=8.8 Hz, 2H), 7.29-7.17 (m, 1H), 6.93-6.90 (d, J=8.8 Hz, 2H), 4.26-4.20 (m, 2H), 4.11-4.04 (m, 2H), 3.81-3.76 (m, 1H), 3.50-3.45 (m, 1H), 3.26-3.20 (m, 1H), 2.75-2.55 (m, 5H), 2.42-2.39 (m, 1H), 2.28-2.19 (m, 2H), 1.93-1.74 (m, 4H), 1.70 (s, 3H). m/z (ESI, +ve ion) 546.6 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.154 μM; GK-GKRP EC50 (LC MS/MS)=0.178 μM.
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>>[Cl:38][CH2:2][NH:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(CCC(=O)OCc1ccccc1)NCO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(CCC(=O)OCc1ccccc1)NCCl

Procedure:
A solution of 24.2 g. (0.10 mole) of benzyl N-hydroxymethylsuccinamate and 28.9 g. (0.11 mole) of triphenylphosphine in 500 ml. carbon tetrachloride is stirred at reflux for 12 hours. After filtering and washing the precipitate with benzene, the organic solvents are removed at 15-20 mm. and 30°-40° C. to give benzyl N-chloromethylsuccinamate of sufficient purity for use in the next step.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11].[CH3:12][Sn](C)(C)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:12][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:11]
Reactant: C[Sn](C)(C)C
Reactant: Nc1ccc2nc[nH]c2c1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1c(N)ccc2nc[nH]c12
Temperature: 145 °C
Reaction time: 12 h
Yield: 98.8 %

Procedure:
A solution of 4-bromo-5-aminobenzimidazole (180 mg, 0.84 mmol), tetramethyltin (330 mg, 2.4 mmol) and bis(triphenylphosphine)palladium (II) chloride (20 mg) in 5 ml of anhydrous DMF was placed in sealed tube and stirred for 12 h at 145° C. The reaction mixture was concentrated in vacuo, yielding an oily residue which was subjected to column chromatographic separation (NH3 sat'd 10% MeOH/EtOAc) to yield 140 mg (0.83 mmol, >95%) of 4-methyl-5-aminobenzimidazole.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[CH2:22]2.N1CCCCC1>CCO>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:1][C:3]1[O:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([NH2:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: NS(=O)(=O)c1ccc(-c2ccc(C=O)o2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NS(=O)(=O)c1ccc(-c2ccc(C=C3C(=O)Nc4ccc(Cl)cc43)o2)cc1
Temperature: 70 °C

Procedure:
To 4-(5-formylfuran-2-yl)benzenesulfonamide (30 mg, 0.120 mmol) in EtOH was added 5-chlorooxindole (20 mg, 0.120 mmol) and piperidine (12 μL, 0.120 mmol). The mixture was stirred at 70° C. for several hours. The solid formed was isolated by filtration and air dried to yield 4-(5-((5-chloro-2-oxoindolin-3-ylidene)methyl)furan-2-yl)benzenesulfonamide. LC-MS (M+1=401).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Br[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1.OO.C([O-])([O-])=[O:49].[K+].[K+]>>[CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]([NH2:4])=[O:49]
Reactant: Cn1ccc(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)C(N)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 4-bromo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 6 Step 1, followed by treatment with H2O2, K2CO3. LC-MS Method 2 tR=1.133 min, m/z=488.1; 1H NMR (CDCl3) 1.12 (s, 3H), 1.19 (s, 3H), 1.49 (d, 3H), 2.09-2.28 (m, 3H), 2.32-2.58 (m, 2H), 2.89 (m, 1H), 3.59 (s, 3H), 5.61 (m, 1H), 6.54 (m, 1H), 6.88 (m, 1H), 6.97-7.10 (m, 2H), 7.28 (m, 6H), 7.42 (m, 1H), 7.53 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22](Cl)(=[O:24])[CH3:23].C(N(CC)CC)C>ClCCl>[C:22]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
A mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.5 g, 1.66 mmol), acetyl chloride (0.118 ml, 1.67 mmol), triethylamine (1.2 ml, 8.61 mmol), and dichloromethane (50 ml) was stirred for three hours at room temperature. The reaction mixture was washed with 50 ml water. The organic extract was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO2, 5% EtOAc in dichloromethane) to afford the product as a purple solid (0.327 g, 57%). M.p.=252-255° C.; 400 MHz 1H NMR (CDCl3) δ: 8.09-8.06 (m, 1H), 7.75-7.72 (m, 1H), 7.69-7.64 (m, 1H), 7.54-7.48 (m, 1H), 4.59-4.52 (m, 1H), 3.82-3.68 (m, 1H), 3.55-3.46 (m, 1H), 3.22-3.12 (m, 1H), 3.0-2.91 (m, 2H), 2.26-2.18 (m, 2H), 2.18 (s, 3H), 1.82-1.72 (m, 2H); LCMS: 344 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CC1CCC(CCN)CC1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CCC(CCNS(=O)(=O)c2ccc(C#N)cc2)CC1
Yield: 95 %

Procedure:
by the reaction of 4-cyanobenzenesulphonyl chloride with ethyl 4-(2-aminoethyl)-cyclohexylacetate hydrochloride in methylene chloride in the presence of triethylamine. Yield 95% of theory, colourless oil.
Reaction SMILES: CN(C)C=O.[OH:6][CH:7]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=1)[CH:8]([O:11][CH3:12])[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(OCC)(=O)C>[OH:6][CH:7]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:15]([CH3:21])[CH:14]=1)[CH:8]([O:9][CH3:10])[O:11][CH3:12]
Reactant: COC(OC)C(O)c1cc(C)c(O)cc1C
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(C)c(C(O)C(OC)OC)cc1C
Yield: 77.1 %

Procedure:
To N,N-dimethylformamide (81 g) were added 4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol (20.0 g), potassium carbonate (15.8 g) and ethyl chloroacetate (12.4 g) at room temperature with stirring. The mixture was stirred at room temperature for an hour, and then stirred at 71° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and a mixture of ethyl acetate and hexane was added to the residue. The precipitated crystals were collected by filtration to give ethyl 2-[4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (21.3 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH2:13][C:14](Cl)=[N:15][OH:16])[CH:10]=[CH:11][CH:12]=1.O1CCCC1.[C:23]([C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=1)#[CH:24].C(N(CC)CC)C>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH2:13][C:14]1[CH:24]=[C:23]([C:25]2[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[CH:29][CH:30]=2)[O:16][N:15]=1
Reactant: ON=C(Cl)Cc1cccc(-c2ccccn2)c1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3cccc(-c4ccccn4)c3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (3-(pyridin-2-yl)-phenyl)-acetohydroximoyl chloride (50 mg) described in Manufacturing Example 84-1-3 and tetrahydrofuran (2 mL) were added 3-ethynyl-pyridin-2,6-diamine (6.0 mg, 0.045 mmol) described in Manufacturing Example 13-1-3 and triethylamine (38 μL, 0.27 mmol), which was stirred for 2 hours at room temperature. Water was added to the reaction mixture at the same temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound in a crude product. Then, the residue was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (3.7 mg, 14%) as a ditrifluoroacetic acid salt.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][C:6](=O)[CH2:5]1)[C:2]#[CH:3].[CH2:10](Br)C#C.[K].[NH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].C=O.C(NCC)C>>[CH2:5]([N:4]([CH2:8][CH3:7])[CH2:1][C:2]#[C:3][CH2:10][N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20])[CH3:6]
Reactant: O=C1CCCN1
Reactant: C#CCBr
Reactant: C#CCN1CCC(=O)C1
Agent: C=O
Agent: [K]
Solvent: CCNCC
Product: CCN(CC)CC#CCN1CCCC1=O

Procedure:
1-(2-propynyl)-3-pyrrolidinone, prepared from propargyl bromide and the potassium salt of pyrrolidinone, is reacted with paraformaldehyde and diethylamine using cuprous chloride as catalyst to give 1-[4-(diethylamino)-2-butynyl]-2-pyrrolidinone. This compound is reacted with cyanogen bromide to give 1-(4-bromo-2-propynyl)-2-pyrrolidinone (BPP) which is then reacted with excess imidazole to give 1-[4-(1H-imidazol-1-yl)-2-butynyl]-2-pyrrolidinone (Compound 1, shown in Table 1). It was essential to avoid the use of strong bases in this reaction, because when BPP is reacted with the potassium salt of imidazole the allene is yielded as the major product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[CH:5][CH:4]=1)#[N:2].[Cl:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:15][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:10]([CH3:14])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nccn1-c1ccc(C#N)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ncc(Cl)n1-c1ccc(C#N)cc1

Procedure:
A solution of 1-(4-cyanophenyl)-2-methylimidazole (3 g, 16.4 mmol) and N-chlorosuccinimide (2.18 g, 16.3 mmol) in chloroform (180 ml) was heated at reflux for 4 hours, then washed with water, dried over magnesium sulphate and evaporated to a yellow solid. Trituration with ether left a pale-yellow solid (2.38 g, 67%).