Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:20][CH2:19][CH2:18][C:17]([C:21]([O:23]CC)=[O:22])=[CH:16][C:15]=3[CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:20][CH2:19][CH2:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][C:15]=3[CH:26]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1=Cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reaction time: 64 h
Yield: 85.4 %

Procedure:
To a solution of ethyl 7—(4-tert-butylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (503.8 mg) in ethanol (10 ml)was added 1N sodium hydroxide (2.0m) at room temperature, and the mixture was stirred for 64 hours and concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (15 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with. magnesium sulfate and concentrated. The resulting crystal was collected by filtration to give 7—(4-tert-butyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (396 mg) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:28])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20]C(OC(C)(C)C)=O)[CH:15]=1.I[Si](C)(C)C>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:28])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(NC(=O)OC(C)(C)C)c2)c(=O)n1C
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(N)c2)c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.9 %

Procedure:
To a solution of 2.00 g of 4-hydroxy-3-[3-[3-(tert-butoxycarbonylamino)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 200 ml of chloroform was added 2.96 g of iodotrimethylsilane at room temperature, and this was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was washed with 60 ml of chloroform to obtain 1.64 g of 4-hydroxy-3-[3-(3-aminophenyl)-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone as a yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[O:40](C(OC(C)(C)C)=O)[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=O.Cl>C1COCC1.C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][N:14]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:40])[C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:25])([F:24])[F:26])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (85 mg, 0.16 mmol) in THF (10 mL) was added BOC2O (4 g, 18.6 mmol) in THF (10 mL), and the reaction mixture was stirred at RT for 16 h. Then the reaction was diluted with CH2Cl2, cooled to 0° C., and the pH adjusted to 2 with 2 N HCl. The reaction mixture was then extracted CH2Cl2 and concentrated in vacuo to provide (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as an off-white solid that was used directly without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>C(Cl)(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:8]2[N:7]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[C@@H:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCCl)CC[C@H]2c2ccc(F)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCn3ccnc3)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=442.3 (M+H+) and [α]D20=−64.3° (c=0.2673 in chloroform), was prepared in accordance with the general method of example 82b from (2S,5S)-2-(4-chloro-butyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-imidazole.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[C:20]([O:31][CH3:32])[N:19]=[C:18]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[N:17]=1>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:20]([O:31][CH3:32])[N:19]=[C:18]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:17]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(N)nc(-c2ncccn2)nc1OC
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OC
Reaction time: 36 h
Yield: 3.1 %

Procedure:
4-tert-Butyl-benzene sulphonyl chloride (286 mg) was added to a stirred solution of 4-amino-6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine (EP 713875A1) (100 mg) in dry pyridine (2 ml) at room temperature and the resulting mixture stirred for 36 hours. The reaction was then partitioned between ethyl acetate (20 ml) and 2N aqueous hydrochloric acid (10 ml) and the organic phase separated, washed (2N aqueous hydrochloric acid 2×10 ml, water 2×10 ml), dried (MgSO4) and evaporated under reduced pressure. Column chromatography on silica eluting with a solvent gradient of pentane:ethyl acetate 25:75 changing to 0:100, then dichloromethane:methanol 95:5 gave 4-tert-butyl-N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzenesulfonamide as an off-white coloured solid (5 mg).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([F:15])([F:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)C.[OH-].[Na+]>C(O)C.C(Cl)Cl>[F:14][C:7]([F:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCC(F)(F)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: OCCC(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of Intermediate 76 (0.30 g, 1.40 mol) in ethanol (4 mL) was added a solution of 35% sodium hydroxide (1 mL). The mixture was stirred at room temperature for 2 hours. The crude reaction was diluted with methylene chloride (50 mL), washed with water (1×30 ML) and 1N hydrochloric acid (2×30 mL), dried (Na2SO4), and the solvent removed under reduced pressure. The title compound was obtained (0.22 g, 89%) as orange oil, and was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[C:8]([CH3:43])=[N:7]1.C(N(CC)CC)C.[C:54](Cl)(=[O:56])[CH3:55]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([C:54](=[O:56])[CH3:55])[CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:34])=[O:35])[CH:13]=2)[C:8]([CH3:43])=[N:7]1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3c(C)nn(Cc5cccc(F)c5)c3C)cn4S(=O)(=O)c3ccc(C)cc3)cc2)CC1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A stirred solution of 3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.157 mmol), triethylamine (47.8 mg, 0.473 mmol), DCM (3 ml) was added acetyl chloride (18.5 mg, 0.236 mmol) drop wise at 0° C. Reaction mass was gradually warmed to room temperature, reaction completed in an hour. Reaction mass was diluted with DCM and washed with water, dried over sodium sulfate and concentrated to give 98 mg (92.4% yield) of the titled compound. MS: m/z=677.2 (M+1).
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:35][CH:34](O)[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=2)[O:27]1>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=2)[O:27]1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccccc1Cl)O2
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1ccc2c(c1)CCC(c1ccccc1Cl)O2

Procedure:
2-(2-Chlorophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 500 mg of 2-(2-chlorophenyl)-chroman-4,6-diol. 1H NMR (300 MHz, d6-DMSO) δ: 7.58-7.36 (m, 4H), 6.66 (m, 1H), 6.55-6.51 (m, 2H), 5.23 (dd, 1H, J 10.1, 2.1 Hz), 2.92 (m, 1H), 2.68 (m, 1H), 2.17 (m, 1H), 1.87 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].ClC(F)C(N(CC)CC)(F)[F:36]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([OH:20])=[O:19])=[C:14]([F:36])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: CCN(CC)C(F)(F)C(F)Cl
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(F)CS[C@H]12

Procedure:
To a solution of 325 mg. (0.7 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 10 ml. of methylene chloride was slowly added an equivalent amount of N-(2-chloro-1,1,2-trifluoroethyl) diethylamine. The reaction mixture was heated for 30 minutes under gentle reflux and was then evaporated to dryness in vacuo. The residue was dissolved in a mixture of ethyl acetate-water and the organic layer was separated. The organic layer was washed with 5% hydrochloric acid, water and brine and was then dried. The dried reaction product solution was concentrated to a small volume and n-hexane was added to precipitate, p-Nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-fluoro-3-cephem-4-carboxylate.
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][C:11](=[O:13])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>CN(C=O)C.[Cl-].[NH4+]>[CH2:1]([C:8]1[NH:9][N:10]=[C:11]([O:13][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(Cc2ccccc2)=NN1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(Cc4ccccc4)[nH]n3)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
3-Benzyl-4,5-dihydro-1H-pyrazol-5-one (174 mg, 1 mmol), (J. Chem. Soc. Perk. Trans 1, 1980, 1618-1621), was added to a suspension of sodium hydride (40 mg, 1 mmol, prewashed with pentane) in DMF (3 ml) under nitrogen. After stirring for 30 minutes at ambient temperature, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (135 mg, 0.4 mmol) was added and the mixture was heated at 80° C for 1 hour. After cooling, the mixture was diluted with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The precipitate was collected by filtration, washed with water, followed by ethanol, ether and dried under vacuum to give 4-(5-benzylpyrazol-3-yloxy)-6-methoxy-7-(3-morpholinopropoxy)quinazoline (150 mg, 79%).
Reaction SMILES: CN[C@H]1[C@H](NC)CCCC1.[CH2:11]=[C:12]1[C:21]2[C:22](=[O:26])[NH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]2[CH:17]=[CH:16][C:15]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:14][C:13]1=2.I[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CS(C)=O>[CH2:11]=[C:12]1[C:21]2[C:22](=[O:26])[N:23]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[CH:24]=[CH:25][C:20]=2[O:19][C:18]2[CH:17]=[CH:16][C:15]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:14][C:13]1=2
Reactant: Cc1ccc(I)cc1
Reactant: C=C1c2cc(-c3cccnc3)ccc2Oc2cc[nH]c(=O)c21
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: C=C1c2cc(-c3cccnc3)ccc2Oc2ccn(-c3ccc(C)cc3)c(=O)c21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A resealable tube was charged with (1R,2R)-diaminomethylcyclohexane (9.77 mg, 0.069 mmol), copper(I) iodide (8.72 mg, 0.046 mmol), 10-methylene-8-(pyridin-3-yl)-2,10-dihydro-1H-chromeno[3,2-c]pyridin-1-one (0.066 g, 0.229 mmol), 4-iodotoluene (0.055 g, 0.252 mmol), potassium carbonate (0.063 g, 0.458 mmol), and DMSO (2.5 mL). The system was purged with argon and the tube was sealed. The mixture stirred in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 100° C. for 2 h. The reaction mixture was diluted with dichloromethane and filtered through a pad of celite. The filtrate was concentrated and partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 10-methylene-8-(pyridin-3-yl)-2-p-tolyl-2,10-dihydro-1H-chromeno[3,2-c]pyridin-1-one. MS m/z=379.0 [M+H]+. Calcd for C25H18N2O2: 378.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.Cl>C1COCC1>[C:10]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: O=C1CCCC1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1ccc(C2=CCCC2)cc1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a 0.5M solution of 4-fluorophenylmagnesium bromide (298 mL, 149 mmol) in THF at 0° C. was carefully added cyclopentanone (13.23 mL, 149 mmol). Upon the end of the addition, the reaction mixture was heated at reflux for 2 h. Ice (10 g) and 6N aqueous hydrochloric acid were added. The reaction mixture was extracted with ether. The combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen sulfite, a saturated aqueous solution of sodium bicarbonate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 1-cyclopentenyl-4-fluorobenzene (24.155 g, 149 mmol, 100% yield) as colorless oil. LC-MS (M+H)+=163.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.35-7.42 (2H, m), 6.95-7.02 (2H, m), 6.06-6.13 (1H, m), 2.63-2.71 (2H, m), 2.47-2.56 (2H, m), 1.96-2.06 (2H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:14]([CH3:28])[O:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:2]3[N:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][N:3]=3)(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[C:14]([CH3:28])[O:13][N:12]=1
Reactant: CCc1cnc(Cl)nc1
Reactant: Cc1noc(C)c1COc1ccc(S(N)(=O)=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CO
Product: CCc1cnc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nc1
Temperature: 130 °C
Yield: 27.6 %

Procedure:
A suspension of 2-chloro-5-ethylpyrimidine (0.021 mL, 0.177 mmol), 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonamide (50 mg, 0.177 mmol), palladium(II) acetate (0.397 mg, 1.770 μmol), Xantphos (2.048 mg, 3.54 μmol) and cesium carbonate (144 mg, 0.443 mmol) was prepared in 1,4-dioxane (2 mL). The reaction vessel was sealed and heated by microwaves to 130° C. for 30 minutes. After cooling the reaction, additional Xantphos (2.048 mg, 3.54 μmol) and palladium(II) acetate (0.397 mg, 1.770 μmol) were added. The reaction was heated by microwaves to 130° C. for a further 30 minutes. The reaction mixture was then diluted with methanol (2 mL) and passed through a silica solid phase extraction (SPE) cartridge to remove particulates. The filtrate was evaporated in vacuo and purified by mass directed autoprep (formic acid modifier) to give the title compound (19 mg). LCMS (2 min, formic) Rt 0.93 min, m/z (ES+) 389 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.O>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:13]([CH2:5][CH:6]([CH3:18])[CH3:7])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCCCC1
Solvent: ClCCCl
Solvent: O
Product: COC(=O)C1=Cc2cc(Br)ccc2N(CC(C)C)CCCC1
Reaction time: 8 h
Yield: 181.2 %

Procedure:
To a solution of methyl 9-bromo-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.0 g) in 1,2-dichloroethane (20 ml) were added isobutyl aldehyde (2.32 g) and triacetoxy sodium borohydride (4.11 g) and the mixture was stirred overnight. Water was added and the mixture was extracted with ethyl acetate, after which it was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give methyl 9-bromo-1-isobutyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (2.14 g) as a yellow oily material.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[O:7][C:6]2[C:14]([F:19])=[C:15](F)[CH:16]=[CH:17][C:5]=2[NH:4][C:3]1=[O:20].FC1C(F)=CC=CC=1[N+]([O-])=O>>[NH2:1][CH:2]1[C:8]2([CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[O:7][C:6]2[C:14]([F:19])=[CH:15][CH:16]=[CH:17][C:5]=2[NH:4][C:3]1=[O:20]
Reactant: NC1C(=O)Nc2ccc(F)c(F)c2OC12CCOCC2
Agent: O=[N+]([O-])c1cccc(F)c1F
Product: NC1C(=O)Nc2cccc(F)c2OC12CCOCC2
Reaction time: 8 h

Procedure:
In a similar manner to that described for the preparation of 3-amino-8,9-difluoro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-4(5H)-one except in step 4 the mixture was hydrogenated overnight, 2,3-difluoronitrobenzene (4.48 g, 2.98 mL, 28.1 mmol) was converted to the title compound as a beige solid (480 mg) which was used without purification. MS m/z 266.9 (MH+)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][N:15]=[CH:16]3)(=[O:10])=[O:9])[CH2:4][CH2:3]1>Cl.CO.O=[Pt]=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][NH:15][CH2:16]3)(=[O:9])=[O:10])[CH2:4][CH2:3]1
Reactant: CN1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: CN1CCN(S(=O)(=O)c2cccc3c2CCNC3)CC1
Reaction time: 3.5 h
Yield: 124.1 %

Procedure:
5-(4-Methyl-piperazine-1-sulfonyl)-isoquinoline 10a (0.99 g, 3.41 mmol) was dissolved in a solution 2% of HCl in methanol (100 mL) under nitrogen. PtO2 (250 mg) was added under nitrogen and the mixture was hydrogenated in a Parr apparatus at 45 psi for 3.5 h. The catalyst was removed by filtration, rinsed with MeOH, and the filtrate was concentrated in vacuo to give 1.25 g of 5-(4-methyl-piperazine-1-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline 11 a as a pale yellow foam. The crude hydrochloride salt of the product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]2=[O:33]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]3=[O:33])[C:10]([OH:17])([C:13]([F:15])([F:16])[F:14])[CH2:9][C:8]2([CH3:19])[CH3:18]
Reactant: Cn1ncc2c(N)cccc2c1=O
Reactant: COc1c(Cl)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(Cl)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Yield: 7.7 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 1.0 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 542 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 3, 840 mg of the imine is reacted by reaction with 43.6 ml of titanium tetrachloride (1 M in dichloromethane) in 40 ml of dichloromethane, and 114 mg of the title compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH2:21][CH:22]([N:28]=C(C2C=CC=CC=2)C2C=CC=CC=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[NH2:28][CH:22]([CH2:21][C:10]1[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:14][CH:13]=[C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:11]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)N=C(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(N)Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
A solution of 1J (2.1 g, 3.82 mmol) in THF (30 mL) and H2O (30 mL) at RT was added citric acid (5 g). The reaction was stirred at RT for 1 h. After this time, no starting material was detected by LC-MS. The reaction mixture was extracted with Et2O (3×90 mL). The organic layers were combined and washed with 0.5 N citric acid (2×60 mL). The combined aqueous layers were basified to pH 8 by using 1 N NaOH (dropwise), and then extracted with Et2O (3×90 mL). The combined Et2O extracts were dried (Na2SO4), filtered and concentrated to give the title compound as a oil (1.24 g, 84%). LC/MS (method A): retention time=2.94 min, (M+H)+=386.