Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:18][C:19]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:20]=1[C:21]#[N:22]>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:14]([F:17])([F:16])[F:15])[CH2:13][CH2:12][N:11]([C:24]3[CH:25]=[CH:26][C:19]([F:18])=[C:20]([CH:23]=3)[C:21]#[N:22])[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#Cc1cc(I)ccc1F
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCNC1
Solvent: Cc1ccccc1
Product: N#Cc1cc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (0.6 g) and 2-fluoro-5-iodobenzonitrile (0.57 g) was dissolved in toluene, which was then degassed 3 times. To the solution in toluene was added sodium tert-butoxide (0.20 g), Tris(dibenzylidene acetone)dipalladium chloroform complex (0.04 g) and Xantphos (0.07 g) under argon atmosphere, and the mixture was stirred at 80° C. for two hours. The mixture was cooled to room temperature and then diluted with ethyl acetate, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-fluorobenzonitrile (0.54 g). m.p. 184-186° C.
Reaction SMILES: [Mg].ClC1C=CC(C=CC)=CC=1.II.Cl[C:15]1[CH:23]=[CH:22][C:18]([C:19]([CH3:21])=[CH2:20])=[CH:17][CH:16]=1.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1.O>[CH3:26][Si:25]([CH3:28])([CH3:27])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([CH3:21])=[CH2:20])=[CH:17][CH:16]=1
Reactant: C=C(C)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)Cl
Agent: CC=Cc1ccc(Cl)cc1
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)c1ccc([Si](C)(C)C)cc1
Temperature: 40 °C

Procedure:
Placing 2 g (83 mmol) of dry magnesium into a 250 mL flask equipped with a condenser, a dropping funnel and a magnetic stirrer, the reaction was carried out in a nitrogen atmosphere. The magnesium was initially activated by adding 1 mL of p-chloro-methylstyrene (Aldrich, Germany) with 0.5 g iodine in 5 mL THF at 50° C. for a period of 30 minutes. Into the mixture a solution of 11 g (72 mmol) of p-chloro-α-methylstyrene in 50 mL THF was dropped over a period of 12 hours under reflux. The reaction mixture was cooled to 40° C., then 7.8 g (72 mmol) of chlorotrimethylsilane (Fluka, Japan) in 30 mL of THF were added dropwise and reacted for 24 hours. After the reaction was completed, a large amount of water was added and the reaction mixture was extracted with ether. The ether layer was dried over magnesium sulfate, and distilled under reduced pressure, bp 66°-67° C./2 mmHg. Yield, 56%. The colorless liquid crude product was purified by column chromatography, which was performed on silica gel using n-hexane as an eluent. The product was identified by IR and 1H-NMR spectroscopy.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([NH2:17])[CH:6]=[C:7]([CH2:12][P:13]([OH:16])([OH:15])=[O:14])[CH2:8][CH2:9][O:10][CH3:11])C>O>[NH2:17][CH:5]([CH:6]=[C:7]([CH2:12][P:13]([OH:16])([OH:15])=[O:14])[CH2:8][CH2:9][O:10][CH3:11])[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(N)C=C(CCOC)CP(=O)(O)O
Solvent: O
Product: COCCC(=CC(N)C(=O)O)CP(=O)(O)O

Procedure:
0.98 g (3.5 mmol) of 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid ethyl ester is heated under reflux in 7 ml of water for 17 hours. The reaction mixture is concentrated by evaporation and crystallised from a mixture of water and ethanol. 2-amino-6-methoxy-4-phosphonomethyl-hex-3-enoic acid having a melting point of 214° C. (decomp.) is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11](O)[CH:10]([N:14]([CH2:16][CH2:17][OH:18])[CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>S(=O)(=O)(O)O>[CH2:1]([N:8]1[CH2:12][CH:11]2[CH:10]([N:14]([CH3:15])[CH2:16][CH2:17][O:18]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCO)C1CN(Cc2ccccc2)CC1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CN1CCOC2CN(Cc3ccccc3)CC21

Procedure:
18 g (71.9 mmol) of 1-benzyl-4-hydroxy-3-(2-hydroxyethylmethyl-amino)-pyrrolidine are reacted in 60 ml of concentrated sulphuric acid and 30 ml of water as in Example F a).
Reaction SMILES: [C:1]([N:8]([CH3:20])[C@@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+](=[CH2:23])=[N-]>C(Cl)Cl.CCOCC>[CH3:23][O:18][C:17](=[O:19])[C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A stirred solution of N-BOC-N-methyl-(D)-phenylalanine (3 g, 10.5 mmol) in methylenchoride (25 ml) is treated at 0° C. with slight excess of diazomethane in ether (25 ml). The reaction mixture is stirred at 0° C. and concentrated in vacuo to give N-BOC-N-methyl-(D)-phenylalanine methyl ester as a colorless oil. The above crude material is dissolved in a mixture of trifluoroacetic acid (8 ml) and ethanedithiol (2 ml) and stirred under nitrogen at r.t. for 1 hour. A 4M solution of hydrogen chloride in dioxane (3.6 ml) is added. The hydrochloride is precipitated by addition of ether (400 ml) and hexane (300 ml), filtered and washed with ether to give N-methyl-(D)-phenylalanine methyl ester hydrochloride (2.4 g) as a white powder. A solution of the above N-methyl-(D)-phenylalanine methyl ester hydrochloride (2.4 g, 10 mmol) and, 5-dimethylbenzoic acid (1.8 g, 11 mmol) in DMF (15 ml) at 0° C. is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.2 ml, 11 mmol). The reaction mixture is slowly warmed to r.t. and stirring continued overnight. The homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is chromatographed on silica with ethyl acetate/hexane 1:2 to give N-(3,5-dimethylbenzoyl)-N-methyl-(D)-phenylalanine methyl ester as a colorless oil. [a]D =+111° (c=0.94, ethanol).
Reaction SMILES: C(I)I.[Zn](CC)[CH2:5]C.C(OC([N:16]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([Cl:41])[CH:39]=2)[C:18]2([CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:22][C:21](=[O:31])[NH:20][CH:19]2[C:32]([CH3:34])=[CH2:33])[C:17]1=[O:42])=O)(C)(C)C>C1(C)C=CC=CC=1>[Cl:41][C:38]1[CH:39]=[C:40]2[NH:16][C:17](=[O:42])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32]3([CH3:33])[CH2:5][CH2:34]3)[C:35]2=[CH:36][CH:37]=1
Reactant: CC[Zn]CC
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Solvent: ICI
Solvent: Cc1ccccc1
Product: CC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)CC1
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
To a solution of CH2I2 (1.2 g, 4.6 mmol) in anhydrous toluene (5 mL) under Argon at 0° C. was added a toluene solution of Et2Zn (1.1M, 3.3 ml, 3.67 mmol). The mixture was stirred for 15 min, then a toluene solution (10 mL) of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (230 mg, 0.46 mmol) prepared in example 171a was added. The reaction mixture was stirred at room temperature for 3 h, then quenched with aqueous saturated NH4Cl (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (162 mg). Then racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione by chiral SFC to give chiral (2′R,3R,4′S)-6-chloro-4′-(3-chloro-phenyl)-2′-(1-methyl-cyclopropyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (50 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([Cl:12])=[CH:7][N:6]=1)(=[O:3])[CH3:2].[CH:13](N1CCOCC1)=[O:14]>C1COCC1>[C:1]([NH:4][C:5]1[C:10]([F:11])=[C:9]([CH:13]=[O:14])[C:8]([Cl:12])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)cc1F
Reactant: O=CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(Cl)c(C=O)c1F
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, 2-acetylamino-5-chloro-3-fluoropyridine (20 mg, 0.11 mmol) and 4-formylmorpholine (64 μL, 0.64 mmol) were dissolved in THF (0.2 mL) at room temperature. The solution was cooled to −20° C., a 1.0 M lithium hexamethyldisilazide THF solution (244 μL, 0.24 mmol) was added dropwise, and the mixture was stirred for 2 hours at that temperature. The reaction mixture was subjected to HPLC analysis under the following conditions, and the purity and conversion rate were calculated from the area ratio of the title compound and the starting compound (2-acetylamino-5-chloro-3-fluoropyridine). The formula used was: Conversion rate (%)=100−(area ratio of starting compound).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>CC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1c(=O)sc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a clear solution of 78 (500 mg) in acetone (5 mL) was added sodium phosphate buffer (pH=7.0, 0.1 M, 25 mL), upon which the solution became cloudy (white precipitate). Candida antarctica lipase resin (250 mg) was added to the mixture and the suspension was subsequently gently shaken for 10 h at room temperature. The resulting clear mixture was filtered, and organic solvent was removed under vacuum. The aqueous solution was then extracted with ethyl acetate (3×25 mL) and the organic layers were combined, dried over MgSO4, and concentrated. The resulting solid could be further purified in a manner similar to that described in Example 43, step 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(c1ccccn1)C1(c2ccc(Cl)cc2)CC1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(C2(Cc3ccccn3)CC2)ccc1Cl

Procedure:
Prepared analogously to Example 231c from [1-(4-chlorophenyl)-cyclopropan-1-yl]-pyridin-2-yl-methanone and fuming nitric acid.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][C:12]([OH:18])=[CH:11][CH:10]=4.N1C=CC=CC=1.[C:25](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26]>C(Cl)Cl>[CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][C:12]([O:18][C:25](=[O:26])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:11][CH:10]=4
Reactant: Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Temperature: 25 °C

Procedure:
6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (1.01 g, 3.99 mmoL) in CH2Cl2 (5 mL) was treated with pyridine (0.387 mL, 4.788 mmoL) followed by PivCl (0.541 mL, 4.389 mmoL) at 0° C. The reaction mixture was slowly warmed to room temperature over 2 hours. The reaction mixture was then partitioned between CH2Cl2 and saturated NH4Cl. The aqueous phase was extracted two times with CH2Cl2. The organic layer from each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, hexanes:EtOAc 4:1 as eluent) to yield the title compound as a pale foam.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][CH3:6])=[CH2:4].[C:7]([O:12][CH2:13][CH3:14])(=[O:11])[CH:8]=[C:9]=[CH2:10]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1([O:5][CH3:6])[CH2:10][C:9](=[CH:8][C:7]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4]1
Reactant: C=C(OC)OC
Reactant: C=C=CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CC(OC)(OC)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3.93 g (44.59 mmol) of 1,1-dimethoxyethene and 5 g (44.59 mmol) of ethyl buta-2,3-dienoate in 50 ml of toluene was heated at reflux and stirred for 24 h. After cooling to room temperature, the reaction mixture was freed from the solvent, and the crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 1.9 g (21% of theory) of the title compound as a colourless liquid which was used without further characterization for subsequent reactions.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]#N)=[CH:28][CH:27]=3)[CH:15]=[CH:14][C:13]1=2.C(O)(=O)C(C(C(O)=O)O)[OH:37]>CCCCCC.CCOCC>[CH3:11][C:12]1([CH3:34])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16]([C:24]#[C:25][C:26]3[CH:33]=[CH:32][C:29]([CH:30]=[O:37])=[CH:28][CH:27]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C=O)cc3)ccc21
Reaction time: 0.67 h
Yield: 38 %

Procedure:
56 ml (67 millimoles) of a 20% strength solution of diisobutylaluminum hydride in hexane were added to a solution of 10 g (32 millimoles) of 4-[(5,6,7,8-tetrahydro- 5,5,8,8-tetramethylnaphth-2-yl)-ethynyl]-benzonitrile (Example 1) in 120 ml of absolute ether. The mixture was stirred for a further 40 minutes, 150 ml of saturated tartaric acid solution were added dropwise and stirring was continued for a further hour. Thereafter, the mixture was extracted three times with ether and the combined ether phases were washed twice with water, dried over Na2SO4 and evaporated down. Recrystallization of the residue from isopropanol gave 3.8 g (38%) of the title compound of melting point 130° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].C(O)(=O)C.Cl[CH2:11][C:12](=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[C:1]([O:4][CH2:11][C:12](=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: COC(=O)CC(=O)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)CC(=O)COC(C)=O
Yield: 61 %

Procedure:
108 g (1.1 mol) of potassium acetate and 11.4 g (0.05 mol) of benzyltriethylammonium chloride are suspended in 900 ml of acetonitrile, treated with 50 ml of acetic acid and heated to reflux temperature. Within 31/2 hours there are added dropwise thereto 150.5 g (1 mol) of methyl 4-chloroacetoacetate in 100 ml of acetonitrile and the mixture is subsequently held at reflux temperature for 4 hours. The reaction mixture is washed 3 times with 200 ml of 5% NaH2PO4 solution each time and the aqueous phases are back-extracted with 200 ml of CH2Cl2. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product distils at 76°-85° C./0.6 mbar and gives 106.17 g (61%) of methyl 4-acetoxyacetoacetate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:25]=[CH:24][C:11]3[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:25]=[CH:24][C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=3[CH:9]=2)[C:5]([O:26][CH2:27][C:28]2[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccnc(COc2ccc(Cl)nc2-c2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccnc(COc2ccc(Cl)nc2-c2ccc3c(c2)CCNCC3)c1
Temperature: 25 °C

Procedure:
To an ice cooled solution of 1,1-dimethylethyl 7-(6-chloro-3-{[(4-methyl-2-pyridinyl)methyl]oxy}-2-pyridinyl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in DCM (1 ml) was added dropwise TFA (1 ml) and the reaction mixture stirred at room temperature until the starting material had been consumed. The reaction mixture was concentrated in vacuo, dissolved in water and backwashed with ethyl acetate. The aqueous layer was neutralised with aqueous sodium bicarbonate then extracted with ethyl acetate, dried over sodium sulphate and concentrated in vacuo to yield the title compound, 27 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[C:11](=[O:13])[CH3:12].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=2[C:11](=[O:13])[CH3:12])[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: CC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Product: CC(=O)c1c(N2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 68.9 %

Procedure:
In a cylindrical quartz tube were placed 1-(2-chloro-6-nitro-phenyl)-ethanone (300 mg, 1.5 mmol) and N-methyl-piperazine (12 ml, 180 mmol). The reaction was heated for 40 hours at 120° C. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The solution was washed twice with water and the organic phase was dried over anhydrous Na2SO4. The crude was purified by flash chromatography (acetone/MeOH 75:25) affording the desired compound (272 mg, 46% yield), as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1.Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:19]2[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[N:6]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: Fc1ccccc1Cc1n[nH]c2ccccc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1nc(N)nc(-n2nc(Cc3ccccc3F)c3ccccc32)n1
Temperature: 90 °C

Procedure:
Under argon, 130 mg (0.58 mmol) of 3-(2-fluorobenzyl)-1H-indazole from example 5A, 84 mg (0.58 mmol) of 6-chloro-1,3,5-triazine-2,4-diamine, 11 mg (0.011 mmol) of tris(dibenzylidene-acetone)dipalladium, 16 mg (0.034 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPHOS) and 262 mg (0.80 mmol) of cesium carbonate are introduced into 4 ml of degassed toluene and heated at 90° C. for 20 h. The mixture is then diluted with ethyl acetate and methanol, filtered and concentrated in vacuo. The residue is purified by preparative HPLC to result in 36 mg (19% of theory) of the title compound. In addition, 65 mg of the starting compound are recovered.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(-c2ccccc2)nc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cnc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 64b (205 mg, 1.20 mmol), NBS (236 mg, 1.32 mmol) and DBPO (14.6 mg, 0.06 mmol) in carbon tetrachloride according to Method A. Crude product was purified by flash chromatography on silica-gel using hexane/ethyl acetate (10:1) as eluent. Product was used directly in the next step without further characterization. White solid. Yield: 89 mg, 30%. (ESI): m/z=250.68 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][C:7]1=[O:17])C.[Li+].[OH-].CC#N.O.FC(F)(F)C(O)=O>O1CCCC1.O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][C:7](=[O:17])[N:6]([CH2:5][C:4]([OH:18])=[O:3])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)Cn1c(=O)oc2ccc(OC)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2oc(=O)n(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
Ethyl[5-(methyloxy)-2-oxo-1,3-benzoxazol-3(2H)-yl]acetate (0.98 g, 3.9 mmol) was dissolved in 12.5 mL of tetrahydrofuran and treated with a solution of LiOH (0.094 g, 3.9 mmol) dissolved in 1.25 mL of water. The reaction was stirred vigorously at room temperature for 18 hours before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=1.5 min and m/e 224 [M+1]+. The solvent was removed by rotary evaporation and the residue was then dissolved in 100 mL of ethyl acetate. The organic layer was washed with a 10% hydrochloric acid solution (3×30 mL) and the organic phase was then dried over Na2SO4, filtered and concentrated to give [5-(methyloxy)-2-oxo-1,3-benzoxazol-3(2H)-yl]acetic acid (0.64 g, 2.8 mmol, 73%) as a brown amorphous solid. MS (ES) m/e 224 [M+H]+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CC.[CH3:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH3:13][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:21]
Reactant: C=CCCCCC(C)C
Reactant: C=CCCCCCCCCCC
Product: CCCCCCCCCCC=CCCCCC(C)C

Procedure:
In the manner described in Example 4, 110 g. (0.66 mole) of 1-dodecene and 16 g. (0.13 mole) of 7-methyl-1-octene are reacted at a reaction temperature of 100° C. After 21/2 hours and a throughput of 200 ml. of olefin mixture per hour, 8.7% by weight of 2-methyl-7-octadecene is obtained. The extractor contains in this case 26.6 g. of the catalyst described in Example 4.