Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12]1(N=C=NC2CCCCC2)CCCCC1.CO>ClCCl.CN(C)C1C=CN=CC=1>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromophenylacetic acid (1.0 g, 4.65 mmol), 1,3-dicyclohexylcarbodiimide (1.44 g, 6.98 mmol) and MeOH (149 mg, 4.65 mmol) in dichloromethane (40 ml) was added 4-dimethylaminopyridine (57 mg, 0.465 mmol). The reaction mixture was stirred at RT for 1 hr. The white solid was precipitated out which was removed with filtration. The reaction solution was concentrated to give a crude product which was purified on silica gel column with dichloromethane. The product was collected which contain a little amount of DCU (1.36 g). NMR (CDCl3): □ 7.20-7.46 (4H, m), 3.72 (3H, s), 3.621(2H, s).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[S:18][CH:19]=3)=[CH:11][CH:10]=2)O1.Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[S:44][C:43]([C@@H:45]3[CH2:49][CH2:48][CH2:47][N:46]3[C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[N:42][CH:41]=2)=[CH:36][CH:35]=1.CC1(C)C(C)(C)OB(C2C=CC(C3SC([C@@H]4CCCN4C(OC(C)(C)C)=O)=NC=3)=CC=2)O1>>[C:28]([O:27][C:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[C:17]1[S:18][CH:19]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[S:44][C:43]([C@@H:45]5[CH2:49][CH2:48][CH2:47][N:46]5[C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])=[N:42][CH:41]=4)=[CH:36][CH:35]=3)=[CH:10][CH:11]=2)[N:16]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cs1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)s1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)s1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)s4)cc3)cc2)cs1

Procedure:
Compound 43a was prepared in the same manner as described in Example 4 except that Compounds 13a and 21a, instead of Compounds 2a and 3a, were used.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:2]#[CH:3].N1C=CC=CC=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>CCOCC>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:25]([CH:22]1[CH2:24][CH2:23]1)=[O:26])[C:2]#[CH:3]
Reactant: O=C(Cl)C1CC1
Reactant: C#CCOCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: C#CCOCCCCCCCCCCOC(=O)C1CC1

Procedure:
91 g. of 10-(2-propynyloxy)-1-decanol are dissolved in 500 ml. of ether and treated with 37 g. of pyridine. While cooling with ice and stirring, there are added dropwise 49.5 g. of cyclopropane carboxylic acid chloride and 50 ml. of ether thereto. Subsequently, the mixture is stirred at room temperature for 3 hours. The mixture is poured onto ice-water, exhaustively extracted with ether and the extract is washed with 2 N hydrochloric acid, water, 10% potassium bicarbonate solution, semi-saturated and saturated sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (95:5 parts by volume) there is obtained pure cyclopropane carboxylic acid 10-(2-propynyloxy)decyl ester; nD25 =1.4616.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH:14]1([C:17]#[CH:18])[CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C=O)C.C1(C)C=CC=CC=1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:5]1[CH:4]=[CH:3][C:2]([C:18]#[C:17][CH:14]2[CH2:16][CH2:15]2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C#CC1CC1
Reactant: CCOC(=O)c1cc(Br)ccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C#CC2CC2)ccc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
To a solution of ethyl 5-bromo-2-chlorobenzoate (1.9 g) in DMF (12 mL), toluene (0.3 mL), cyclopropylacetylene (714 mg), copper iodide (275 mg), dichloro bis(triphenylphosphine)palladium (1.01 g) and triethylamine (20.1 mL) were added, and the mixture was degassed, stirred at 100° C. under argon atmosphere for 8 hours, and then the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The insoluble material was filtered off on celite. The mother liquor was washed with brine, dried over magnesium sulfate and concentrated. By purification on column chromatography, ethyl 2-chloro-5-(cyclopropylethynyl)benzoate (1.86 g) was obtained as brown oil.
Reaction SMILES: [CH2:1]([CH:4]([CH2:14][CH2:15][CH3:16])[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=O)=[O:6])[CH2:2][CH3:3].[NH4+:17].[OH-:18]>O1CCOCC1>[CH2:1]([CH:4]([CH2:14][CH2:15][CH3:16])[C:5]([NH:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][NH2:17])=[O:6])[CH2:2][CH3:3]
Reactant: CCCC(CCC)C(=O)NCCCC(=O)Cl
Reactant: [OH-]
Reactant: [NH4+]
Solvent: C1COCCO1
Product: CCCC(CCC)C(=O)NC(=O)CCCN
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
To an ice-cooled solution of N-(2-propylpentanoyl)-4-aminobutyroyl chloride (prepared from N-(2-propylpentanoyl)-4-aminobutyric acid and SOC12, 5.9 g, 24.0 mmole) in dioxane (25 ml), was added dropwise conc. NH4OH (34 ml) over 1 hr. The reaction mixture was then stirred at RT for 20 hrs and evaporated to dryness under reduced pressure. The residue was taken up in an H2O (20 ml) and EtOAC (30 ml) mixture, the mixture stirred vigorously for 5 min. The organic phase was separated, evaporated to dryness under reduced pressure, and the residue crystallized from EtOAc to give 1.4 g (6.1 mmole, 26%) of a crystalline solid, mp 138° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[C:13]([OH:15])=[O:14])([O-])=O>CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])[C:13]([OH:15])=[O:14]
Reactant: O=C(O)[C@H](CSc1ccccc1[N+](=O)[O-])N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1SC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Yield: 91.4 %

Procedure:
Catalytic reduction of 10 g of 3-(o-nitrophenyl)thio-2(R)-phthalimidopropionic acid in 300 ml of methanol is carried out at ordinary temperature and under atmospheric pressure using 5% palladium-carbon as catalyst. After absorption of the calculated amount of hydrogen, the catalyst is removed and the methanol is evaporated off under reduced pressure. The residue is crystallized from a mixture of ether and petroleum ether to give 8.4 g of 3-(o-aminophenyl)thio-2(R)-phthalimidopropionic acid as pale yellow crystals. To a stirred solution of 8.4 g of this product in 50 ml N,N-dimethylformamide is added dropwise 5.5 g of diethyl phosphorocyanidate at ice bath temperature. After the reaction mixture is stirred for 5 minutes, 2.28 g of triethylamine, is added dropwise at ice bath temperature. The resulting mixture is stirred for 30 minutes in an ice bath and for another 1 hour at room temperature, diluted with 200 ml of water and allowed to stand overnight. The deposited solid is collected by filtration and purified by silica gel column chromatography (dichloromethane:ethyl acetate=2:1 ) to give 5.4 g of 3(R)-phthalimido-2,3-dihydro-1,5(5H)-benzothiazepin-4-one as colorless prisms.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([CH2:18][CH:19]=O)[C:9](=[O:21])[CH:8]=1)(=[O:5])=[O:4].[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][N:35]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(OCC)(=O)C>[F:23][C:2]([F:1])([F:22])[S:3]([O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([F:17])=[CH:14][CH:15]=2)[N:10]([CH2:18][CH2:19][N:46]2[CH2:47][CH2:48][CH:43]([N:35]([CH2:34][C:31]3[N:30]=[CH:29][C:28]4[O:27][CH2:26][CH2:25][O:24][C:33]=4[CH:32]=3)[C:36]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:42])[CH2:44][CH2:45]2)[C:9](=[O:21])[CH:8]=1)(=[O:5])=[O:4]
Reactant: O=CCn1c(=O)cc(OS(=O)(=O)C(F)(F)F)c2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)cc(OS(=O)(=O)C(F)(F)F)c3ccc(F)cc32)CC1
Reaction time: 18 h

Procedure:
The crude 7-fluoro-2-oxo-1-(2-oxoethyl)-1,2-dihydro-4-quinolinyl trifluoromethanesulfonate (5.6 g, 15.9 mmol assumed 100% from previous step) was dissolved in THF (50 ml) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (5.60 g, 15.9 mmol) added followed by sodium sulphate (˜15 g). After 2 h sodium triacetoxyborohydride (12.3 g, 58 mmol) was added portionwise over 1 h and the solution stirred for 18 h. The solution was diluted with ethyl acetate and washed with sodium bicarbonate solution, dried and concentrated. Chromatography (70 g silica SPE, eluting with ethyl acetate) provided product (4.88 g) contaminated with an impurity. Further chromatography (70 g silica SPE gradient elution with 2:1 ethyl acetate/hexane to ethyl acetate to ethyl acetate/10% methanol) provided the title compound as a clear oil (2.81 g, 26%).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C1(C)C=CC=CC=1>[CH3:8][N:9]([C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[CH2:10][CH2:11][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc([N+](=O)[O-])cc2)cc1
Reactant: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(CCN1CCCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-[methyl-(4-nitro-phenyl)-amino]-ethyl ester TFA salt (74 mg, 0.21 mmol) in toluene (1 mL) is added triethylamine (50 μL) and piperidine (62 μL, 0.63 mmol). The mixture is shaken in 70° C. block shaker overnight. The reaction mixture is concentrated and purified by reverse phase high performance liquid chromatography to give methyl-(4-nitro-phenyl)-(2-piperidin-1-yl-ethyl)-amine as a di-TFA salt (74 mg).
Reaction SMILES: C(O[C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=O)(C)(C)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH2:27][NH2:28])[CH2:25][NH2:26])=[CH:20][C:19]=1[CH3:29].C(=O)([O-])[O-].[K+].[K+].II>CN(C)C=O.C(O)(C)(C)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:27][N:28]3[C:6](=[O:16])[NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[C:14]3=[N:26][CH2:25]2)=[CH:20][C:19]=1[CH3:29]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C=O
Reactant: Cc1cc(C(CN)CN)ccc1N
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: Cc1cc(C2CN=C3c4ccccc4NC(=O)N3C2)ccc1N
Temperature: 75 °C
Reaction time: 3 h
Yield: 23.7 %

Procedure:
A flask was charged with (2-formyl-phenyl)-carbamic acid tert-butyl ester (8.8 g, 0.040 mol), 2-(4-amino-3-methyl-phenyl)-propane-1,3-diamine (10.0 g, 0.056 mol), t-butanol (177 mL), and N,N-dimethylformamide (53 mL). The mixture was stirred at 70-80° C. for 3 h. To the stirred, cooled (40-50° C.) mixture were added anhydrous potassium carbonate (16.6 g) and iodine (20.3 g). The batch was then stirred at 80° C. for at least 5 h or until HPLC analysis showed that the reaction had proceeded to greater the 98% completion. The cooled reaction mixture was filtered through a celite pad (8.8 g) and the filter cake was rinsed with MeOH (110 mL). The filtrate and rinse were diluted with toluene (90 mL) and concentrated to dryness under reduced pressure. The residue was stirred with aqueous 20 wt % sodium thiosulfate pentahydrate (180 mL) for 1 h at ambient temperature. This mixture was extracted with CH2Cl2 (2×180 mL) and the separated organic layers were concentrated to dryness in vacuo. The concentrate (20 g) was dissolved with methanol (10 mL) and loaded onto a Biotage KP-Sil SNAP cartridge (100 g) that had been pre-equilibrated with 300 mL 5% v/v triethylamine in hexane. A Biotage unit was used to elute the cartridge with an ethyl acetate-hexane gradient (0% to 80%). Clean fractions were collected, combined, and concentrated to dryness under reduced pressure as quickly as possible to provide the title compound as a yellow solid (2.9 g 23% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=O)[NH:6][CH:5]2[OH:13].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[F:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[F:1])[C:5](=[O:13])[NH:6][CH2:7]2
Reactant: O=C1NC(O)c2cc(F)c(F)cc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
748 mg of 5,6-difluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (crude product, about 4.04 mmol) were initially charged in 50 ml of dichloromethane, 3.8 ml (48.5 mmol) of trifluoroacetic acid and 1.3 ml (8.08 mmol) of triethylsilane were added and the mixture was stirred overnight at RT. The reaction mixture was then concentrated, and the residue was dissolved in dichloromethane and washed with sodium bicarbonate solution. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 1:1 to 0:1). This gave 72 mg (10.6% of theory) of the target compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:14][CH:13]=[CH:12][CH:11]=2>ClCCl>[ClH:1].[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[N:14][CH:13]=[CH:12][CH:11]=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2cccnc12
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNc1c(NC(=O)CCl)cnc2cccnc12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (5.00 mL, 63.4 mmol) was added dropwise to a 0° C. solution of tert-butyl 3-[(3-amino[1,5]naphthyridin-4-yl)amino]propylcarbamate (from Part D, approximately 57.6 mmol) in dichloromethane (230 mL). The reaction was allowed to warm to room temperature and was stirred for 1 hour. The solvent was removed under reduced pressure to afford tert-butyl 3-({3-[(chloroacetyl)amino][1,5]naphthyridin-4-yl}amino)propylcarbamate hydrochloride as a solid, all of which was used in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:22])[C:12]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:11]=2[O:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccc(F)cc2NC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)COc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To a solution of 1.62 g (5.46 mmol) ((S)-2-Fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 20 ml tetrahydrofurane were added at −75° C. 4.57 g (5.46 mmol) lithium bis(trimethylsilyl)amide (20% in tetrahydrofurane) followed after 10 minutes by 0.34 ml (6.55 mmol) methyliodide. Stirring was continued overnight while the mixture was allowed to warm to room temperature. The solvent was removed by distillation and 300 ml saturated aqueous sodium hydrogensulfate solution was added. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 2:8 yielded 0.87 g (51%) ((S)-2-fluoro-9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester as white solid, MS m/e (%): 333 (M+Na+, 15), 311 (M+H+, 70), 255 (100).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:24][CH3:25])C1C=CC=CC=1>ClCCl.Br.C(O)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:24][CH3:25]
Reactant: COc1cc(C(=O)Cc2ccccc2)ccc1OCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)Cc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5.9 g, (17.8 mmol) of the above ketone in a mixture of dichloromethane (60 mL) and 30% hydrobromic acid in acetic acid (27 mL) was stirred for 1.5 h at room temperature and then the dichloromethane was evaporated at reduced pressure and the reaction mixture was poured onto 200 mL of an ice/water mixture. The precipitate formed was filtered off, and dried under vacuum to provide 1-(4-hydroxy-3-methoxyphenyl)-2-phenyl-1-ethanone as beige crystals, m.p. 107 to 108° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:16][N:17]([CH3:39])[C:18]1[CH:38]=[CH:37][C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27](/[CH:31]=[CH:32]/[N+:33]([O-:35])=[O:34])[C:26]=2[F:36])=[O:23])=[CH:20][CH:19]=1.FC(F)(F)S(O[Yb](OS(C(F)(F)F)(=O)=O)OS(C(F)(F)F)(=O)=O)(=O)=O.C(OCC)(=O)C.CCCCCC>C(#N)C>[CH3:39][N:17]([CH3:16])[C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([C:3]3[C:4]4[C:9](=[CH:8][C:7]([N:10]5[CH2:15][CH2:14][O:13][CH2:12][CH2:11]5)=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:32][N+:33]([O-:35])=[O:34])[C:26]=2[F:36])=[O:23])=[CH:37][CH:38]=1
Reactant: CN(C)c1ccc(C(=O)Nc2cccc(/C=C/[N+](=O)[O-])c2F)cc1
Reactant: c1cc2ccc(N3CCOCC3)cc2[nH]1
Agent: O=S(=O)(O[Yb](OS(=O)(=O)C(F)(F)F)OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: CN(C)c1ccc(C(=O)Nc2cccc(C(C[N+](=O)[O-])c3c[nH]c4cc(N5CCOCC5)ccc34)c2F)cc1
Temperature: 50 °C
Yield: 61.7 %

Procedure:
A mixture of 4-(1H-indol-6-yl)morpholine (0.393 g, 1.943 mmol), (E)-4-(dimethylamino)-N-(2-fluoro-3-(2-nitrovinyl)phenyl)benzamide (0.400 g, 1.215 mmol), and tris(trifluoromethylsulfonyloxy)ytterbium (0.075 g, 0.121 mmol) in acetonitrile (25 mL) was heated at 50° C. for 20 h. The acetonitrile was removed under vacuum. The residue was diluted with ethyl acetate (180 mL), washed with 10% NaHCO3 solution (2×40 mL) and brine (40 mL), and dried over anhydrous MgSO4. The desired product (0.412 g, 0.750 mmol, 61.8% yield) was isolated with ISCO (80 g silica gel, 30-80% ethyl acetate/hexane) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=O>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Product: Nc1cc(Br)cc2nc(-c3ccccn3)nn12

Procedure:
The title compound, MS m/e (%): 290 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and pyridine-2-carbaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [C:1]([N:4]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[C:5]1([C:18]([O:20]CC)=O)[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].O.Cl>C1COCC1.CCOC(C)=O>[CH2:11]([N:8]1[CH2:9][CH2:10][C:5]2([N:4]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:1](=[O:3])[CH2:2][C:18]2=[O:20])[CH2:6][CH2:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(N(C(C)=O)c2cccc(F)c2)CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a 0° C. solution of 0.86 g (2.2 mmol) ethyl 4-[acetyl(3-fluorophenyl)amino]-1-benzylpiperidine-4-carboxylate in 1 mL THF was added 3.2 mL (6.5 mmol, 2M solution in heptane, THF, ethylbenzene) lithium diisopropylamide solution and the reaction mixture was allowed to slowly warm to rt and stirred for an additional 14 hr. To this mixture was added 50 mL water and 50 mL EtOAc and the pH was adjusted to pH=6 with 1N HCl (approx 11 mL). The aqueous layer was extracted 3×100 mL EtOAc and the combined extracts washed with 100 mL brine, dried over MgSO4, filtered, and concentrated to give 8-benzyl-1-(3-fluorophenyl)-1,8-diazaspiro[4.5]decane-2,4-dione as a solid. 1H NMR (CDCl3, 400 MHz) δ 7.44 (ddd, J=8.06, 8.06 and 6.23 Hz, 1H); 7.14-7.30 (m, 6H); 6.95 (br d, J=7.88 Hz, 1H); 6.89 (ddd, J=9.16, 2.02, and 2.02 Hz, 1H); 3.52 (s, 2H); 3.26 (s, 2H); 2.73 (m, 2H); 2.65 (m, 2H); 1.85 (br m, 4H). Electrospray mass spectrum M+H=353.1
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[CH:34]2[C:43]3[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:34]2[C:43]3[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=3)[CH2:37][CH2:36][CH2:35]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCCc3cc(OC)ccc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCCc3cc(OC)ccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.26, 6.78, 6.69, 5.33, 4.49, 3.82, 2.89–2.78, 2.55, 2.05–1.84, 1.33–1.26; HRMS (FAB) calcd for C19H24BrN3O+H 390.1181, found 390.1180.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cu:15]>O.[Cl-].C([N+](CC)(CC)CC)C.CO>[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cu+2:15].[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: [Cu]
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCC(=O)[O-]
Product: [Cu+2]
Temperature: 50 °C

Procedure:
To A reaction flask was charged 24.0 g (0.120 mole) of lauric acid, 60.0 g methanol and 0.40 g of tetraethylammonium chloride hydrate. Copper foil was used as the anode and a graphite rod as the cathode. The reaction mixture was heated to 50° C. and a direct current was passed between the two electrodes. A bluish solid precipitated out which was removed from the electrode surface periodically. After passing 7,803 coulombs of electricity, 3.1 g (0.049 mole) of copper was consumed. The solid was filtered and dried to give a blue solid containing 13.50% copper.