Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:37])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=3)=[CH:15][C:14]=2[CH3:36])=[N:9][CH:10]=1)#[N:4].[H][H].Cl[C:41]([O:43][CH3:44])=[O:42]>O1CCCC1>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:12](=[O:37])[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:23][C:22]([C:28]4[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=3)=[CH:15][C:14]=2[CH3:36])[C:41](=[O:42])[O:43][CH3:44])=[N:9][CH:10]=1)#[N:4]
Reactant: [H][H]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ccc(C#N)cn1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1ccc(C#N)cn1
Temperature: 0 °C
Yield: 83 %

Procedure:
In a suspension of 0.03 g of 55% oily sodium hydride suspended in 3 mL of tetrahydrofuran, a solution of 0.26 g of N-(5-cyano-2-pyridyl)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-yl]-2-methyl benzoic acid amide in 3 mL of tetrahydrofuran was added under cooling with ice and with stirring and continued to stir at the same temperature for 10 minutes. After ceasing the generation of hydrogen gas, 0.07 g of methyl chloroformate was added, ice bath was removed and continued to stir further for 7 hours. After the completion of the reaction, the reaction mixture was poured in 10 mL of ice water, extracted with ethyl acetate (10 mL×2), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.24 g of the aimed product as colorless resinous substance.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:36])=[C:25]([CH:27]=[N:28][C:29]([O:31][Si](C)(C)C)=[CH2:30])[CH:26]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:11])[C:6]3([CH:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=4)[CH2:30][C:29](=[O:31])[NH:28][CH:27]3[C:25]3[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[CH3:36])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Yield: 54 %

Procedure:
In a manner similar to the method described in example 157b, E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 157a was reacted with 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 36a in toluene to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.3 g, 54%).
Reaction SMILES: C(O[C:4](=O)[CH2:5][C:6]([CH2:8]Cl)=[O:7])C.P([O-])([O-])([O-])=O.C(O)[C:17](N)([CH2:20]O)[CH2:18]O.Cl.N[CH2:26]C(O)=O>>[CH3:8][C@@H:6]([OH:7])[CH2:5][CH2:4][CH2:26][CH2:18][CH2:17][CH3:20]
Reactant: NCC(=O)O
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(CO)(CO)CO
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Product: CCCCCC[C@@H](C)O

Procedure:
Then, we examined 4-chloroacetoacetic acid ethyl ester reductase activity of the enzyme obtained from Example 3 changing pH by using phosphate buffer (KPB), Tris-HCl buffer, and Glycine buffer. FIG. 2 shows relative activity with taking the maximal activity as 100. As a result, the optimum pH of the enzyme was from 5.0 to 6.5.
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[C:9]1([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:13][CH:12]=[CH:11][CH:10]=1.[CH2:34]([O:41][C:42]1[CH:49]=[C:48]([N:50]([CH2:55][CH2:56][CH2:57][CH3:58])[CH2:51][CH2:52][CH2:53][CH3:54])[CH:47]=[CH:46][C:43]=1[CH:44]=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>O1CCCC1.C(OCC)(=O)C>[CH2:34]([O:41][C:42]1[CH:49]=[C:48]([N:50]([CH2:55][CH2:56][CH2:57][CH3:58])[CH2:51][CH2:52][CH2:53][CH3:54])[CH:47]=[CH:46][C:43]=1[CH:44]=[CH:14][C:9]1[S:13][CH:12]=[CH:11][CH:10]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: c1ccc([P+](Cc2cccs2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
In a stream of argon, to 25 ml of tetrahydrofuran was added 3.3 g of phenyllithium (19% solution in dibutylether) (7.46 mmol), and 2.68 g (6.79 mmol) of 2-thenyl triphenylphosphonium chloride was added thereto under ice cooling. Next, 2.3 g (6.78 mmol) of 2-benzyloxy-4-dibutylaminobenzaldehyde was dissolved in tetrahydrofuran and added dropwise. The mixture was stirred under ice cooling for 2 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. To the residue, 40 ml of ethyl acetate/hexane (4/1) was added and the precipitate was filtered off. The filtrate was concentrated and then purified by silica gel column chromatography to give 2.64 g of a yellow oily matter (yield: 92.9%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[C:10][Si](C)(C)C)=[CH:5][N:4]=1.[F-].[K+].C(OCC)C>CN(C=O)C.O>[C:9]([C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=1)#[CH:10]
Reactant: COc1ncc(C#C[Si](C)(C)C)cn1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: C#Cc1cnc(OC)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methoxy-5-((trimethylsilyl)ethynyl)pyrimidine (520 mg, 2.5 mmol) in DMF (10 mL) and water (1 mL) was added potassium fluoride (290 mg, 5 mmol) and the mixture was stirred at 0° C. for 1 h. Diethyl ether (100 mL) was added and the solution was washed with water (2×10 mL) and brine (10 mL), dried over MgSO4 and concentrated. The title compound was isolated by silica gel:chromatography (9:1 CH2Cl2/hexane) as a clear oil (120 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 2H), 4.05 (s, 3H), 3.28 (s, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>N.[Ni]>[NH3:1].[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH2:18])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#CCc1ccc(OCCCN2CCCC2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: NCCc1ccc(OCCCN2CCCC2)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of [4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-acetonitrile (preparation 104), (1 g, 4.1 mmol) and Raney® nickel (100 mg) in 2M methanolic ammonia (35 mL) was stirred under 60 psi of hydrogen gas at 50° C. for 6 hours. Tlc analysis showed that not all of the starting material had been consumed and so further Raney® nickel (200 mg) was added to the reaction mixture and heating continued for 5 hours. Tlc analysis again showed that starting material was still present and so additional Raney® nickel (200 mg) was added and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was then filtered through Arbocel® and was concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography using a 4 g RediSep® silica cartridge, eluting with dichloromethane:methanol:0.88 ammonia, 85:15:1.5 to 80:20:2, to afford the title compound in 16% yield, 160 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](OB(C=C)OCCCC)[CH2:29]CC.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:1]([O:8][C:9]1[C:10]([N:20]2[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]2)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([CH:28]=[CH2:29])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CB(OCCCC)OCCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C=Cc1ccc2cc(OCc3ccccc3)c(N3CC(=O)NS3(=O)=O)cc2c1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
To a microwave vial containing 5-(3-benzyloxy-7-bromonaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Example 3, step D) (0.21 g, 0.46 mmol), vinylboronic acid dibutyl ester (0.20 mL, 0.92 mmol), and PS-tetrakistriphenylphosphine palladium (0.36 mg, 0.046 mmol) in DME (4 mL) is added Na2CO3 (2.0M, 0.92 mL, 1.83 mmol). This is stirred in the microwave at 110° C. for 10 min, at which time LC/MS reveals complete conversion to the desired product. The resin-bound palladium is removed by filtration and the filtrate is concentrated in vacuo, and purified by reverse-phase Biotage MPLC to afford 5-(3-benzyloxy-7-vinylnaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a light brown oil.
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19]([OH:21])=[O:20])=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH:22]1C2=C3C(=CC=C2C=CC=1)N=C1C(C=CC=C1C(O)=O)=N3>CO.C(Cl)(=O)C>[CH3:22][O:20][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:21]
Reactant: O=C(O)c1cccc2nc3ccc4ccccc4c3nc12
Reactant: O=C(O)c1cccc2nc3c(ccc4ccccc43)nc12
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)c1cccc2nc3ccc4ccccc4c3nc12

Procedure:
The mixture of benzo[a]phenazine-11-carboxylic acid (II.20) and benzo[a]phenazine-8-carboxylic acid (885 mg), prepared as described in Reference Example 1L above, was heated to reflux in a mixture of methanol (40 mL) and acetyl chloride (920 μL) for 90 minutes. The reaction mixture was then cooled slowly to yield the title compound as a single isomer which was collected by filtration (377 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:6])[CH2:4][OH:5].CCN(CC)CC.[Cl:14][CH2:15][C:16](Cl)=[O:17]>CO.CC#N>[Cl:14][CH2:15][C:16]([NH:1][CH2:2][C@H:3]([OH:6])[CH2:4][OH:5])=[O:17]
Reactant: NC[C@H](O)CO
Reactant: O=C(Cl)CCl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CCl)NC[C@H](O)CO
Temperature: -10 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
(S)-3-Amino-1,2-propanediol (16.8 g, 184 mmol) was dissolved in MeOH (90 mL) at room temperature and the solution was diluted with MeCN (550 mL). NEt3 (30.5 mL, 219 mmol) was added and the reaction mixture was cooled to −10° C. Chloroacetyl chloride (22.2 g, 15.6 mL, 197 mmol) was added dropwise at −10° C. during 1.5 h under nitrogen. The temperature was maintained at −10° C. for an additional hour and then the reaction mixture was allowed to reach room temperature and stirred overnight (16 h). The solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, Apollo Scientific silica, 40-60μ, 60 Å, gradient 1% to 10% MeOH in EtOAc). The combined fractions were evaporated to afford 2-chloro-N—[(S)-2,3-dihydroxypropyl]-acetamide (28.5 g, 92%) as a colourless oil which gave a white solid on standing.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[N:12][C:7]3[O:8][CH2:9][CH2:10][NH:11][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Br:26])[C:23]=1[O:24][CH3:25])[C:18](Cl)=[O:19].C(N(CC)CC)C.Cl>ClCCl>[CH:1]1([C:4]2[CH:13]=[N:12][C:7]3[O:8][CH2:9][CH2:10][N:11]([C:18]([C:17]4[CH:21]=[C:22]([Br:26])[C:23]([O:24][CH3:25])=[C:15]([Br:14])[CH:16]=4)=[O:19])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: c1nc2c(cc1C1CC1)NCCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(C4CC4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.7 %

Procedure:
To a 10 ml flask, 7-cyclopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (10 mg, 0.057 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (28 mg, 0.085 mmol) were dissolved in dichloromethane (1.2 ml). After cooling to 0□, triethylamine (0.04 ml, 0.285 mmol) was added thereto and then stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N hydrochloric acid solution and extracted with dichloromethane, and then the combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate and n-hexane (1:1). The fractions containing the product were collected and evaporated to obtain the target compound as white solid (9.0 mg, 33%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Cl[C:11]([F:16])([F:15])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:11]([F:16])[F:15]
Reactant: Oc1ccc(Cl)cc1Br
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(Cl)cc1Br
Temperature: 100 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
To a solution of 2-bromo-4-chlorophenol (4.98 g, 24.0 mmol) in 25 mL DMF was added sodium chlorodifluoroacetate (8.42 g, 55.2 mmol), cesium carbonate (10.97 g, 33.67 mmol) and 2.5 mL water. The reaction was stirred at 100° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (0 to 20% ethyl acetate in heptanes) to yield 2.98 g (48%) of 2-bromo-4-chloro-1-(difluoromethoxy)benzene as a clear, colorless oil. LCMS (ESI) no m/z signal; 1H NMR (400 MHz, DMSO-d6) δ: 7.90 (d, 1H), 7.54 (dd, 1H), 7.38 (d, 1H), 7.28 (t, 1H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][C:11]#[N:12])=[CH:8][CH:7]=1.O.O.[Cl:17][Sn]Cl>Cl>[ClH:17].[NH:5]([C:6]1[CH:14]=[CH:13][C:9]([CH2:10][C:11]#[N:12])=[CH:8][CH:7]=1)[NH2:1]
Reactant: Cl[Sn]Cl
Reactant: N#CCc1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc(NN)cc1
Temperature: -10 °C
Yield: 100 %

Procedure:
A solution of NaNO2 (80 g, 1.16 mol) was added dropwise to a cooled (-10° C.), stirred, suspension of 4-aminobenzyl cyanide (153.5 g, 1.16 mol) in concentrated HCl (1500 ml), at such a rate that the temperature did not rise above -10° C. The mixture was stirred at -10° C. for 0.25 h before being filtered rapidly under vacuum into an addition funnel. The solution was added portionwise over a 0.25 h period to a rapidly stirred mixture of SnCl2.2H2O (1.05 kg, 4.64 mol) in concentrated HCl (800 ml) keeping the temperature below -5° C. The mixture was allowed to warm to room temperature and stir for 0.25 h before filtering the sandy coloured precipitate under vacuum and washing with ether (5×500 ml). The resultant solid was dried over P2O5 in a vacuum oven (80° C.) for 16 h to give the title compound (213 g, 100%), m.p. 181°-183° C.; 1H NMR (360MHz, D2O) δ3.90 (2H, s, CH2); 7.06 (2H, d, J=8.7 Hz, Ar--H); 7.40 (2H, d, J=8.7 Hz, Ar--H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]#[N:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH-].[K+].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[S:19].C(OCC)(=O)C>CC(C)=O.O>[C:12]([C:3]1[C:2]([O:1][C:18](=[S:19])[N:17]([CH3:21])[CH3:16])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)#[N:13]
Reactant: CN(C)C(=S)Cl
Reactant: N#Cc1cc2c(cc1O)CCCC2
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C(=S)Oc1cc2c(cc1C#N)CCCC2
Reaction time: 0.75 h
Yield: 64.3 %

Procedure:
To a solution of 3-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbonitrile prepared in method II-2 (3.00 g, 17.3 mmol) in acetone (60 mL) was added dropwise a solution of potassium hydroxide (1.07 g, 19.1 mmol, 1.1 eq) in water (40 mL) at 0° C. After stirring for 45 min, a solution of dimethylthiocarbamoyl chloride (2.35 g, 19.1 mmol, 1.1 eq) in acetone (40 mL) was added at 0° C. over 30 min. The reaction mixture was then stirred at room temperature for 16 h, and poured into ethyl acetate and water. The organic layer was washed with saturated aqueous ammonium chloride, water, and brine. The combined aqueous wash was re-extracted with ethyl acetate, and the organic washes were dried over magnesium sulfate and evaporated at reduced pressure. The crude oil was crystallized from ether/hexane to give dimethyl-thiocarbamic acid O-(3-cyano-5,6,7,8-tetrahydro-naphthalene-2-yl) ester (2.90 g, 64.3%) as a beige solid. 1H-NMR (Acetone-d6) δ 7.46 (s, 1H), 6.98 (s, 1H), 3.43 (d, J=4.2 Hz, 6H), 2.80 (m, 4H), 1.81 (m, 4H); MS ES (MH+=261). Rf=0.70 (30% ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:6])=[O:5])[CH3:2].[Fe:11]>[Cl-].C([N+](CC)(CC)CC)C.O>[CH3:10][CH2:9][CH2:8][CH2:7][CH:3]([C:4]([O-:6])=[O:5])[CH2:1][CH3:2].[CH3:10][CH2:9][CH2:8][CH2:7][CH:3]([C:4]([O-:6])=[O:5])[CH2:1][CH3:2].[CH3:10][CH2:9][CH2:8][CH2:7][CH:3]([C:4]([O-:6])=[O:5])[CH2:1][CH3:2].[Fe+3:11]
Reactant: CCCCC(CC)C(=O)O
Reactant: [Fe]
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: O
Product: CCCCC(CC)C(=O)[O-]
Product: [Fe+3]

Procedure:
To a reaction flask equipped with a mechanical agitator and thermometer was charged 10.0 g (0,069 mole) of 2-ethylhexanoic acid, 10.0 g mineral spirit, 80.0 g water and 0.40 g tetraethylammonium chloride. Iron foil was used as the anode and a graphite rod as the cathode. After passing 11,109 coulombs of direct current, 3.43 g (0,061 mole) of iron was consumed. The precipitated brown solid was then filtered and dried, and found to contain 45.60% iron. The organic layer was separated from the aqueous phase and was dried to give a brown solution of iron octoate in mineral spirits containing 14.10% iron.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1.[CH3:30][C:31]1([CH3:44])[CH2:43][O:42][C:34]2([CH2:38][C@@H:37]([C:39](O)=[O:40])[CH2:36][CH2:35]2)[O:33][CH2:32]1>ClCCl.CC(C)=O>[CH3:30][C:31]1([CH3:44])[CH2:32][O:33][C:34]2([CH2:38][C@@H:37]([C:39]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:40])[CH2:36][CH2:35]2)[O:42][CH2:43]1
Reactant: CC1(C)COC2(CC[C@H](C(=O)O)C2)OC1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)COC2(CC[C@H](C(=O)OCc3ccccc3)C2)OC1
Temperature: 27.5 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
Benzyl alcohol (7.28 ml, 70.0 mmol), DCC (0.43 g, 2.1 mmol) and a catalytic amount of 4-dimethylammino pyridine (0.20 g, 1.68 mmol) were successively added to a solution of (S)-8,8-dimethyl-6,10-dioxaspiro[4.5]decane-2-carboxylic acid (Synthesized following procedure as described in DE4312832 and US20080161564, 3 g, 14.00 mmol) in anhydrous Dichloromethane (50 ml). The reaction mixture was stirred for 24 h at 25-30° C. and then acetone (10 ml) was added. The resulting suspension was filtered and subsequently concentrated under vacuum. The residue was purified by silica gel column chromatography using ethyl acetate in hexane as eluents to obtain (S)-benzyl 8,8-dimethyl-6,10-dioxaspiro[4.5]decane-2-carboxylate (3.5 g, 82%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([CH3:30])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([CH3:30])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc([N+](=O)[O-])c(C)cc1N
Product: COc1cc([N+](=O)[O-])c(C)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (51 mg, 0.194 mmol) and 2-methoxy-5-methyl-4-nitroaniline (43 mg, 0.236 mmol) similar to Example 160 and was isolated as off-white crystalline solid (mp 128-133° C., 23 mg, 0.057 mmol, 29%). 1H NMR (CDCl3/MeOH-d4): 9.42 (s, 1H), 8.75 (m, 1H), 8.62 (m, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.42 (dd, J=4.8, 8.1 Hz, 1H), 6.82 (s, 1H), 4.01 (s, 3H), 2.01 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=O)=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH3:18]>>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][NH:27][C:24]2[CH:23]=[CH:22][C:21]([C:20]([O:19][CH2:17][CH3:18])=[O:28])=[CH:26][CH:25]=2)=[N:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nccnc1OCc1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NCc2nccnc2OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
2-Benzyloxypyrazine-3-aldehyde (455 mg) was mixed with ethyl-4-aminobenzoate (321 mg) and stirred at 120° C. for 1 hour. The solid was then azeotroped with toluene (20 mL) to remove the last traces of water. The residue was dissolved in ethanol (10 mL) under argon, and sodium borohydride (81 mg) added with stirring at ambient temperature. The mixture was then heated to reflux for one hour, and allowed to cool to ambient temperature over 16 hours. Water (70 mL) was added, and the mixture acidified to pH 3 with acetic acid and then extracted with ethyl acetate (4×10 mL), washed with water (50 mL), brine (50 mL) and dried over magnesium sulphate. The residue was purified by MPLC (3% ethyl acetate in dichloromethane, silica) to give ethyl 4-[2-benzyloxypyrazin-3-ylmethylamino]benzoate yield, 460 mg, mp 111.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.Cl[C:26](OC1C=CC=CC=1)=[O:27].[CH3:35][O:36][CH2:37][CH2:38][CH2:39][NH2:40]>C1COCC1>[Cl:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:17])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26]([NH:40][CH2:39][CH2:38][CH2:37][O:36][CH3:35])=[O:27])[CH:7]=1)=[O:18]
Reactant: Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Reactant: COCCCN
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCCCNC(=O)Nc1cc(NC(=O)c2c(Cl)cccc2Cl)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To a solution of N-(2-amino-pyridin-4-yl)-2,6-dichloro-benzamide (281 mg, 1.0 mmol) in anhydrous THF (5 mL) were added pyridine (97 μL, 1.2 mmol) and phenyl chloroformate (138 μL, 1.1 mmol). The reaction mixture was stirred at room temperature for 1 hr and then 3-methoxy propylamine (123 μL, 1.2 mmol) was added. The reaction mixture was stirred for 1 hr then partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was washed with 1 N HCl, water and brine, dried over sodium sulfate, and concentraged under reduced pressure. The residue was purified by silica gel column chromatography (EtOAC/cyclohexane: gradient 0% to 100%) to give the desired compound (105 mg, yield: 26%). NMR (400 MHz, DMSO-d6): δ 11.09 (br s, 1H), 9.18 (br s, 1H), 8.20 (br s, 1H), 8.09 (d, J=5.7 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.57-7.58 (m, 2H), 7.51 (dd, J=9.2, 6.8 Hz, 1H), 7.24 (dd, J=5.7, 1.9 Hz, 1H), 3.37 (t, J=6.2 Hz, 2H), 3.24 (s, 3H), 3.21-3.19 (m, 2H), 1.69 (m, 2H). LCMS (ESI) m/z: 397, 399 [M+H]+.