Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[H][H].[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C@@H:15]2[C@H:20]([NH:21][C@@H](C3C=CC=CC=3)C)[CH2:19][CH2:18][O:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH3:5]>[Pd].CO>[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C@@H:15]2[C@H:20]([NH2:21])[CH2:19][CH2:18][O:17][CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH3:5]
Reactant: [H][H]
Reactant: CCOc1cc([C@H]2COCC[C@H]2N[C@H](C)c2ccccc2)ccc1OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOc1cc([C@H]2COCC[C@H]2N)ccc1OC
Temperature: 25 °C

Procedure:
A suspension of 50 mmol of 3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-one, 75 mmol of (R)-phenylethyl amine, 5 mmol of p-toluenesulfonic acid mono-hydrate and 1 g of platin-on-carbon catalyst (3% Pt) in 400 ml of absolute methanol is hydrogenated at 60° C. and 100 mbar hydrogen pressure until no further ketone can be detected by TLC. After cooling to RT the suspension is filtered over a tonsil layer and the filtrate is concentrated under vacuum. The viscous residue is partitioned between dichloromethane and 20% citric acid solution. The pH of the aqueous phase is neutralized to about 6.0 with diluted sodium hydroxide solution and the aqueous phase is extracted 4 times with dichloromethane. The combined organic phases are dried over sodium sulfate and concentrated under vacuum yielding [(3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-yl]-((R)-1-phenyl-ethyl)-amine as main compound. The viscous residue is not further purified and used for the next step as raw product as it is. The viscous residue is dissolved in 1.2 equivalent of 37% hydrochloric acid and methanol and palladium-on-carbon catalyst is added. The slurry is hydrogenated at 60° C. and 100 mbar hydrogen pressure until no further [(3R,4R)-3-(3-ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-yl]-((R)-1-phenyl-ethyl)-amine can be detected by TLC. After cooling to RT the suspension is filtered over a tonsil layer and the filtrate is concentrated under vacuum. The viscous residue is purified by silica gel or aluminium oxide chromatography. The main product fraction is concentrated in vacuo and affords the title compound as solid foaming residue.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5](Cl)[CH2:4][CH2:3]1.[Mg].[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[C:25](=[O:26])[C:20]3[NH:21][CH2:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][C:16]=2[CH:27]=1)#[N:11].[Cl-].[NH4+]>O1CCCC1>[C:10]([C:12]1[CH:13]=[CH:14][C:15]2[C:25]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)([OH:26])[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH2:18][CH2:17][C:16]=2[CH:27]=1)#[N:11]
Reactant: N#Cc1ccc2c(c1)CCC1=C(NCC=C1)C2=O
Reactant: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccc(C#N)cc3CCc3cccnc32)CC1
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
Into a tetrahydrofuran (THF) solution of a Grignard reagent prepared from 6.7 g of N-methyl-4-chloropiperidine and 1.2 g of magnesium, 4.68 g of 8-cyano5,6-dihydro-1H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (the compound prepared in Referential Example 1) were added under ice cooling. After the resultant mixture was stirred for 3 hours at room temperature, a saturated aqueous solution of ammonium chloride was added, followed by stirring for 15 minutes. The reaction mixture was then extracted with chloroform. The Extract was dried over anhydrous Na2SO4 and then filtered. The filtrate so obtained was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (50:1), 3.1 g of 8-cyano-6,11-dihydro-11-(1-methyl-4-piperidyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol were obtained (yield: 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 100.1 %

Procedure:
The mixture of 4-chloro-3-(trifluoromethyl)phenol (3.2 g, 16.28 mmol), 4-fluorobenz aldehyde (2.425 g, 19.54 mmol) and K2CO3 (3.38 g, 24.42 mmol) in DMF (25 mL) was heated with a microwave reactor at 120° C. for 20 min. Purification via an ISCO system then afforded the title compound as a yellow solid (4.9 g, 100% yield). LCMS: rt=3.78 min, [M+H+]=300.9
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[CH:10][C:5]=23)[CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Product: COc1cccc(Nc2nc(-c3ccncc3)nc3c2cnn3C)c1

Procedure:
6-Chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6 was reacted with pyridine-4-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 123. NMR: (CDCl3): 3.89 (s, 3H, CH3), 4.14 (s, 3H, CH3), 6.89-6.92 (m, H, ArH), 7.16 (m, H, ArH), 7.25 (s, H, ArH), 7.41 (t, H, ArH, J=8.1 HZ), 7.49 (sbr, H, NH), 8.39 (dd, 2H, 2×ArH, J=1.5 Hz, 4.5 Hz), 8.80 (dd, 2H, 2×ArH, J=1.5 Hz, 4.5 Hz). MS: (ESI+) MH+=333.24
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Mg]Br)=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2.S1C(CCCCCCBr)=CC2C=CC=CC1=2.[Mg].BrCCBr.[CH3:39][Si:40]([CH3:49])([CH3:48])[C:41]1[O:45][CH:44]=[C:43]([CH:46]=[O:47])[CH:42]=1>O1CCCC1>[S:1]1[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:46]([C:43]2[CH:42]=[C:41]([Si:40]([CH3:49])([CH3:48])[CH3:39])[O:45][CH:44]=2)[OH:47])=[CH:4][C:3]2[CH:14]=[CH:15][CH:16]=[CH:17][C:2]1=2
Reactant: Br[Mg]CCCCCCc1cc2ccccc2s1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: BrCCCCCCc1cc2ccccc2s1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)CCCCCCc2cc3ccccc3s2)co1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 6-(benzo[b]thien-2-yl)hexylmagnesium bromide (1.22 mmol, prepared from 1.22 mmol 6-(benzo[b]thien-2-yl)-1-bromohexane and 2.44 mmol magnesium, initiated with a catalytic amount of 1,2-dibromoethane) in 1.5 ml tetrahydrofuran at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.167 g., 0.99 mmol) in 1 ml tetrahydrofuran. This solution was allowed to warm to room temperature, stirred for 30 minutes, and then quenched with a 5% ammonium chloride solution. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a pale yellow oil. This material was purified by flash chromatography (silica, 100% hexane to 20% ethyl acetate/hexane) to give the desired alcohol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[OH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35](B4OC(C)(C)C(C)(C)O4)[CH:36]=3)[C:31]2=[O:48])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:35]3[CH:36]=[C:37]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:48])[N:30]([C@H:27]3[CH2:26][CH2:25][C@H:24]([OH:23])[CH2:29][CH2:28]3)[CH2:38]4)[C:16]2=[CH:15][N:14]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CN([C@H]2CC[C@H](O)CC2)C3=O)OC1(C)C
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CN([C@H]4CC[C@H](O)CC4)C5=O)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 7 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-(trans-4-hydroxycyclohexyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=554.1/556.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[BH4-].[Na+].CO.Cl>C1COCC1>[OH:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:11]=[C:10]([O:12][C:13]([F:14])([F:15])[F:16])[CH:9]=1)[C:1]#[N:2]
Reactant: N#Cc1cc(OC(F)(F)F)cc(C(=O)Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(CO)cc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.9 %

Procedure:
3-Cyano-5-(trifluoromethoxy)benzoyl chloride (844 mg, 3.38 mmol) was dissolved in THF (10 mL) and cooled to 0° C. Sodium borohydride (320 mg, 8.45 mmol) was added, followed by methanol (2 mL) and the reaction was stirred for 20 min at 0° C. before it was allowed to warm to room temperature. After 2 h, the reaction mixture was acidified to pH 3 with 1.0 M HCl. The aqueous mixture was extracted with ethyl acetate and the combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (440 mg). LCMS m/z=218.3 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[CH3:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][SH:12])=[CH:9][CH:8]=1.[H-].[Na+]>O1CCCC1>[CH3:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][S:12][CH2:1][CH:3]([OH:5])[CH2:4][S:12][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([CH3:6])=[CH:8][CH:9]=2)=[CH:9][CH:8]=1
Reactant: BrCC1CO1
Reactant: Cc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CSCC(O)CSCc2ccc(C)cc2)cc1

Procedure:
Epibromohydrin (1.37 g.) in 2 ml. dry tetrahydrofuran is added to a stirred suspension of the salt obtained by mixing 3 g. of 4-methylbenzyl mercaptan and 550 mg. of sodium hydride (56% dispersion in mineral oil) in 60 ml. dry tetrahydrofuran. The resulting solution is heated at reflux for 4 hours. Thereafter, the solvent is removed and 30 ml. of water is added to the residue. The resultant aqueous mixture is extracted with ether and the ether extracts washed with water, dried over magnesium sulfate and evaporated to dryness to yield 1,3-bis(4'-methylbenzylthio)-2-propanol.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=O)[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:20][OH:21].Cl>N1C=CC=CC=1.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[N:20][OH:21])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: ON=C1CCCc2cc(OCCn3ccnc3)ccc21
Yield: 83.2 %

Procedure:
A solution of 1.0 g (3.9 mmol) of 6-[2-(1H-1-imidazolyl)ethoxy]-1,2,3,4-tetrahydro-1-naphthalenone in 10 mL of pyridine was treated with 0.41 g (5.9 mmol) of hydroxylamine×HCl and the solution heated at reflux overnight. The solution was diluted with H2O and the product collected and dried. There was obtained 0.88 g (83% yield) of the product as a white solid, mp 177-179° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 272 (M+H+).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C:6]([OH:26])([CH2:23][CH:24]=[CH2:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])[CH:4]=[CH2:5].Cl>>[CH2:3]([C:6]([OH:26])([CH2:23][CH:24]=[CH2:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:21])([CH3:22])[C:19]([OH:1])=[O:20])[CH:4]=[CH2:5]
Reactant: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(=O)O
Yield: 46 %

Procedure:
The NaOH extracts from the product of Example 7 were brought to pH 2 with dilute HCl and extracted with ether. These extracts were dried (Na2SO4), evaporated and the yellow glass dried at 30° centigrade/0.5 mm. yielding 18.4 g (46%) of the title compound. A 0 28 g-sample prepared in this manner was flash chromatographed on a 1×15 cm column of silica gel in 20% C2H5OCOCH3 --CH2Cl2 and furnished 0.13 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[C:13]([CH3:23])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[C:13]([CH3:23])=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10])[OH:22]
Reactant: COc1ccc(Cl)cc1Br
Reactant: Cc1c(Cl)ccc2c1C(=O)C(=O)N2
Product: COc1ccc(Cl)cc1C1(O)C(=O)Nc2ccc(Cl)c(C)c21
Yield: 71.7 %

Procedure:
With 4.75 g of 2-bromo-4-chloro-1-methoxy benzene and 1.96 g of 5-chloro-4-methyl-1H-indol-2,3-dione as starting materials, 2.43 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].ClC1C2C(=CC=CC=2)C=CC=1.[C:21](Cl)(Cl)=[O:22]>>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[C:21]=[O:22])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(F)c(F)c1
Solvent: Clc1cccc2ccccc12
Product: O=C=Nc1ccc(F)c(F)c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
At -10° to 0° and while stirring, 120 g of 3,4-difluoroaniline (J. Chem. Soc., 73, 5884-5, 1951) is metered into a solution of 180 parts by weight of phosgene in 1,100 parts by weight of chloronaphthalene. The reaction mixture is then slowly heated to 150° C. while passing in additional phosgene, and phosgenated for 2 hours at this temperature. Excess phosgene is expelled with nitrogen and the isocyanate distilled from the solution; b.p. (30 mm Hg): 79°-85° C.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[C:5]([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7]=2[CH:13]=1.C([Li])CCC.[CH2:39]([O:46][C:47]1[CH:54]=[CH:53][C:50]([CH:51]=O)=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH:51]=[CH:14][C:5]2[C:6]3[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][C:7]=3[CH:13]=[C:3]([F:2])[CH:4]=2)=[CH:53][CH:54]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC1(C)Cc2cc(F)cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2O1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(F)cc(C=Cc3ccc(OCc4ccccc4)cc3)c2O1
Reaction time: 3 h

Procedure:
To a solution of ((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl)triphenyl phosphonium chloride (648) (500 mg, 1.09 mmol) in anhydrous tetrahydrofuran at room temperature (10 mL) was added n-butyllithium (0.67 mL, 1.31 mmol, 2 M in hexane). After stirring for 10 min 4-(benzyloxy)benzaldehyde (231 mg, 1.09 mmol) was added and stirred for an additional 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (20%) to give 7-(4-(benzyloxy)styryl)-5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran as a cis/trans mixture (649).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:10]12[CH2:15][CH:14]1[C:13](=[O:16])[O:12][C:11]2=O>>[C:1]1([CH2:7][CH2:8][N:9]2[C:11](=[O:12])[CH:10]3[CH:14]([CH2:15]3)[C:13]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: NCCC1=CCCCC1
Product: O=C1C2CC2C(=O)N1CCC1=CCCCC1
Temperature: 180 °C

Procedure:
A mixture of 2-(cyclohexen-1-yl)ethylamine (0.59 g) and 3-oxabicyclo[3.1.0]hexane-2,4-dione (0.5 g) was heated at 180° C. for 3 hours. The resulting mixture was cooled to room temperature to give the title compound as a yellow solid, m.p. 60-61° C.
Reaction SMILES: C(OC([NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1)([CH3:14])[CH3:13])=O)C1C=CC=CC=1.[H][H]>CO.C(Cl)(Cl)Cl.[C].[Pd]>[NH2:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1)([CH3:13])[CH3:14]
Reactant: CC(=O)NCc1ccc(C(C)(C)NC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)NCc1ccc(C(C)(C)N)cc1
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of N-(4-(1-benzyloxycarbonylamino-1-methylethyl)phenylmethyl)acetamide (9.57 g) in methanol (200 ml) and chloroform (200 ml) was added 10% palladium-carbon (5.0 g) and the mixture was stirred for 5 hr while introducing a hydrogen gas. The reaction mixture was passed through Celite and the solvent was evaporated to give the title compound (5.8 g) as a pale-yellow amorphous solid.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.Br[C:13]1[CH:18]=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=1>C1COCC1>[O:19]1[C:16]2[CH:17]=[CH:18][C:13]([C:7]3([OH:10])[CH2:6][CH2:5][C:4]4([O:3][CH2:2][CH2:1][O:11]4)[CH2:9][CH2:8]3)=[CH:14][C:15]=2[O:21][CH2:20]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Yield: 52 %

Procedure:
A solution of 1,4-cyclohexanedione monoethylene ketal in dry THF was reacted with the Grignard reagent prepared from 4-bromo-1,2-methylenedioxybenzene as described in example 1 to give the product (52%, mp: 95°-96° C.). Calc'd for C15H18O5 : C, 64.74%; H, 6.52%. Found: C, 64.41%; H, 6.41%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[CH:8](O)[N:7]1[CH:21]=[O:22])=[O:5])[CH3:2].CO.[H][H]>[Ni].C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:5])[C:6]([NH:7][CH:21]=[O:22])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][C:9]1[C:11]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:17][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(c2ccccc2[N+](=O)[O-])C(O)N1C=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(Cc1c[nH]c2ccccc12)(NC=O)C(=O)OCC
Temperature: 25 °C
Yield: 97.9 %

Procedure:
50.0 g (0.13 mol) of the compound of Example 4 in 500 ml. of methanol and 1 ml of acetic acid was hydrogenated in a rocking autoclave at room temperature and 200 psi in the presence of 6 g. of Raney nickel. After the hydrogen uptake (3 equivalents) was complete the filtered reaction mixture was concentrated in vacuo to a volume of 140 ml. Toluene (600 ml.) was added and the remaining methanol was removed by azeotropic distillation. The mixture was heated at reflux for an additional 30 minutes and then allowed to cool to room temperature. The precipitate was collected, washed with toluene and dried to yield 42.3 g (97%) of white crystals, m.p. 179-180° (lit. m.p. 179°). The analytical sample was prepared by recrystallization from ethaniol: m.p. 180-181°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][C:12]1[C:17]([S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>C(#N)C.O>[Cl:11][C:12]1[C:17]([S:18]([NH:21][C:22]([NH:1][C:2]2[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2)=[O:23])(=[O:19])=[O:20])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C=NS(=O)(=O)c1cccnc1Cl
Reactant: COc1cc(C)nc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccnc2Cl)n1

Procedure:
To a stirred suspension of 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 20 ml of dry acetonitrile at room temperature was added 2.2 g of 2-chloropyridine-3-sulfonylisocyanate. The mixture was stirred for several hours and filtered. Evaporation of the filtrate yielded a solid residue which was stirred in approximately 30 ml of water while adjusting the pH of this mixture to 11 by the addition of 10% of NaOH. This solution was filtered, the filtrate pH adjusted to pH 7 by adding 10% hydrochloric acid and the resulting neutral solution was again filtered. The desired product was then precipitated from this filtrate by adjusting the pH to 2, collected in a sintered funnel and dried in a vacuum oven at room temperature. It melted at 165°-168°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C@@H:7]([CH2:12][CH2:13][CH3:14])[CH2:6][C@H:5]2[NH:15][CH:16]=[O:17].[C:18](Cl)(=[O:20])[CH3:19].N1C=CC=CC=1>C(Cl)Cl>[C:18]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[C@H:5]([NH:15][CH:16]=[O:17])[CH2:6][C@@H:7]1[CH2:12][CH2:13][CH3:14])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: CCC[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1C(C)=O
Reaction time: 1 h
Yield: 68 %

Procedure:
[(cis)-6-Bromo-2-propyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (for a preparation see intermediate 89) (8.0 g, 26.9 mmol) in DCM (100 mL) was added dropwise at room temperature to a mixture of acetyl chloride (6.7 mL, 94.28 mmol) and pyridine (10.85 mL, 134.7 mmol) in DCM (150 mL). The resulting mixture was stirred at this temperature for 1 h then was washed with 1M NaOH aqueous solution, 1M HCl aqueous solution, a saturated NaHCO3 aqueous solution then brine, was dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue by flash chromatography on silica gel (20:1 DCM/MeOH) gave [(cis)-1-acetyl-6-bromo-2-propyl-1,2,3,4-tetrahydro-4-quinolinyl]formamide (6.29 g, 18.5 mmol, 68%) as a light orange solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH3:14]
Reactant: CCCC1(C(=O)OCC)CCCC1O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h
Yield: 109.7 %

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.67 ml) was slowly added, then benzoyl chloride (5.33 ml, 0.045 mol) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 10.00 g of yellow liquid, MS: m/e 305(M+″+1), 304(M+), 259, 230, 199, 182, 153, 105(base), 77.
Reaction SMILES: N#N.[N+:3]([C:6]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])([O-:5])=[O:4].[N+:16]([CH2:19][CH3:20])([O-:18])=[O:17].[F-].[K+]>O.C(O)(C)C>[N+:3]([C:6]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]([OH:9])[CH:19]([N+:16]([O-:18])=[O:17])[CH3:20])([O-:5])=[O:4]
Reactant: CC[N+](=O)[O-]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Agent: N#N
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COc1cccc(C(O)C(C)[N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a 2 L round-bottomed flask equipped with a magnetic stirrer and a N2 bubbler were added 2-nitro-3-methoxybenzaldehyde (125.7 g, 0.6939 mol), nitroethane (73 g, 0.97 mol), 18-C-6 (18 g), isopropanol (420 mL) and KF (20 g). The mixture was stirred at RT for 16 h. The solvent was removed under vacuum to give an oil. Isopropanol (100 mL) and water (250 mL) were added. The mixture was placed under vacuum to give a slurry. The slurry was stirred for 1 h and filtered. The cake was washed with water (4×100 mL) and dried to give 1-(2-nitro-3-methoxyphenyl)-2-nitropropanol as a diastereomeric mixture in a ratio of 3:2 (170.3 g, 96% yield). 1H NMR for major isomer (CDCl3) δ1.38 (d, J=6.9 Hz, 3H), 2.94 (s, 1H), 3.92 (s, 3H), 4.90 (m, 1H), 5.08 (d, J=8.6 Hz, 1H), 7.05-7.52 (m, 3H). 1H NMR for minor isomer (CDCl3) δ1.55 (d, J=6.9 Hz, 3H), 2.94 (s, 1H), 4.80 (m, 1H), 5.46 (d, J=3.0 Hz), 7.05-7.52 (m, 3H).