Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([OH:17])[C:6]=1[CH:7]=[O:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:17][C:9]1[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[CH:7]=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1cc(O)c(C=O)c(C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(OCc2ccccc2)c(C=O)c(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1.17 g (5.0 mmol) of 2,4-di-tert-butyl-6-hydroxybenzaldehyde (from Step A of Example 35) in 10 mL of dry DMF was added 0.25 g (10.4 mmol) of powdered sodium hydride and the resulting mixture was stirred for 30 min under a nitrogen atmosphere. Benzyl bromide (1.0 g, 5.9 mmol) was then added and the resulting mixture was stirred for an additional 3 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ether and water. The aqueous layer was re extracted with ether and the organic layers were then combined, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0-10% EtOAc-hexane. Combination of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10]([F:13])([F:12])[CH:9]([C:14]3[N:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1.[H-].[Na+].[CH2:32](Br)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].O>CN(C=O)C>[CH2:32]([O:20][C:17]1[CH:16]=[N:15][C:14]([CH:9]2[C:10]([F:12])([F:13])[C:11]3[C:2]([F:1])=[N:3][C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:19][CH:18]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCOc1cc2c(c(F)n1)C(F)(F)C(c1ncc(O)cn1)CC2
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cnc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2(F)F)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1,8,8-trifluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxy-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1,8,8-trifluoro-3-octyloxy-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].CO>N1C=CC=CC=1>[S:23]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[O:13][C:12]([C:14]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)([CH3:22])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccc(CN2CCC(O)CC2)o1)N1CCCCC1
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)OC1CCN(Cc2ccc(C(=O)N3CCCCC3)o2)CC1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 91.8 %

Procedure:
In 70 ml of pyridine was dissolved 3.47 g (11.88 mmol) of Compound t and with ice-cooling, 1.9 ml (23.77 mmol) of methanesulfonyl chloride was added dropwise. The mixture was stirred at 0° C. for 4.5 hours and, after addition of 5 ml of methanol, stirred at room temperature for 30 minutes. The solvent was then distilled off under reduced pressure and the residue was dissolved in 100 ml of methylene chloride. This solution was washed with 3 portions of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 4.04 g (91.8%) of 1-[5-(4-mesyloxypiperidinomethyl)-2-furancarbonyl]piperidine (Compound u) as red-brown oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([N+:35]([O-:37])=[O:36])[CH:34]=1)[C:29](Cl)=[O:30])([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([N+:35]([O-:37])=[O:36])[CH:34]=1)[C:29]([NH:2][C@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:30])([O-:25])=[O:24]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCOC(=O)C[C@H](N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
11.49 g of ethyl (S)-3-amino-3-phenylpropionate hydrochloride were suspended in 100 ml of tetrahydrofuran and cooled to 0-10° C. in an icebath. After adding 14 ml of triethylamine, a solution of 11.52 g of 3,5-dinitrobenzoyl chloride in 40 ml of tetrahydrofuran was added with stirring and cooling over a period of 30 min. The cooling bath was removed, and the reaction mixture stirred for a further 120 min, in the course of which it warmed to room temperature. The reaction mixture was filtered, and the filtrate concentrated to dryness (product fraction 1). The filtercake—consisting of triethylamine hydrochloride and further product—was taken up in 100 ml of ethyl acetate and digested at 35° C. for 20 min. The suspension was filtered, and the filtercake discarded. The filtrate was concentrated to dryness under reduced pressure at 40° C. (product fraction 2). The product fractions were combined. Yield: 16.4 g; HPLC purity >97 area %. For further purification, the crude product was digested in 400 ml of water at room temperature for 2 h and then filtered. The moist yield was 15.4 g; HPLC purity 99.8 area %. The product was reacted further without further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1>C(OCC)C>[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([N+:1]([O-:4])=[O:2])[C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
65% aq. nitric acid solution (2.4 mL, 54 mmol) and fuming nitric acid (2.2 mL, 54 mmol) were added at −10° C. to a solution of 3-chloro-4-hydroxy-benzoic acid methyl ester (5.00 g, 26.8 mmol) in diethyl ether (65 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to afford 3-chloro-4-hydroxy-5-nitro-benzoic acid methyl ester (6.24 g, 100%). Yellow solid, MS (ISP)=230.3 (M−H)−.
Reaction SMILES: C(O)=O.C(N(CC)CC)C.[CH:11]([CH:13]1[CH2:18][O:17][CH2:16][CH2:15][N:14]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O.[CH3:26][C:27]1(C)[O:34]C(=O)CC(=O)[O:28]1>[OH-].[Na+]>[C:22]([O:21][C:19]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH:13]1[CH2:11][CH2:26][C:27]([OH:34])=[O:28])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCOCC1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(C)(C)OC(=O)N1CCOCC1CCC(=O)O
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
A mixture of formic acid (2.26 mL, 58.9 mmol) and triethylamine (3.36 mL, 24.11 mmol) was stirred for 5 minutes in an ice bath. To the mixture were added tert-butyl 3-formylmorpholine-4-carboxylate (0.47 g, 2.2 mmol) and Meldrum's acid (0.32 g, 2.2 mmol) in turn at 0° C. The reaction mixture was heated at 100° C. for 5 hours, and cooled down in an ice bath. To the resulting mixture was added aqueous NaOH solution (2 mol/L, 40 mL). The aqueous layer was extracted with EtOAc (50 mL×3) and the organic layer was discarded. To the aqueous layer was added EtOAc (80 mL), and the mixture was adjusted to pH 4-5 with HCl (1 mol/L) under stirring. The aqueous layer was extracted with EtOAc (80 mL). The organic layer was dried over anhydrous Na2SO4, then filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (0.23 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:19])[CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:19])[CH2:17][N:36]1[CH2:37][CH2:38][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(Cc2ccccc2)c1NC(=O)CBr
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: Cc1cccc(Cc2ccccc2)c1NC(=O)CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The compound (13) synthesized in Reference Example 13 and the compound (4) synthesized in Reference Example 4 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [Li+].C[CH:3]([N-:5][CH:6]([CH3:8])[CH3:7])[CH3:4].COC(C#N)=O.[CH2:15]1[CH2:19]OC[CH2:16]1>>[NH:5]1[C:6]2[C:7](=[CH:16][CH:15]=[CH:19][CH:8]=2)[CH:4]=[CH:3]1
Reactant: C1CCOC1
Reactant: CC(C)[N-]C(C)C
Agent: COC(=O)C#N
Agent: [Li+]
Product: c1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 1 (473 mg, 1.40 mmol) in THF (6.5 mL) at −78° C. was added dropwise a 1.8 M solution of LDA in THF (1.71 mL, 3.08 mmol) and the reaction stirred for 1 hour, then methylcyanoformate (0.244 mL, 3.08 mmol) added dropwise and the reaction was stirred for 1 hour. The reaction was quenched by the addition of satd NH4Cl (10 mL), the layers separated, and the aqueous extracted with Et2O (3×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on silica gel gradiently eluted with 20 to 30% EtOAc/hexanes to give 2 (153 mg, 28% yield) as an off-white solid. Rt=1.83 min using Phenomenex 30×4.6 5u column with flow rate of 5 mL/min over 2 min gradient. 0 to 100% B. Solvent A=10/90/0.1% MeOH/H2O/TFA. Solvent B=90/10/0.1%. [M+H]=396.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[O:5].Cl.[CH3:12][S:13]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14].CCN(C(C)C)C(C)C>C(#N)C>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([N:19]2[CH2:20][CH2:21][CH:16]([S:13]([CH3:12])(=[O:15])=[O:14])[CH2:17][CH2:18]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1F
Reactant: CS(=O)(=O)C1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)C1CCN(c2cccc(F)c2C=O)CC1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
In a 250 mL round bottom flask, 2,6-difluorobenzaldehyde (7.12 g, 5.4 mL, 50.1 mmol), 4-methanesulfonylpiperidine hydrochloride (10 g, 50.1 mmol) and DIPEA (7.77 g, 60.1 mmol) were combined with acetonitrile (75 mL). The mixture was stirred and heated at 80° C. overnight. The mixture was evaporated and extracted with dichloromethane and citric acid solution. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The crude solid was triturated with cold ethyl acetate to afford 2-fluoro-6-(4-methanesulfonylpiperidine-1-yl)benzaldehyde (12 g, 84% yield). LC-MS calcd for C13H16FNO3S (m/e) 285.08, obsd 286.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][OH:12].C(S)[CH2:14][S:15]([O-])(=O)=O.[Na+]>CS(C)=O.CO>[OH:12][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[S:15][CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(CO)c1
Reactant: O=S(=O)([O-])CCS
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CSc1ccc([N+](=O)[O-])cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
To a solution of 4-chloro-3-(hydroxymethyl)nitrobenzene (20 g, 0.10 mol) in DMSO (160 mL) and MeOH (80 mL), MeSNa (8.2 g, 0.12 mol) was added portionwise at 0° C. and the mixture was stirred for 2 h at room temperature. The mixture was poured into ice water (300 mL) and the yellow precipitate was collected by filtration and washed with ether (150 mL) gave the title compound (21 g, quantitative).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][O-:11].[Na+].CO>CO>[CH3:10][O:11][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: N#Cc1cnccc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccncc1C#N
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of compound (20)(2.77 g, 20.0 mmol) in methanol (5 ml) was added a 28% sodium methylate-methanol solution (5.0 g, 24.0 mmol) at room temperature and the mixture was stirred for one hr. The solvent was concentrated and the obtained residue was partitioned between ethyl acetate and iced-brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from a small amount of isopropyl ether to give the title compound (2.3 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.Br>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(-c3ccc(Br)cc3)nccc2c1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Oc1ccc2c(-c3ccc(Br)cc3)nccc2c1
Temperature: 25 °C

Procedure:
The 1-(4-bromo-phenyl)-6-methoxy-isoquinoline obtained is boiled under reflux in 53 ml of acetic acid and 37 ml of 62% aqueous hydrobromic acid. Subsequently, after cooling to room temperature and addition of 150 ml of ethyl acetate the separated precipitate is filtered off. The crystals are washed with ethyl acetate and dried. There are obtained 7.6 g of 1-(4-bromo-phenyl)-isoquinolin-6-ol, MS: m/e 300 (M+H+, 1 Br).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16](O)[O:15][C:14](=O)[CH:13]=2)=[CH:8][CH:7]=1.O.[NH2:20][NH2:21]>CCO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[N:21][NH:20][C:14](=[O:15])[CH:13]=2)=[CH:8][CH:7]=1
Reactant: O=C1C=C(c2ccc(OCCCCl)cc2)C(O)O1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1cc(-c2ccc(OCCCCl)cc2)cn[nH]1
Yield: 60.8 %

Procedure:
A solution of the product from example 94 step 3 (2.0 g, 7.45 mmol) and hydrazine hydrate (0.59 g, 1.5 eq.) in 20 mL of EtOH was stirred at 85° C. for 2 h. The solvent was reduced and the solid was collected and washed with cold EtOH to give 1.2 g (61%) of 5-[4-(3-chloropropoxy)phenyl)-2H-pyridazin-3-one: Mp 197-9° C.; MS m/z 265 (M+H).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[CH2:43][C:44]([C:46]1[S:54][CH:53]2[CH:48]([CH2:49][N:50]([CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[Cl:62])[CH2:51][CH2:52]2)[CH:47]=1)=[O:45]>>[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][N:38]([CH2:43][C:44]([C:46]2[S:54][C:53]3[CH2:52][CH2:51][N:50]([CH2:55][C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=4[Cl:62])[CH2:49][C:48]=3[CH:47]=2)=[O:45])[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: O=C(CCl)C1=CC2CN(Cc3ccccc3Cl)CCC2S1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1cc2c(s1)CCN(Cc1ccccc1Cl)C2

Procedure:
4-Benzyloxy-1-{2-[5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-2-yl]-2-oxo-ethyl}-1H-pyridin-2-one is prepared following preparation 15b (in DMSO as solvent) from 500 mg (2.49 mmol) 4-benzyloxy-1H-pyridin-2-one and 936 mg (2.49 mmol) 2-chloro-1-[5-(2-chloro-benzyl)-3a,4,5,6,7,7a-hexahydro-thieno[3,2-c]pyridin-2-yl]-ethanone (preparation 24).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[Br:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([Br:30])[C:21]=1[CH2:22]Br>C1COCC1.C(Cl)(Cl)(Cl)Cl>[Br:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([Br:30])[C:21]=1[CH2:22][CH2:12][C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(=O)OC(C)(C)C
Reactant: COc1cc(Br)c(CBr)c(Br)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Br)c(CCC(=O)OC(C)(C)C)c(Br)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To 5 mL of THF at −78° C. was added 6.5 mL of a 1.0M solution of lithium hexamethyldisilazane in THF. t-Butyl acetate (0.9 mL) was added dropwise to the resulting cold solution, and the resulting mixture was stirred for 10 min at −78° C. 2,6-Dibromo-4-methoxy-benzyl bromide (1.2 g) in 5 mL of CCl4 was added dropwise over 5 min. The mixture was stirred 20 min at −78° C., then quenched by addition of 1 mL of saturated aqueous NaHCO3. The mixture was warmed to room temperature, diluted with 50 mL of saturated aqueous NaHCO3, and extracted with 3×20 mL of EtOAc. The combined organics were washed with 25 mL of brine, dried over MgSO4, and concentrated to yield t-Butyl 3-(2,6-dibromo-4-methoxyphenyl)-propionate as an oily yellow solid. Mass spectrum (ESI) 320.9 (M-OtBu). 1H NMR (500 MHz, CDCl3): δ 7.08 (s, 2H); 3.76 (s, 3H); 3.20 (m, 2H); 2.45 (m, 2H); 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16].[OH-].[K+].O>COCCO>[NH2:16][C:15]1[N:17]=[C:18]([NH2:20])[N:19]=[C:13]([C:12]2[C:3]([O:2][CH3:1])=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:14]=1
Reactant: N#CNC(=N)N
Reactant: COc1cc2ccccc2cc1C#N
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: COc1cc2ccccc2cc1-c1nc(N)nc(N)n1

Procedure:
A mixture of 3.24 grams of 2-methoxy-3-naphthonitrile, 2.23 grams of cyanoguanidine and 0.24 gram of KOH was dissolved in 30 ml of methyl cellosolve with heating and the mixture was heated to reflux for 6.5 hours. After the reaction was completed, the reaction solution was was poured into water, the crystals separated out were taken by filtration, and were recrystallized from ethyl alcohol to give 2,4-diamino-6-(2-methoxy-3-naphthyl)-s-triazine, colourless needles, melting point 243° to 244° C., the yield being 4.12 grams.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][C:34]=2[CH3:35])[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][C:34]=3[CH3:35])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Example 32 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.98 (s, 1H), 7.59 (d, 1H, J=1.8 Hz), 7.54–7.51 (m, 1H), 7.32 (m, 3H), 7.21–7.18 (m, 1H), 6.99–6.94 (m, 5H), 4.87 (s, 1H), 3.36 (q, 2H, J=5.8 Hz), 2.92–2.97 (m, 2H), 2.68–2.58 (m, 1H), 2.5 (quintet, 1H, J=7.2 Hz), 2.37 (t, 2H, J=5.7 Hz), 2.25 (s, 3H), 2.01–1.92 (m, 2H), 1.71–1.52 (m, 6H), 1.16 (d, 6H, J=7.2 Hz); ESMS m/e: 548.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]CC3C=CC=CC=3)[CH:21]=2)=[CH:5][CH:4]=1.O.C([O-])=O.[NH4+]>CCO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(OCc3ccccc3)c2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(O)c2)cc1

Procedure:
A slurry was prepared consisting of 2-(4-methoxyphenyl)-3-(3-benzyloxyphenyl)-6-methoxybenzo[b]thiophene in 1 L of EtOH, 250 mL of EtOAc, and 40 mL of water. Palladium(0) black 4.04 g (38 mmol) and ammonium formate 12.6 g (200 mmol) was added. The reaction mixture was heated to reflux for one hour, then filtered hot through celite and evaporated to dryness. The solid was partioned between EtOAc and a saturated solution of Na2HCO3. The organic layer was washed with brine, dried with Na2SO4, and evaporated to dryness. This yielded 12.8 g of the title compound as a white solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][C@@H:35]1[C@H:40]2[CH2:41][C@H:37]([CH:38]=[CH:39]2)[C@@H:36]1[C:42]([NH2:44])=[O:43]>>[NH2:44][C:42]([C@H:36]1[C@@H:37]2[CH2:41][C@@H:40]([CH:39]=[CH:38]2)[C@H:35]1[NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:31]1[CH:30]=[CH:29][C:28]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:7])=[O:18])=[O:43]
Reactant: NC(=O)[C@@H]1[C@H](N)[C@@H]2C=C[C@H]1C2
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CON=C1C[C@@H](C(=O)N[C@H]2[C@@H](C(N)=O)[C@H]3C=C[C@@H]2C3)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the title compound was obtained in 68% purity by HPLC. MS(ESI+): m/z=473.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10](Cl)=[O:11])[CH2:2]1.[CH2:14]([CH2:16][NH2:17])[OH:15]>C(Cl)(Cl)Cl>[OH:15][CH2:14][CH2:16][NH:17][C:10]([CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:13])[CH2:2]1)=[O:11]
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: NCCO
Solvent: ClC(Cl)Cl
Product: CC1CCC(C(C)C)C(C(=O)NCCO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of p-menth-3-oyl chloride prepared as in Example 1 (4.0g., 0.020 moles) in chloroform (30 ml.) was added dropwise to a stirred solution of ethanolamine (3 g., 0.043 moles) in chloroform (50 ml.). The reaction mixture becomes warm, goes cloudy and finally a yellow oil starts to separate out. After stirring for 2 hours at room temperature the mixture was poured into water. The organic layer was separated, washed with dilute H2SO4, and dried (MgSO4). Removal of the solvent left a viscous oil (3.8 g.). This was distilled under vacuum to yield N-(2-hydroxyethyl)-p-menthane-3-carboxamide as a colourless very viscous oil, b.p. 160°/01. mm.