Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][S:12](Cl)(=[O:14])=[O:13])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].Cl.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([S:12]([CH2:11][C:5]3([C:3]([OH:2])=[O:4])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)(=[O:14])=[O:13])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)C1(CS(=O)(=O)Cl)CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1(CS(=O)(=O)N2CCN(c3ccc(Br)cc3)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
4-Chlorosulfonylmethyltetrahydropyran-4-carboxylic acid methyl ester (5.10 g) was added to a stirred suspension of 4-bromophenylpiperazine hydrochloride (5.51 g) and triethylamine (6.09 ml) in dichloromethane (120 ml), and the mixture was stirred at room temperature for 18 h. The dichloromethane was then removed under reduced pressure, and the residue redissolved in tetrahydrofuran (60 ml), methanol (30 ml) and water (15 ml), treated with lithium hydroxide monohydrate (4.15 g) and heated to reflux for 2 h. The organic solvents were removed in vacuo and the residue was diluted with 1 M sodium hydroxide (30 ml) and washed with diethyl ether (3×40 ml). The aqueous phase was then acidified to pH 4-5 with citric acid, forming a white precipitate, which was filtered, washed with water and dried to constant weight under vacuum at 40° C. to provide the title compound as a white solid (4.55 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH2:23]([O:30][C:31]1[CH:64]=[CH:63][C:34]([C:35]([O:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][N:45]([CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C:46](=[O:54])[C:47]3[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=3)=[CH:40][CH:39]=2)=[O:36])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.CN(C=O)C>[CH2:23]([O:30][C:31]1[CH:64]=[CH:63][C:34]([C:35]([O:37][C:38]2[CH:43]=[CH:42][C:41]([CH2:44][N:45]([CH2:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[C:46](=[O:54])[C:47]3[CH:48]=[CH:49][C:50]([NH:53][C:10](=[O:12])[CH2:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:13]([F:16])([F:15])[F:14])=[CH:51][CH:52]=3)=[CH:40][CH:39]=2)=[O:36])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc(CC(=O)O)c(C(F)(F)F)c1
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(N)cc3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Prepared using General Procedure 7: To 2-(4-methoxy-2-(trifluoromethyl)phenyl)acetic acid (299 mg, 1.28 mmol) in DCM (5 mL) and DMF (20 μL) was added oxalyl chloride (0.117 mL, 1.34 mmol). After stirring at room temperature for 30 min, 4-((4-amino-N-(2-(tert-butoxy)-2-oxoethyl)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-4 (700 mg, 1.22 mmol) and TEA (0.424 mL, 3.05 mmol) in DCM (10 mL) were added. The reaction was stirred for 1 h then diluted with DCM (100 mL) and washed with NaHCO3 (100 mL). The crude product was purified by chromatography to provide 555 mg (58%) of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-6. LCMS-ESI (m/z) calculated for C44H49F3N2O8: 791; no m/z observed, tR=3.28 min (Method 4).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5](S(C)(=O)=O)=[C:6]2[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]=12)#[N:2].[CH2:19]([Mg]Cl)[CH:20]([CH3:22])[CH3:21]>C1COCC1>[C:1]([C:3]1[S:4][C:5]([CH2:19][CH:20]([CH3:22])[CH3:21])=[C:6]2[C:11](=[O:12])[CH2:10][C:9]([CH3:14])([CH3:13])[CH2:8][C:7]=12)#[N:2]
Reactant: CC(C)C[Mg]Cl
Reactant: CC1(C)CC(=O)c2c(S(C)(=O)=O)sc(C#N)c2C1
Solvent: C1CCOC1
Product: CC(C)Cc1sc(C#N)c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a stirred solution of 1-cyano-6,6-dimethyl-3-methanesulphonyl-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (1.5 g, 5.3 mmol) in THF (15 mL) at −10° C. was added isobutylmagnesium chloride. After 1 h the cooling bath was removed and the mixture stirred at room temperature for 2 h. After this time the mixture was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with petrol: EtOAc (6:1), to give the title compound (526 mg, 38%) as an orange oil. 1HNMR (360 MHz, CDCl3) δ 0.97 (6H, d, J=6.6 Hz), 1.08 (6H, s), 1.94-2.02 (1H, m), 2,42 (2H, s), 2.85 (2H, s), 3.16 (2H, d, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][N:13]=1>C(OCC)(=O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
A suspension of 143.0 g (0.46 mol) of N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine in 7.15 liters of ethyl acetate is stirred with 14.3 g of palladium on active carbon (10% Pd) under a hydrogen atmosphere at normal pressure for 6.5 hours. The suspension is filtered and the filtrate is concentrated in a rotary evaporator. The crude product is recrystallised from methylene chloride, yielding N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine; m.p. 138° C.-140° C., Rf=0.36 (methylene chloride:methanol=9:1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].[C:15]1(=[O:24])[C:18]2([CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:17][O:16]1>C1COCC1>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][CH2:17][C:18]2([C:15]([OH:24])=[O:16])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:12][CH:13]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(S)cc1
Reactant: O=C1OCC12CCOCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCOc1ccc(SCC2(C(=O)O)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 0.112 g (2.81 mmol) of 60% sodium hydride in 2 mL of THF, cooled to 0° C., was added a solution of 0.500 g (2.81 mmol) of 4-but-2-ynyloxy-benzenethiol, dissolved in 3 mL of THF. The resulting mixture was stirred for 0.5 h at room temperature, then cooled to 5° C., followed by the addition of 0.518 g (3.65 on mol) of neat 2,7-dioxaspiro[3,5]nonane-1-one while keeping the reaction temperature below 10° C. The reaction was allowed to warm to room temperature and stirred for an additional 0.5 h and then quenched with 3 mL of 3N HCl solution and 3 mL of water. The resulting mixture was extracted with dichloromethane and the combined organics were washed with water and brine, dried over Na2SO4, filtered through a plug of silica gel and concentrated in vacuo. The residue was triturated with hexanes and acetonitrile and filtered to give 0.72 g of the carboxylic acid as a semi-solid. Electrospray Mass Spec: 319 (M−H)−
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:70]1[CH:74]=[C:73]([CH2:75][CH2:76][NH2:77])[N:72]=[CH:71]1>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:77][CH2:76][CH2:75][C:73]2[N:72]=[CH:71][NH:70][CH:74]=2)=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: NCCc1c[nH]cn1
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCCc3c[nH]cn3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and [2-(1H-imidazol-4-yl)ethyl]amine (22.2 mg, 0.2 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (26 mg, 85%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[S:25]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[NH:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:28]2[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:25][CH2:26][CH2:27]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: c1ccc2c(c1)NCCS2
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCSc4ccccc43)CC2C)cc1OC
Yield: 24.8 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (1.00 g, 2.93 mmol) prepared in Reference Example 1 and 3,4-dihydro-2H-1,4-benzothiazine (1.22 g, 8.07 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (335 mg, yield: 25%) as a white crystal. (cis:trans=1.5:1)
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:13])(=[O:12])[N:5]=1)C.[C:14]([O:18][C:19](=[O:30])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH2:21])([CH3:17])([CH3:16])[CH3:15]>C(O)C>[C:14]([O:18][C:19](=[O:30])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:21][C:4]1[C:8]([O:9][CH2:10][CH3:11])=[N:7][S:6](=[O:12])(=[O:13])[N:5]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC1=NS(=O)(=O)N=C1OCC
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: CCO
Product: CCOC1=NS(=O)(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C

Procedure:
A solution of 3,4-diethyloxy-1,1-dioxo-1,2,5-thiadiazole (400 mg, 1.94 mmol) and L-tyrosine t-butyl ester (1.25 g, 5.2 mmol) in ethanol (25 mL) was stirred at room temperature overnight. Solvent was removed under reduced pressure and the product used in further transformations without further purification (Yield 790 mg).
Reaction SMILES: BrC1C=C2C(=CC=1)C(CC(O)=O)OCC2.O.Cl.Cl.C1(CCN2CCN(C3C=CC=CC=3OC)CC2)C2C(=CC=CC=2)CCO1.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:58](=O)[CH2:59][CH:60]3[C:69]4[C:64](=[CH:65][C:66]([Br:70])=[CH:67][CH:68]=4)[CH2:63][CH2:62][O:61]3)[CH2:54][CH2:53]2)=[CH:48][CH:47]=1>>[CH3:45][C:46]1[CH:47]=[CH:48][C:49]([N:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][CH:60]3[C:69]4[C:64](=[CH:65][C:66]([Br:70])=[CH:67][CH:68]=4)[CH2:63][CH2:62][O:61]3)[CH2:54][CH2:53]2)=[CH:50][CH:51]=1
Reactant: Cc1ccc(N2CCN(C(=O)CC3OCCc4cc(Br)ccc43)CC2)cc1
Agent: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Agent: Cl
Agent: O=C(O)CC1OCCc2cc(Br)ccc21
Solvent: O
Product: Cc1ccc(N2CCN(CCC3OCCc4cc(Br)ccc43)CC2)cc1

Procedure:
(6-Bromoisochroman-1-yl)acetic acid (EXAMPLE 22, LXVIII) is coupled with 4-methylphenylpiperazine (XI) and the resulting amide, 1-(4-methylphenyl)-4-[2-(6-bromoisochroman-1-yl)]acetyl piperazine (LXIII, 1.49 mmol) is reduced according to the general procedure of EXAMPLE 50 making non-critical variations, to give the title compound, NMR (300 MHz, CDCl3) 7.32-7.26, 7.07, 6.97, 6.84, 4.78, 4.14-3.07, 3.78-3.69, 3.16, 2.94, 2.7-2.48, 2.26, 2.15-1.90 δ; CMR (75 MHz, CDCl3) 149.0, 136.9, 136.1, 131.4, 129.4, 129.0, 128.9, 126.3, 119.8, 116.1, 74.1, 62.6, 54.4, 53.2, 49.5, 33.0, 28.6 and 20.2 δ.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:40])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:22][C:21]([N:23](C(OC(C)(C)C)=O)CC3C=CC(OC)=CC=3)=[N:20][CH:19]=2)=[CH:14][CH:13]=1)[CH3:9]>>[CH2:8]([O:10][C:11](=[O:40])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:22][C:21]([NH2:23])=[N:20][CH:19]=2)=[CH:16][CH:17]=1)[CH3:9]
Reactant: CCOC(=O)c1ccc(-c2cnc(N(Cc3ccc(OC)cc3)C(=O)OC(C)(C)C)s2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(-c2cnc(N)s2)cc1

Procedure:
Trifluoroacetic acid (5 ml) was added to 4-{2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)-amino]-thiazol-5-yl}-benzoic acid ethyl ester (300 mg, 0.64 mmol) at room temperature and reaction mixture was refluxed for 5 hrs. Trifluoroacetic acid was removed on rotavapour. The residue was taken in water (10 ml) and ethyl acetate (15 ml) and basified this with sodium bicarbonate, layers were separated, and aq. layer was re-extracted with ethyl acetate (15 ml). The combined organic layer was washed with brine (15 ml) and dried over anhydrous sodium sulfate. Solvent was evaporated on rotavapour to get the solid product. The crude material was used for the next step with out any further purification,(150 mg).
Reaction SMILES: [C:1]([C:9]1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:8])[CH3:9]
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)c1ccccc1

Procedure:
A method according to claim 1 wherein the ketone is benzophenone and the carboxylic acid is acetic acid to yield acetophenone.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:19]=[CH:18][C:13]3[N:14]([CH3:17])[N:15]=[N:16][C:12]=3[CH:11]=2)[C:7]#[C:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[N:1]1([CH:6]([C:10]2[CH:19]=[CH:18][C:13]3[N:14]([CH3:17])[N:15]=[N:16][C:12]=3[CH:11]=2)[CH:7]=[CH:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC#CC(c1ccc2c(c1)nnn2C)n1ccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC=CC(c1ccc2c(c1)nnn2C)n1ccnc1
Yield: 19.7 %

Procedure:
A mixture of 7 parts of 5-[1(1H-imidazol-1-yl)-2-butynyl]-1-methyl-1H-benzotriazole, 0.1 parts of quinoline, 54 parts of ethyl acetate and 32 parts of ethanol was hydrogenated at 931.00 Pa and at room temperature with 0.3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of dichloromethane and 1,1'-oxybisethane. The product was filtered off and dried, yielding 1.4 parts (19.7%) of 5-[1-(1H-imidazol-1-yl)-2-butenyl]-1-methyl-1H-benzotriazole; mp. 104° C. (compound 240).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=[O:5].[C:7]1([CH3:17])[CH:12]=CC(S(O)(=O)=O)=[CH:9][CH:8]=1>O1CCCC1>[CH3:1][C:2]1[CH2:6][CH2:9][C:8](=[C:7]([CH3:17])[CH3:12])[C:4](=[O:5])[CH:3]=1
Reactant: CC(C)=CC=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC1=CC(=O)C(=C(C)C)CC1
Yield: 78 %

Procedure:
A mixture of 200 parts of 3,3-dimethylacrolein and 600 parts of tetrahydrofuran is heated with 0.008 part of p-toluenesulfonic acid in an autoclave for three hours at a pressure of 50 atmospheres and a temperature of 210°C. The reaction product is worked up by distillation. 72.5 parts of piperitenone is obtained. The yield is 78% of theory at a conversion of 52%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2.[CH3:24][Sn:25](Cl)([CH3:27])[CH3:26].O>C1COCC1>[CH2:18]([N:17]([CH2:21][CH2:22][CH3:23])[CH:14]1[CH2:13][CH2:12][C:11]2[C:16](=[C:7]([Sn:25]([CH3:27])([CH3:26])[CH3:24])[CH:8]=[CH:9][CH:10]=2)[CH2:15]1)[CH2:19][CH3:20]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc([Sn](C)(C)C)c2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 152.2 %

Procedure:
Butyllithium (1.2M in hexane; 2.8 ml; 3.4 mmol) was added to a solution of 8-bromo-2-di-n-propylamino-1,2,3,4-tetrahydronaphthalene (1 g; 3.22 mmol) in THF (50 ml) at -78° C. After 1.5 hr., a solution of trimethyltin chloride (1.3 g, 2.0 mmol) in THF (20 ml) was added. The reaction mixture was allowed to warm to room temperature, stirred overnight at room temperature, poured into water, and extracted with methylene chloride. The extract was dried (Na2SO4) and concentrated to give the crude product. Purification by chromatography using 1:10 methanol:methylene chloride gave 1.2 g of the desired product which was used directly in the next step.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:39]=[CH:38][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])[N:13]=2)=[CH:8][CH:7]=1.Cl>O1CCOCC1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:31]=[CH:30][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH:15]=[C:14]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])[N:13]=2)=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2cc(OCC(F)(F)F)nc(NCc3ccc(OCCCBr)cc3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2cc(OCC(F)(F)F)nc(NCc3ccc(OCCCBr)cc3)n2)cc1

Procedure:
Tert-butyl 4-((2-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (36 mg, 0.06 mmol) and 4 N HCl in dioxane (1 mL) were stirred for 8 hs then concentrated under vacuum to give 4-((2-((4-(3-bromopropoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoic acid which was carried to the next step without purification.
Reaction SMILES: O[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[CH:13]2)[CH2:4][CH2:3]1.Cl>C(O)C>[C:21]1([C:2]2[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH2:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC1(c2ccccc2)CCN(CCCCn2cnc3ccccc32)CC1
Agent: Cl
Solvent: CCO
Product: C1=C(c2ccccc2)CCN(CCCCn2cnc3ccccc32)C1
Yield: 72 %

Procedure:
A solution of 13.4 g (38.2 mmol) of 1-[4-(4-hydroxy-4-phenyl-1-piperidyl)butyl]-1H-benzimidazole, 150 ml of concentrated HCl and 75 ml of ethanol is heated at reflux for 6 hours. The ethanol is then evaporated and the aqueous solution is cooled, basified with dilute NaOH and extracted with chloroform. The organic phase is dried with anhydrous sodium sulfate and evaporated at reduced pressure, a crude product being obtained which is purified by chromatography on silica gel. 9.1 g (27.5 mmol) of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]-1H-benzimidazole are obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH3:18][O:19][CH2:20][CH2:21][NH2:22]>CCO>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:22][CH2:21][CH2:20][O:19][CH3:18])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COCCN
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NCCOC)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 85.4 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.200 g, 0.833 mmol), 2-methoxyethanamine (0.065 mL, 0.757 mmol) in 80% aq. EtOH (5 mL) was heated at 90° C. overnight: After work-up, the crude product was purified by silica gel column chromatography (33% EtOAc/Hexanes to 50% EtOAc/Hexanes) to provide the title compound (0.191 g, 85%) as a bright yellow solid. 1H-NMR (CDCl3): δ 8.34 (s, 1H), 8.28 (d, J=2.8 Hz, 1H), 7.56 (dd, J=8.4 Hz, J=1.6 Hz, 1H), 6.91 (d, J=9.2 Hz, 1H), 3.69 (t, J=5.6 Hz, 2H), 3.53 (q, J=5.6 Hz, 2H), 3.44 (s overlapping with br s, 7H), 1.22 (t, J=6.4 Hz, 6H). MS (ESI) (M+H)+=296
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].C1(C)C=CC=CC=1.O>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7](=[CH:6][CH:5]=1)[CH2:8][CH2:9][CH:10]=[CH:11]2)([O-:3])=[O:2]
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C=CCC2
Yield: 84.8 %

Procedure:
A suspension of 7-nitrotetralone (20 g, 0.105 mol) in MeOH (300 mL) was treated with NaBH4 (4.1 g) with intermitent cooling. After the addition, cooling was removed and the reaction stirred over night. The reaction was cooled in ice-water and quenched with a solution of MeOH (200 mL) and concentrated HCl (35 mL). The solvent was evaporated, the residue was suspended in H2O, and the mixture was extracted with CHCl. The extracts were dried and the solvent evaporated to give a tan solid. A mixture of the solid, p-toluenesulfonic acid (0.4 g), and toluene (300 mL) was heated to reflux for over night with water being collected in a Dean-Stark trap. The reaction was cooled, washed with H2O, aqueous NaHCO3, and brine, then the solvent was dried and evaporated to give a dark liquid (15.6 g) that had an nmr consistent with the desired material.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:24])[C:15]=1[C:25]([F:28])([F:27])[F:26]>O>[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:8]([O-:11])=[O:9])[C:20]=2[CH3:24])[C:15]=1[C:25]([F:26])([F:28])[F:27]
Reactant: COc1ccc2c(C)cccc2c1C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(C)c([N+](=O)[O-])ccc2c1C(F)(F)F
Temperature: 5 °C
Yield: 41 %

Procedure:
To a cooled solution (3° to 4° C.) of acetic anhydride (640 mL) was added fuming nitric acid (90%, specific gravity=1.5, 160 mL) dropwise via an addition funnel at such a rate as to keep the internal temperature at or below 8° C. (~1 hour 20 minutes total addition time). After the internal temperature had again cooled to 3°-4° C., 2-methoxy-5-methyl-1-trifluoromethylnaphthalene (200 g, 0.833 mol) was added portion wise. The portions added were small enough such that the internal temperature did not rise above 10° C. and each portion was added when the temperature had cooled to 5° C. (addition time ~1 hour 15 minutes). After an additional 15 minutes the reaction mixture was added to water (3 L). The resulting amorphous solid was filtered, washed with water and the lumps broken up and dried in vacuo overnight. The dry solid (~225 g) was recrystallized from 95:5 ethanol:isopropanol (3 L). The resulting long yellow needles were filtered and washed with ethanol (2×50 mL) to provide the product (97.5 g, 41%), m.p. 141°-142° C. A small amount of the desired product was recrystallized from 4:1 petroleum ether:ethyl acetate.