Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)NC(C)(C)C/C=C/[C:12](=O)[N:13]([C@@H:15]([C:27](=[O:48])[N:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:41])=[O:40])[CH3:29])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:42]1([S:39]([NH:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH2:31][CH2:30][N:28]([CH3:29])[C:27](=[O:48])[C@H:15]([NH:13][CH3:12])[CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)(=[O:41])=[O:40])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CN(CCc1ccccc1NS(=O)(=O)c1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 111.6 %

Procedure:
A solution of {(3E)-4-[N-((1R)-1-{N-[2-(2-(phenylsulfonylamino)phenyl)ethyl]-N-methylcarbamoyl}2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl}carbamic acid tert-butyl ester (330 mg, 0.45 mmol) in dichloromethane (3 ml) was cooled to 0° C. Trifluoroacetic acid (3 ml) was added. The reaction mixture was stirred for 40 min at 0° C. It was diluted with dichloromethane (20 ml). A saturated aqueous solution of sodium hydrogen carbonate (6 ml) was added. Solid sodium hydrogen carbonate was added until pH 7 was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (3×20 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (20 g), using dichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent, to give 252 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:19](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[CH2:20][CH2:21]O)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:54]C(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[C:18](/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:19](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)/[CH2:20][CH2:21][Cl:54])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: ClCC/C(=C(\c1ccccc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1

Procedure:
Z-4-[4-(2-benzyloxyethoxy)-phenyl]-3,4-diphenyl-but-3-en-1-ol prepared in the previous stage was dissolved in acetonitrile (400 ml). Triphenyl phosphine (103.5 g, 0.4 mol) and tetrachloromethane (120 g, 0.79 mol) were added and the mixture was refluxed for 2 hours. Then the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in methanol (160 ml) and water (40 ml) and extracted three times with petroleum ether (3×200 ml) at boiling point. Petroleum ether layers were combined and evaporated to dryness under reduced pressure. The residue was crystallized twice from ethanol (700 ml). Yield 36 g.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[Br:13]N1C(=O)CCC1=O>C(OC)(C)(C)C.C(#N)C>[Br:13][C:11]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccccc1C1CCCO1
Solvent: CC#N
Solvent: COC(C)(C)C
Product: Nc1ccc(Br)cc1C1CCCO1

Procedure:
To a stirring solution of 2-tetrahydrofuran-2-yl-aniline (4) (53.45 g, 327.5 mmol) in methyl tert-butyl ether (MTBE, 641.4 mL) and acetonitrile (213.8 mL) cooled to 2° C. was added N-bromosuccinimide (NBS, 58.88 g, 99%, 327.5 mmol, Aldrich B81255) in 4 portions maintaining internal temperature below about 8° C. The reaction mixture was stirred while cooling with an ice-water bath for 30 minutes (NMR of a worked-up aliquot showed complete consumption of starting material). Aqueous 1 N Na2S2O3 (330 mL) was added to the reaction mixture, removed the cold bath and stirred for 20 minutes. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with saturated aqueous NaHCO3 (2×), water, brine, dried over MgSO4, filtered through a short plug of silica, eluted with EtOAc, and concentrated under reduced pressure to give (5) as a very dark amber oil (82.25 g, 77-94% HPLC purity). Carried forward without further purification. LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 242.10 (2.89 min). 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J=2.3 Hz, 1H), 7.16 (dd, J=8.4, 2.3 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.79-4.73 (m, 1H), 4.15 (s, 2H), 4.10-4.01 (m, 1H), 3.93-3.85 (m, 1H), 2.26-2.13 (m, 1H), 2.12-1.97 (m, 3H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:28])([CH3:27])[C@H:21]23)=[O:16])=[CH:8][C:7]=1[CH3:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:61](O)(=[O:64])[CH2:62][OH:63]>C(Cl)Cl>[CH3:12][C:11]1[CH:10]=[C:9]([CH2:13][CH2:14][C:15](=[O:16])[C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:27])([CH3:28])[C@H:21]23)[CH:8]=[C:7]([CH3:29])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:62](=[O:63])[CH2:61][OH:64]
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCN
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCNC(=O)CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.7 %

Procedure:
A solution of 3-[4-(3-amino-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (18 mg, 0.043 mmol, Example 81) in DCM (2 mL) is treated with DIPEA (22 mg, 0.171 mmol), TBTU (19 mg, 0.06 mmol) and glycolic acid (5 mg, 0.064 mmol). The mixture is stirred at rt for 1.5 h before it is separated by chromatography on prep. TLC plates with DCM:methanol 9:1 to give N-(3-{2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-propyl)-2-hydroxy-acetamide (7 mg) as a white solid; LC-MS: tR=1.01 min, [M+1]+=470.07.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15][CH2:16][C:17](Br)=[O:18].O>ClCCl>[Br:15][CH2:16][C:17]([C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:8][CH:9]=1)=[O:18]
Reactant: Fc1ccnc2[nH]ccc12
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)c1c[nH]c2nccc(F)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 0.0147 mol) (Org. Lett., 2003, 5, 5023-5025) in dichloromethane was added aluminum chloride (3.92 g, 0.0294 mol) in portions, the mixture was stirred at RT for 30 min, then bromoacetyl bromide (4.45 g, 0.022 mol) was added dropwise. The reaction mixture was stirred at 50° C. for 1 h, when TLC indicated no starting material. To the reaction mixture was added 150 mL water, and the resulting suspension was heated at 100° C. for 1 h, then filtered to afford the desired product, 90% pure. H NMR, DMSO-d6: 4.72(s, 2H), 7.12(m, 1H), 8.36(m, 1H), 8.67(s, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][C:22]3[C:17](=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:26])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH3:25][O:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[NH:16][C:15](=[O:26])[N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:23]2
Reactant: COc1cccc2c1NC(=O)N(C1CCN(Cc3ccccc3)CC1)C2
Agent: [Pd]
Solvent: CO
Product: COc1cccc2c1NC(=O)N(C1CCNCC1)C2
Reaction time: 8 h
Yield: 92.9 %

Procedure:
3-(1-Benzyl-piperidin-4-yl)-8-methoxy-3,4-dihydro-1H-quinazolin-2-one (100 mg, 0.28 mmol) in methanol (5 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 68 mg (93%) of the desired material. LC/MS: tR=1.11 min, 262.23 (MH)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[CH3:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:20][C:21]1[CH:22]=[C:23]([S:27][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1cccc(S)c1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cccc(Sc2ccc3c(c2)CCCC3=O)c1
Yield: 110 %

Procedure:
The suspension of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1.8 g, 6.1 mmol), 3-methylbenzene-1-thiol (0.76 g, 6.1 mmol), Pd2(dba)3 (142 mg, 0.153 mmol), Xantphos (177 mg, 0.306 mmol) and DIEA (1.58 g, 12.2 mmol) in 1,4-dioxane (60 mL) was stirred at reflux overnight under N2. The reaction was filtered and concentrated. Purification by silica gel chromatography (PE:EtOAc=5:1) gave 1.8 g (100%) of the title compound as an orange oil. [M+H] Calc'd for C17H16OS, 269. Found, 269.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(CC2c3ccc(O)cc3CCN2c2ccc(F)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(CC2c3ccc(O)cc3CCN2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 569.4 %

Procedure:
To a solution of ethyl (2E)-3-(4-{[2-(4-fluorophenyl)-6-hydroxy(1,2,3,4-tetrahydroisoquinolyl)]methyl}phenyl)prop-2-enoate (0.16 g, 0.37 mmol) in tetrahydrofuran (6 mL) was added a solution of lithium hydroxide monohydrate (0.20 g, 4.77 mmol) in water (3 mL). After it stirring at room temperature for 20 hours, the tetrahydrofuran was evaporated. The aqueous solution was neutralized with 5% aqueous HCl and extracted with dichloromethane. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 75-100% ethyl acetate/hexane) to provide the title compound (0.85 g, 57% yield): 1H NMR (CDCl3) 7.72 (d, 1H), 7.40 (d, 2H), 7.02 (d, 2H), 6.93 (m, 2H), 6.76 (m, 2H), 6.61 (m, 2H), 6.56 (dd, 1H), 6.42 (d, 1H), 4.75 (t, 1H), 3.55 (m, 1H), 3.46 (m, 1H), 3.16 (m, 1H), 2.87-3.00(m, 2H), 2.64 (dt, 1H); ES-MS m/z 404 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:23]
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-methylbenzoic acid. MS (ESI) mass calcd. for C22H22N4O, 358.45; m/z found, 359.2 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:14]O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C(O)Cc1cccs1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-thiopheneacetic acid (1.50 g, 10.6 mmol) in MeOH (20 mL) was added thionyl chloride (3.80 mL, 53 mmol) dropwise at 0° C. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to give the title compound as a dark brown oil (1.65 g, quantitative yield) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N[C:20](N)=[O:21]>CN(C=O)C.C(Cl)Cl>[N:13]1([C:9]2[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]3[NH:1][C:20](=[O:21])[NH:12][C:11]=3[CH:10]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: NC(N)=O
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2[nH]c(=O)[nH]c12
Temperature: 170 °C
Yield: 62 %

Procedure:
To a solution of methyl 2,3-diamino-5-(4-morpholinyl)benzoate, prepared as described in Example 45, step a (11.0 g, 4.0 mmol) in DMF (50 mL) was added urea (720 mg, 12 mmol) and the mixture was heated to 170° C. for 4 h. When analysis by TLC showed no starting material remaining, the mixture was cooled to room temperature then diluted with DCM (200 mL), washed with water (50 mL×2) and dried over anhydrous Na2SO4, filtered and concentrated in-vacuo. The residue was then purified by chromatography on silica (eluted with EtOAc) to afford the desired product as a dark-yellow solid (690 mg, 62%). 1H NMR (300 MHz, DMSO-d6): δ ppm 3.02 (t, 4H, J=4.8 Hz), 3.74 (t, 4H, J=4.8 Hz), 3.86 (s, 3H), 6.82 (d, 1H, J=2.1 Hz), 6.99 (d, 1H, J=2.1 Hz), 10.48 (s, 1H), 10.82 (s, 1H). LC-MS: m/e=278 [M+1]+.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O.O.[NH2:20][NH2:21]>CN(C1C=CN=CC=1)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[C:3]3[C:2](=[C:7]([CH3:8])[CH:6]=[CH:5][CH:4]=3)[NH:21][N:20]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)c2cccc(C)c2F)cc1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Yield: 48.5 %

Procedure:
Prepared according to Method D Step A from (2-Fluoro-3-methylphenyl)-(4-methoxyphenyl)-methanone (3.6 g, 14.7 mmol), hydrazine hydrate (4.3 mL, 140 mmol) and DMAP (1.8 g, 14.7 mmol) to give the product (1.7 g) as a yellow solid.
Reaction SMILES: [CH:1]#[CH:2].[CH3:3][C:4]([CH3:6])=O>>[CH3:3][CH:4]([CH2:6][CH2:1][CH2:2][CH:4]([CH2:6][CH2:1][CH2:2][CH:4]([CH2:6][CH2:1][CH2:2][CH2:3][CH:4]([CH2:6][CH2:1][CH2:2][CH:4]([CH2:6][CH2:1][CH2:2][CH:4]([CH3:6])[CH3:3])[CH3:3])[CH3:2])[CH3:3])[CH3:3])[CH3:1]
Reactant: CC(C)=O
Reactant: C#C
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C

Procedure:
Ethynylation of 194 g of citronelliodene acetone was carried out with acetylene in the same manner as in example 20 except that citronellidene acetone was used in place of pseudoionone and 278 g of a crude product was thus obtained. This product was subjected to oxydative-coupling, hydrogenation and hydrogenolysis in sequence in the same manner as in example 20 and squalane was thus obtained in a yield of 36.3 % from citronellidene acetone to squalane.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].C(N(C(C)C)C(C)C)C.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>C(Cl)Cl>[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:25]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)=[O:26])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: O=C(Cl)c1ccco1
Reactant: CC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1cccc(NC(=O)c2ccco2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of 3-aminoacetophenone in 20 mL of CH2Cl2 was added 5 mL of ethyl-di-iso-propylamine. To the stirred reaction mixture was then added 1 mL of 2-furoyl chloride which was allowed to stir at 25° C. for 8 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (CH2Cl2) to yield 900 mg of furan-2-carboxylic acid (3-acetyl-phenyl)-amide as a white solid. 1H NMR (CDCl3, 500 MHz) δ 8.11 (1 H, br s), 8.09 (1H, t, J=2 Hz), 7.93 (1 H, m), 7.66 (1H, m), 7.47 (1 H, m), 7.20 (1 H, m), 6.52 (1 H, m), 2.56 (3H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[CH:37](F)OC1C=CC(S(Cl)(=O)=O)=CC=1>>[CH3:37][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([F:35])[F:34])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccc(C(=O)O)c(Cl)c1)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)F)cc1)CC2
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccc(OC(F)F)cc2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(4-difluoromethoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 523.23 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 4-difluoromethoxy-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(4-difluoromethoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH:4]2[CH2:3]1.[H-].[Na+].Br[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34].B>CN(C)C=O.CO>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH2:13][CH2:14][NH:15][CH2:16][CH:4]2[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Reactant: Clc1ccccc1CBr
Agent: B
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Clc1ccccc1CN1CCC2CNCCN2c2ccccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1C (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (65%, 6.98 mg, 0.19 mmol). The solution was allowed to stir at room temperature for 1 hour before addition of 1-(bromomethyl)-2-chlorobenzene (37.2 mg, 0.181 mmol). The reaction mixture was stirred overnight. The solution was concentrated. To the concentrate was added tetrahydrofuran (10 mL) followed by borane (1 M in tetrahydrofuran, 1 mL, 1 mmol). The solution was heated in an 80° C. oil bath for 4 hours. Methanol (20 mL) was added and heating of the resultant solution was continued in the 80° C. bath for 1 hour before concentration. To the concentrate was added dichloromethane (10 mL), methanol (1 mL) and HCl (4 M in dioxane, 2 mL) Once LC/MS analysis indicated the reaction was complete the solution was concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 7.46 (d, J=8.85 Hz, 1 H) 7.28-7.38 (m, 3 H) 6.95 (dd, J=7.93, 1.53 Hz, 1 H) 6.87-6.92 (m, 1 H) 6.82-6.87 (m, 1 H) 6.70 (dd, J=7.78, 1.37 Hz, 1 H) 4.56 (d, J=16.17 Hz, 1 H) 4.36 (d, J=16.48 Hz, 1 H) 3.46-3.56 (m, 1 H) 3.35-3.43 (m, 2 H) 3.06-3.28 (m, 4 H) 2.93-3.02 (m, 2 H) 1.89-1.99 (m, 1 H) 1.70-1.79 (m, 1 H) MS (ESI) m/z 328.0 (M+H)+.
Reaction SMILES: [C:1](=[N:16][OH:17])([C:3]1[CH:4]=[CH:5][C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]=2[CH:15]=1)[CH3:2].[CH2:18]([OH:20])[CH3:19].Cl.NO>N1C=CC=CC=1>[OH:17][N:16]([CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]=2[CH:15]=1)[CH3:2])[C:18](=[O:20])[CH3:19]
Reactant: CCO
Reactant: CC(=NO)c1ccc2c(c1)oc1ccccc12
Agent: Cl
Agent: NO
Solvent: c1ccncc1
Product: CC(=O)N(O)C(C)c1ccc2c(c1)oc1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Acetyldibenzofuran oxime. The crude ketone prepared as described in step a, was dissolved in pyridine (50 mL) and ethanol (50 mL) and hydroxylamine hydrochloride was added. The mixture was stirred overnight at ambient temperature. The reaction was concentrated and the residue was partitioned between ethyl acetate (300 mL) and 3N HCl. The ethyl acetate layer was dried (Na2SO4), filtered and concentrated in vacuo to give a crystalline residue. The crystals were rinsed with hexane, filtered and dried to give 12.3 g of the desired product, mp 132°-135°.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[S:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[S:8][C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:6]([CH2:5][C:1]#[N:2])[C:10]=2[CH:11]=1
Reactant: [C-]#N
Reactant: Clc1ccc2sc(-c3ccccc3)c(CBr)c2c1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1.2 eq. of NaCN are suspended in 20 ml of dimethyl sulphoxide. The mixture is heated at 60° C. for 30 minutes and then 1 eq. of the compound obtained in Step C is added gradually. The reaction mixture is stirred for 1 hour at 60° C. and is then hydrolysed. Extraction with ethyl acetate is carried out and the organic phase is washed with water, dried over MgSO4 and evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH:6]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:4]=1.S([CH2:38][N+:39]#[C-:40])(C1C=CC(C)=CC=1)(=O)=O.COCCOC>O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([NH:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH:6]=[C:7]([C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]3[O:13][CH:40]=[N:39][CH:38]=3)[CH:10]=2)[N:8]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(C=O)c3)nc(OC)n2)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(-c4cnco4)c3)nc(OC)n2)cc1
Temperature: 85 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
In a tube is combined 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde (200 mg, 0.55 mmol), tosylmethylisocyanide (119 mg, 0.61 mmol), Ambersep 900 OH resin (1 g), ethylene glycol dimethyl ether (3.5 mL) and water (3.5 mL). The tube is sealed and the mixture is heated to 85° C. and stirred for 18 hours. The mixture is allowed to cool to ambient temperature and filtered to remove the resin, and washed the resin with 10 mL methanol. The combined filtrate and washings are concentrated by rotary evaporator and the residue is subjected to flash column chromatography on silica gel eluting with 10 to 40% EtOAc in heptane gradient, to afford [2-methoxy-6-(3-oxazol-5-yl-phenyl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [65 mg, 29.4%, Example 11(b)]. LCMS: RT=2.59 minutes MS: 403 (M+H). IC50=2.6 nM