Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@@H:12]3[CH3:24])[C:5]=2[C@H:4]([CH3:25])[CH2:3]1.[H-].[Na+].[CH3:28]I>C1COCC1>[CH3:28][O:1][C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@@H:12]3[CH3:24])[C:5]=2[C@H:4]([CH3:25])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](C)c2c1ncnc2N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a solution of (S)-tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.098 g, 0.28 mmol) in THF (10 mL) were added NaH (60%, 50 mg, 1.25 mmol) and MeI (0.08 mL, 1.28 mmol). The mixture was stirred at room temperature overnight. The solution was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to give (S)-tert-butyl 4-((5R,7R)-7-methoxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (0.056 g, 55%). 1H NMR (CDCl3, 400 MHz) δ 8.56 (s, 1H), 4.66 (m, 2H), 4.30-3.80 (m, 3H), 3.55 (s, 3H), 3.54-2.90 (m, 4H), 2.25 (m, 1H), 1.98 (m, 1H), 1.49 (s, 9H), 1.24 (d, J=12.4 Hz, 3H), 1.13 (d, J=7.2 Hz, 3H). MS (APCI+) [M+H] +363.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([N:11]3[CH2:16][N:15]([CH3:17])[CH2:14][N:13]([CH2:18][CH3:19])[C:12]3=[O:20])=[N:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][C:30]([CH2:38][CH3:39])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:66]([OH:69])[C:67]#[CH:68]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH2:38]([C:30]1([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28][N:27]([C:24]2[N:23]=[CH:22][C:21]([C:4]3[CH:3]=[C:2]([C:68]#[C:67][CH2:66][OH:69])[C:10]4[S:9][C:8]([N:11]5[CH2:16][N:15]([CH3:17])[CH2:14][N:13]([CH2:18][CH3:19])[C:12]5=[O:20])=[N:7][C:6]=4[CH:5]=3)=[CH:26][N:25]=2)[CH2:32][CH2:31]1)[CH3:39]
Reactant: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(Br)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CC)CCN(c2ncc(-c3cc(C#CCO)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 100 °C

Procedure:
Ethyl 1-[5-[7-bromo-2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-ethyl-piperidine-4-carboxylate (700 mg, 1.14 mmol), PdCl2(PPh3)2 (32 mg, 0.05 mmol) and triphenylphosphine (3 mg, 0.01 mmol) were placed in a 10-20 mL microwave vial and anhydrous DMF (14 mL) added, quickly followed by triethylamine (0.95 mL, 6.81 mmol) and propargyl alcohol (0.13 mL, 2.27 mmol). The solution was bubbled with argon for ˜3 minutes then CuI (4 mg, 0.02 mmol) was added. The vial was capped and mixture degassed then heated in the microwave at 100° C. for 30 minutes. More PdCl2(PPh3)2 (11 mg) and propargyl alcohol (0.05 mL) were added and argon was bubbled through the mixture then CuI (1.5 mg) added. The vial was capped and mixture degassed then heated in the microwave again at 100° C. for 15 minutes. The crude reaction mixture was filtered through a PTFE filter. The filter was rinsed with EtOAc and then water. The filtrate was diluted with water, extracted into EtOAc (4×60 mL) and the combined organic layers washed with water (2×50 mL) and brine, dried over Na2SO4 and concentrated to dryness under reduced pressure to give a brown solid. The mixture was purified by chromatography, Biotage SP4, 40 g Si cartridge, 50-80% EtOAc in cyclohexane and the relevant fractions combined to give the desired product as an off-white solid, 247 mg (37%). MS: 592.13 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].P.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1(C)C(C)=CC=CC=1.ClCCl.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[CH:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([CH:23]3[CH2:24][NH:25][CH2:26][CH2:27][N:22]3[CH3:21])[CH:10]=2)[CH:6]=[CH:7]1)([CH3:13])[CH3:12]
Reactant: CC(C)n1ccc2ccc(Br)cc21
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: CC(C)n1ccc2ccc(C3CNCCN3C)cc21
Temperature: 120 °C
Yield: 43.9 %

Procedure:
A mixture of 6-bromo-1-isopropylindole (23.8 mg, 0.1 mmol), sodium-tbutoxide (NaOtBu; 14.1 mg, 0.15 mmol), tri-tbutyl phosphine (tBu3P; 1 mg), palladium acetylacetonate (Pd(OAc)2; 1 mg) and 1-methylpiperazine (60 mg, 0.6 mmol) in xylene (1 ml) under argon was heated at 120° C. for 3 h., The cooled reaction mixture was diluted with dichloromethane, washed with water and the crude product purified by column chromatography on silica gel, eluting with 1% 2M ammonia/methanol in dichloromethane to give (11.3 mg, 44%) of the title compound.
Reaction SMILES: [P:1]([O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:34]=[C:33]3[C:28]([C:29]([NH:35][C:36]4[S:37][C:38]([CH2:41][C:42]([NH:44][C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=5)=[O:43])=[CH:39][N:40]=4)=[N:30][CH:31]=[N:32]3)=[CH:27][C:26]=2[O:52][CH3:53])[CH2:17][CH2:16]1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>O1CCOCC1>[P:1]([OH:8])([OH:3])([O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:34]=[C:33]3[C:28]([C:29]([NH:35][C:36]4[S:37][C:38]([CH2:41][C:42]([NH:44][C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=5)=[O:43])=[CH:39][N:40]=4)=[N:30][CH:31]=[N:32]3)=[CH:27][C:26]=2[O:52][CH3:53])[CH2:17][CH2:16]1)=[O:2]
Reactant: COc1cc2c(Nc3ncc(CC(=O)Nc4cccc(F)c4)s3)ncnc2cc1OCCCN1CCC(COP(=O)(OC(C)(C)C)OC(C)(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1COCCO1
Product: COc1cc2c(Nc3ncc(CC(=O)Nc4cccc(F)c4)s3)ncnc2cc1OCCCN1CCC(COP(=O)(O)O)CC1
Yield: 118.5 %

Procedure:
Di(tert-butyl) (1-(3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1,3-thiazol-2-yl)amino)-6-methoxyquinazolin-7-yl)oxy)propyl)piperidin-4-yl)methyl phosphate (6.64 g, 8.6 mmol), in 1,4-dioxane (250 ml) was treated with 4.0 N hydrochloric acid in 1,4-dioxane (15 ml, 60 mmol) at 20° C. for 18 hours. The solid product was collected by suction filtration and washed with i) 1,4-dioxane (100 ml), ii) acetonitrile (100 ml) and iii) diethyl ether (100 ml), Prolonged drying in vacuo yielded the title compound (6.73 g, 98% yield) as a yellow dihydrochloride salt:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:21]([O:23][CH2:24][C:25](Cl)=O)[CH3:22]>>[CH2:21]([O:23][CH2:24][C:25]1[N:12]([CH2:13][C:14]2([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:22]
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Reactant: CCOCC(=O)Cl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCOCC1
Yield: 80.2 %

Procedure:
4-{[(3-Aminoquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol (7.50 g, 27.4 mmol) was reacted with ethoxyacetyl chloride (3.70 g, 30.1 mmol) and the resulting product was cyclized according to the method described in Part E of Example 9 to provide 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol as pale tan crystals (7.50 g, 76%) after crystallization from ethanol.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:18]=[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:28])=[C:9]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[OH-].[K+].C(O)C.O>C(O)(=O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]=1[CH:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][C:20]1=[O:28])([OH:16])=[O:15]
Reactant: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3ccccc32)c(CCC(=O)OC)c1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3ccccc32)c1CCC(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
4-(2-Methoxycarbonylethyl)-3-methyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid ethyl ester (81.7 g)), 56.5 g of potassium hydroxide, 200 mL of ethanol and 200 mL of water were charged to a 1 L, 3 neck round bottom flask equipped with mechanical stirring and a thermometer. The mixture was stirred at 90° C. for 90 minutes, cooled to room temperature, and acidified with acetic acid until a precipitate formed. The precipitate was collected by vacuum filtration, washed with 50 mL of water and vacuum dried to give 69.1 g (85%) of 4-(2-carboxyethyl)-3-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid as a red solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-])=O.C(N(C(C)C)CC)(C)C.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])C>>[CH2:24]([O:23][C:20](=[O:22])[NH:1][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:25]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
4-Nitro-aniline (100 g, 0.72 mol) is dissolved in ethyl acetate (800 mL) and diisopropylethylamine (89.6 mL, 0.936 mol) is added. Ethyl chloroformiate (252 mL, 1.45 mol) dissolved in ethyl acetate (200 mL) is added and the solution is stirred for 18 h at ambient temperature. The mixture is washed with 2M HCl (300 mL) and brine (300 mL), dried (MgSO4) and concentrated in vacuo to half of the original volume. To the resulting solution is added palladium on activated carbon (10 g, 5% Pd, 50% H2O) and the mixture is hydrogenated on a Parr apparatus (pH2=3 bar) at ambient temperature for 12 hours. The mixture is filtered through Celite and the solvent evaporated in vacuo to give 118 g (90%) of the title compound as crystalline product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12]([CH3:17])=[C:13]([CH2:15][OH:16])[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12]([CH3:17])=[C:13]([CH:15]=[O:16])[O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1c(CO)oc2cccc(OCCCBr)c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1c(C=O)oc2cccc(OCCCBr)c12
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of [4-(3-bromo-propoxy)-3-methyl-benzofuran-2-yl]methanol (690 mg) in chloroform (10 ml) was added manganese(IV) oxide (1.2 g) at room temperature and the mixture was stirred vigorously overnight. The mixture was filtered through a pad of Celite and concentrated in vacuo. The titled compound (500 mg) was obtained as a white solid after the purification by silica gel column chromatography developed by the mixture of hexane and ethyl acetate. EI-MS: m/z 297 (M+); 1H-NMR (CDCl3): δ 2.38-2.47 (2H, m), 2.74 (3H, s), 3.65 (2H, t, J=6.6 Hz), 4.23 (2H, t, J=5.9 Hz), 6.68 (1H, d, J=7.9 Hz), 7.14 (1H, d, J=8.9 Hz), 7.40 (1H, t, J=8.3 Hz), 9.97 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@H:8]2[CH2:13][C@H:12]3[C@H:14]4[C@H:24]([CH2:25][CH2:26][C@:10]3([CH3:11])[C@H:9]2[OH:35])[C@:22]2([CH3:23])[C@H:17]([CH2:18][C@H:19]([OH:34])[C@@H:20]([N:27]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]3)[CH2:21]2)[CH2:16][CH2:15]4)[CH2:4][CH2:3]1.[CH3:36][C:37]([CH2:39][C:40]([OH:42])=[O:41])=[O:38].[BH4-].[Na+]>>[OH:33][CH:30]1[CH2:31][CH2:32][N:27]([C@H:20]2[CH2:21][C@@:22]3([CH3:23])[C@@H:17]([CH2:16][CH2:15][C@@H:14]4[C@@H:24]3[CH2:25][CH2:26][C@@:10]3([CH3:11])[C@H:12]4[CH2:13][C@H:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[C@@H:9]3[OH:35])[CH2:18][C@@H:19]2[OH:34])[CH2:28][CH2:29]1.[CH3:36][C:37]([CH2:39][C:40]([OH:42])=[O:41])=[O:38]
Reactant: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCC(=O)CC6)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Agent: CC(=O)CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCC(O)CC6)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Yield: 83.05 %

Procedure:
16β-(4-Methyl-1-piperazinyl)-2β-(4-oxo-1-piperidinyl)-5α-androstane-3α,17β-diol-diacetate is reduced by sodium borohydride as described in Example 11 to obtain the foam-like title compound in a yield of 83.05%, Rf2 =0.61.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:7][C:6]([F:9])(F)[C:5]1([Cl:11])F)[CH:2]=[CH2:3].CC1(C=C)CC(F)(F)C1(Cl)F.CC1C=CC=C(F)C=1F.CC1C=CC(F)=C(F)C=1.CC1C=CC(F)=C(Cl)C=1>>[CH3:3][C:2]1[CH:1]=[CH:4][CH:7]=[C:6]([F:9])[C:5]=1[Cl:11]
Reactant: C=CCC1CC(F)(F)C1(F)Cl
Agent: C=CC1(C)CC(F)(F)C1(F)Cl
Agent: Cc1ccc(F)c(Cl)c1
Agent: Cc1ccc(F)c(F)c1
Product: Cc1cccc(F)c1Cl
Yield: 88 %

Procedure:
The general procedure was followed using a mixture of 1-(2-propenyl)-2-chloro-2,3,3-trifluorocyclobutane and 1-methyl-1-vinyl-2-chloro-2,3,3-trifluorocyclobutane as the liquid feed at a flow rate of 1 ml/hr. Nitrogen gas was used as the inert carrier. The reactor was charged with 3 g of AL-0104 (tableted activated alumina containing 99% Al2O3). At 400° C. the yield of the produced aromatic products was 12% combined yield of 1-methyl-2,3-difluorobenzene and 1-methyl-3,4-difluorobenzene and a combined yield of 88% of 1-methyl-2-chloro-3-fluorobenzene and 1-methyl-3-chloro-4-fluorobenzene.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[C@@H:32]([CH3:35])[CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>>[CH3:34][N:33]1[C:26]2[N:27]([C:28](=[O:30])[N:29]=[C:24]([O:22][CH2:21][C:19]3[CH:18]=[CH:17][C:3]([O:4][C:5]4[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:14])[F:15])[CH:6]=4)=[C:2]([F:1])[CH:20]=3)[CH:25]=2)[CH2:31][C@@H:32]1[CH3:35]
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2F)cc1C(F)(F)F
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccc(C#N)c(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 4-(2-fluoro-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]2[CH:13]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[O:17][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 80 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
To a stirred solution of 4-(benzyloxy)-2-hydroxybenzaldehyde (10 g, 43.9 mmol) in DMF (60 mL), was added methyl bromoacetate (48.3 mmol, 4.57 mL), and potassium carbonate (24.2 g, 175.6 mmol). The solution was heated to 80° C. and stirred for 16 h. The reaction was quenched with water (100 mL) and aqueous extraction was performed with AcOEt (2×50 mL). The organic phase was dried with sodium sulfate and concentrated. Purification was achieved via silica gel chromatography employing 0-30% AcOEt in hexane gradient. This afforded 393 as a light yellow solid (4.5 g, 37%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[OH:9])=[CH:4][CH:3]=1.Br[CH:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[O:9][CH:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Br)cc1)c1nccs1
Reactant: COC(=O)C(Br)CC(C)C
Product: COC(=O)C(CC(C)C)OC(c1ccc(Br)cc1)c1nccs1

Procedure:
Using the same protocol as described in example 23, step 2, (4-bromophenyl)(1,3-thiazol-2-yl)methanol from step 1 (983 mg, 3.64 mmol) was added to methyl 2-bromo-4-methylpentanoate (624 μL, 3.82 mmol). The crude residue was chromatographed on silica gel using 25% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH2:9][O:10][CH3:11])([CH3:8])[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:31]([O:33][CH:34]([O:38][CH2:39][CH3:40])[CH2:35][CH2:36][NH2:37])[CH3:32]>C(Cl)Cl.C1COCC1.C(Cl)CCl>[CH2:31]([O:33][CH:34]([O:38][CH2:39][CH3:40])[CH2:35][CH2:36][NH:37][C:5](=[O:7])[C:4]([CH2:3][O:2][CH3:1])([CH3:8])[CH2:9][O:10][CH3:11])[CH3:32]
Reactant: CCOC(CCN)OCC
Reactant: COCC(C)(COC)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNC(=O)C(C)(COC)COC)OCC
Temperature: 25 °C
Reaction time: 23 h
Yield: 80.7 %

Procedure:
5 g of 3-methoxy-2-methoxymethyl-2-methyl-propionic acid (prepared as described in EP609058) were dissolved in 49 mL of DCM and 12 mL of THF. 11.4 mL of DIPEA, 5.84 g of HOBt, 7.07 g of EDC and 5.45 g of 3,3-diethoxy-propylamine were added sequentially. The mixture was stirred for 23 h at rt, diluted with DCM and washed with sat. NaHCO3. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using Hept/EtOAc from 3/1 to 0/1 as eluant to yield 7.25 g of N-(3,3-diethoxy-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide as a yellowish oil.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([CH3:17])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:20])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c[nH]c2c(C)cccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCC(=O)c1cnc2c(C)cccc2c1Cl

Procedure:
3-Butyryl-8-methyl-4(1H)-quinolone (20 g) and phosphoryl chloride (80 ml) were heated under reflux for 45 minutes. Excess phosphoryl chloride was evaporated in vacuo, the residue poured onto ice and neutralised with sodium hydrogen carbonate. Extraction with dichloromethane, drying and evaporation gave 3-butyryl-4-chloro-8-methylquinoline (20 g) as a brown oil, which solidified at -15° C. but melted below room temperature. This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.II.C(N(CC)CC)C.[F:22]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:22][C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: FF
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Fc1cc(Cl)c2ccc(Cl)cc2n1
Yield: 61.1 %

Procedure:
A solution containing 4,7-dichloroquinoline (1.0 g, 5 mmol), iodine (1.28 g, 5 mmol) and triethylamine (0.51 g, 5.1 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (7 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added, the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to a brown oil (1.06 g). GC/MS analysis showed a 69% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2-fluoro-4,7-dichloroquinoline (0.66 g, 88%) as white crystals; m.p. 105°-106° C. (vacuum sublimation oil bath temp. 60° C./<1 mmHg); RF 0.72; (Found: C, 49.7; H, 1.7;N, 6.3. C9H4CI2FN requires: C, 50.0; H, 1.85; N, 6.5%); δH (400 MHz; CDCI3 ; Me4Si) 7.20 ppm (1H, d, JH3,F 2.4,H-3),7.58 (1H, d d, JH5,H6, 9.0 JH6,H8 2.2, H-6), 7.95 (1H, d, JH6,H8 2.0, H-8), 8.13 (1H, d, JH5,H6 9.2, H-5); δF (235MHz; CDCI3 ; Me4Si)-60.0ppm (s); δC (100 MHz, CDCI3, Me4Si)110.38 (d, 2J 45.8, C-3), 123.6 (d,4J 2.3, C-4a), 125.5 (s, C-6), 127.6 (d, 5J 1.2, C-5), 128.1 (d, 4J 2.6, C-8), 137.9 (s, C-7), 146.4 (d, 3J 24.6, C-4), 146.6 (d, 3J 18.5, C-8a), 160.9 (d, 1J 244.1, C-2); m/z (E1+) 215 (M+, 100%), 217 (61, M+ +2), 219 (11, M30 +4), 182(14), 180 (40), 145 (18).
Reaction SMILES: [Li]CCCC.[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].CN(CCN(C)C)C.[Cl:39]N1C(=O)CCC1=O>C1COCC1.C(OCC)C.O>[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]3[CH:24]=[C:25]([F:30])[C:26]([Cl:39])=[C:27]([F:29])[CH:28]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:7][CH3:8]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3cc(F)cc(F)c3)CC2)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3cc(F)c(Cl)c(F)c3)CC2)CC1
Reaction time: 0.5 h

Procedure:
0.1 mol of n-BuLi (1.5M in hexane) is added dropwise at about -65° to a solution of 0.1 mol of 1-[trans-4-(trans-4-n-propylcyclohexyl)cyclohexyl]-2-(3,5-difluorophenyl)-ethane (prepared according to scheme 3) and 0.1 mol of TMEDA in 300 ml of THF. Stirring at this temperature is continued for another 30 minutes, and 0.2 mol of N-chlorosuccinimide in 70 ml of THF are then slowly added. After the addition is completed, the mixture is allowed to warm to -20° and hydrolyzed with H2O. Diethyl ether is added until the product is completely dissolved. Extractive work-up and purification by chromatography and crystallization gives 1-[trans-4-(trans-4-n-propylcyclohexyl)cyclohexyl]-2-(4-chloro-3,5-difluorophenyl)ethane, C 88 N 129 I.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[NH:4][C:5]1[O:6][C:7]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[C:8]=2[N:9]=1>CO.ClCCl.[Pd]>[CH3:1][O:2][C:3](=[O:19])[NH:4][C:5]1[O:6][C:7]2[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:17][CH3:18])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc([N+](=O)[O-])c2o1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Nc1nc2c(OC)ccc(N)c2o1
Reaction time: 18 h
Yield: 58.6 %

Procedure:
To a stirred solution of 220 mg (0.82 mmol) (4-methoxy-7-nitro-benzooxazol-2-yl)-carbamic acid methyl ester in 25 ml methanol and 45 ml dichloromethane was added a spatula end of 10% palladium on charcoal and stirring continued for 18 h at room temperature under an atmosphere of hydrogen. The mixture was then filtered and the filtrate concentrated in vacuo. Flash chromatography (2/98 methanol/dichloromethane) afforded 114 mg (58%) (7-amino-4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester as a white crystalline solid. ES-MS m/e (%): 238 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:13]O)[CH:9]=[CH:8]2.CN(C)C=O.S(Cl)([Cl:22])=O>>[Cl:22][CH2:13][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc2ccc(CO)nc12
Solvent: CN(C)C=O
Product: COc1cccc2ccc(CCl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (8-methoxyquinolin-2-yl)methanol (1.0 g, 5.3 mmol) and N,N-dimethylformamide (39 mg, 0.53 mmol) in sulfurous dichloride (20 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated and ice water was added. The pH of the aqueous layer was adjusted to 7 with 10 N sodium hydroxide solution. The mixture was extracted with DCM (30 mL×3). The combined organic phase was dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography to give 0.66 g of the product as a yellow solid. MS (ESI): m/z 208.0 [M+H]+.