Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([CH3:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: Cc1cc2c(cc1F)-c1cccc(c1)-c1cn3c(c([C@H](OC(C)(C)C)C(=O)O)c(C)cc3n1)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Yield: 100 %

Procedure:
Prepared in 100% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid. 1H NMR (600 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.05 (d, J=7.3 Hz, 1H), 7.96 (s, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.15 (t, J=5.0 Hz, 2H), 7.09 (d, J=6.6 Hz, 1H), 5.64 (br. s., 1H), 4.62 (br. s., 1H), 3.95-3.13 (m, 5H), 2.67 (d, J=9.2 Hz, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 2.00-1.53 (m, 10H), 1.20 (s, 3H), 1.13 (s, 9H), 1.08 (d, J=5.5 Hz, 3H); LCMS (ESI, M): 657.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[N:12]=2)[N:3]=1.C(=O)(O)[O-].[Na+].[C:26]1(B2OCCCO2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:18]=[C:13]3[N:12]=2)[N:3]=1
Reactant: c1ccc(B2OCCCO2)cc1
Reactant: Cc1cc(N)nc(CCc2nc3cc(Br)cnc3[nH]2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4ccccc4)cnc3[nH]2)c1
Temperature: 110 °C
Yield: 80.4 %

Procedure:
350 mg of 2-[2-(amino-4-methylpyridin-6-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine (compound 4) are dissolved in 5.6 ml of anoxic dioxane under a nitrogen atmosphere. Subsequently, 3.15 ml of an aqueous sodium bicarbonate solution (2.0 M), 193 mg of 2-phenyl-1,3,2-dioxaborinane, and 49 mg of trans-dichloro-bis(tricyclohexylphosphane)palladium-(II) are added. The reaction mixture is refluxed at 110° C. for 46 hours. Thereafter, the volatile components are removed in vacuo and the remaining residue is redissolved in 200 ml of a mixture of water/dichloromethane (1:1). The aqueous phase is extracted twice each with 125 ml of dichloromethane. The organic layer is separated, dried using sodium sulfate, and evaporated to dryness to yield a colorless, crude solid. Subsequently, the residue is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 8:1) to afford 279 mg of the title compound as a colorless solid of m.p. 230° C. MS: 330.3 (MH+). TLC: Rf=0.34 (dichloromethane/methanol 8:1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]#[N:17])[CH2:12][CH2:11]3)[S:9][C:5]=2[CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>O1CCCC1.[Cl-].[Na+].O>[Si:36]([O:35][CH2:34][CH2:33][C:13]1([C:16]#[N:17])[CH2:14][CH2:15][N:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:19]=[CH:18][C:6]=3[N:7]=2)[CH2:11][CH2:12]1)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: N#CC1CCN(c2nc3ccc(C(F)(F)F)cc3s2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC1(C#N)CCN(c2nc3ccc(C(F)(F)F)cc3s2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of 1-(6-trifluoromethyl benzothiazole-2-yl)piperidine-4-carbonitrile (1.00 g) in tetrahydrofuran (10 mL) was added lithium bis(trimethylsilyl)amide (3.21 mL) at −15° C. To the reaction solution was added (2-bromoethoxy)-t-butyldimethyl silane (689 μL). The mixture was stirred at 0° C. for 3 hours. To the reaction solution was added brine and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatograph on silica gel to give the title compound (1.23 g). Yield: 82%.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][N:9]=[C:8]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Li+]>C(OCC)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[CH:10][N:9]=[C:8]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)n(C2CCCCC2)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: O=C(O)c1cnc(-c2ccccc2)n(C2CCCCC2)c1=O
Yield: 45 %

Procedure:
Ethyl 1-cyclohexyl-1,6-dihydro-6-oxo-2-phenyl-5-pyrimidinecarboxylate (1.41 g, 4.32 mmol) (i.e. the product from Example 11, Step A) was dissolved in ethyl acetate and treated with lithium iodide (powder, 1.72 g, 12.8 mmol) and heated to reflux for 16 h. The crude reaction mixture was concentrated under reduced pressure and then aqueous sodium bicarbonate was added and the resulting solution was extracted with ethyl acetate which was then discarded. The aqueous layer was made acidic with hydrochloric acid (1 N) and then extracted with dichloromethane (2×40 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure resulting in 0.58 g of the title product as a solid.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.C(NCC)C.[CH:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:7][C:6]1[C:2]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:3][S:4][CH:5]=1
Reactant: C#CCCCCCC
Reactant: Brc1cscc1Br
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: CCCCCCC#Cc1cscc1Br
Temperature: 60 °C
Reaction time: 40 h
Yield: 25.7 %

Procedure:
Into a 250 mL 4 necked RB flask equipped with a magnetic stirring bar, thermometer, rubber septum, argon inlet and reflux condenser with argon outlet (tubed to a silicon oil bubbler) is added 59.4 g (246 mmol) of 3,4-dibromothiophene, 44.0 g of diethylamine, 27.0 g (245 mmol) of 1-octyne, 148 mg of triphenylphosphine, 106 mg of copper iodide and 295 mg dichlorobis(triphenylphosphine) palladium(II). The mixture is heated with a silicon oil bath to 60° C. under argon with stirring for 40 hrs. The cooled mixture is then concentrated on a rotary evaporator at reduced pressure and the residue taken up in 200 mL of pentane and washed with 2×25 mL of water and the pentane phase dried over sodium sulfate and then concentrated on a rotary evaporator. The residue is then distilled at 55-60 ° C. and 0.40 torr to remove 2.3 g of unreacted 3,4-dibromothiophene. The residue was chromatographed through silica gel eluting with hexanes to yield 17.1 g of 3-bromo-4(oct-1-ynyl)thiophene as a light yellow-orange oil which was used directly to prepare 2-hexylselenolo[2,3-c]thiophene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15]([CH2:26][CH3:27])([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=3)[CH2:16][CH3:17])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:20]([CH3:25])[CH:19]=3)([CH2:26][CH3:27])[CH2:16][CH3:17])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(O)c(C)c3)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2ccc(C(CC)(CC)c3ccc(OCC(=O)C(C)(C)C)c(C)c3)cc2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
A solution of 6-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-benzo[b]thiophene-2-carboxylic acid ethyl ester (0.780 g, 2.04 mmol) and 1-bromopinacolone (0.731 g, 4.08 mmol) in acetone (30 mL) is treated with K2CO3 (0.563 g, 4.08 mmol) and stirred at RT for 4 h. The mixture is filtered, and the filtrate is concentrated. The residue is purified using silica gel column chromatography (10-15% EtOAc/Hex) to provide the title compound (0.89 g, 91%).
Reaction SMILES: N1C=CC(CC(=O)C)=CC=1.FC1C=C(C=CC=1OC)C=O.[O:22]=[C:23]([CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1)[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH:50]=O)=[CH:48][CH:47]=1>>[F:45][C:46]1[CH:53]=[CH:52][C:49]([CH:50]=[C:38]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[C:23](=[O:22])[CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH2:27][CH2:26]2)=[CH:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Cc2ccncc2)CC1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)Cc1ccncc1
Agent: COc1ccc(C=O)cc1F
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)C(=Cc2ccc(F)cc2)c2ccncc2)CC1

Procedure:
1,1-Dimethylethyl 4-[4-(4-fluorophenyl)-2-oxo-3-(4-pyridinyl)-3-butenyl]-1-piperidinecarboxylate was prepared by the same method as described for step 1 of Example A-1 by replacing 4-pyridylacetone and 3-fluoro-p-anisaldehyde with the ketone of step 2 of the present Example and 4-fluorobenzaldehyde, respectively.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C:15]4([CH2:18][CH2:17][CH2:16]4)[CH2:14][N:13]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:12]3)=[C:8]([C:29](=[O:31])[NH2:30])[CH:7]=[N:6][N:5]2[CH:32]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.CCOCC>[C:29]([C:8]1[CH:7]=[N:6][N:5]2[CH:32]=[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@H:11]1[C:15]2([CH2:18][CH2:17][CH2:16]2)[CH2:14][N:13]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:12]1)(=[O:31])[NH2:30]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1N[C@@H]1CN(C(=O)OCc2ccccc2)CC12CCC2
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cn1cc(-c2cc3c(N[C@@H]4CN(C(=O)OCc5ccccc5)CC45CCC5)c(C(N)=O)cnn3c2)cn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
A solution of (S)-benzyl 8-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-6-azaspiro[3.4]octane-6-carboxylate (120.0 mg, 0.241 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.482 mmol) in 1,4-dioxane (3.20 mL) and potassium phosphate (2.0M) (0.361 mL, 0.722 mmol) was degassed for several minutes with N2 gas. 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex (19.81 mg, 0.024 mmol) was added, degassing was continued for 1 more minute, vial was sealed, and the contents were heated @ 110° C. for 45 minutes. HPLC and LC/MS after 30 min indicated that the reaction had essentially proceeded to completion (m/e 500.16, M+H for desired product). After cooling to r. t., the reaction was diluted with EtOAc and water. The layers were separated, the EtOAc layer was washed with water, brine, dried over Na2SO4, and concentrated under vacuum to yield a solid. Trituration with ether yielded 124.4 mg of the title compound as a pale mustard-colored solid. LC/MS: m/e 500.15 (M+H). This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH:7]=1.[NH2-].[Na+].Cl[C:21](Cl)([CH3:25])[C:22]([O-:24])=[O:23].[Na+].Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][C:21]([CH3:25])([C:22]([OH:24])=[O:23])[O:9][C:8]([CH3:16])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: CC(Cl)(Cl)C(=O)[O-]
Reactant: CC(O)(c1ccccc1)c1cc(Cl)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [NH2-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C(=O)O)Oc2ccc(Cl)cc2C(C)(c2ccccc2)O1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A dispersion of 24.9 g of 5-chloro-2-hydroxy-α-methyl-α-phenyl-benzenemethanol in 250 ml of toluene was added dropwise with stirring to a mixture of 8 g of sodium amide in 100 ml of toluene and the mixture was refluxed for 6 hours and was then cooled to room temperature. 17 g of sodium dichloropropionate were added thereto in small portions and the mixture was refluxed for 6 hours and was then cooled to room temperature. 700 ml of water were added thereto and the mixture was acidified with N hydrochloric acid solution. The mixture was made alkaline again with a saturated sodium bicarbonate solution and the aqueous phase was washed 3 times with 100 ml of ether and was acidified with 2 N hydrochloric acid. The aqueous phase was extracted 3 times with 100 ml of ether and the combined organic phases were washed 3 times with 80 ml of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to obtain 23 g of 6-chloro-2,4-dimethyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two racemates diastereoisomers) melting at 181° C.
Reaction SMILES: C(N(CC)CC)C.[Br-].Br[C:10]1[N:15]=[C:14]2[N:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([NH3+:19])=[N:18][C:13]2=[CH:12][CH:11]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[CH:33])=[CH:28][CH:27]=1>C(O)C.C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][C:21]([CH3:24])([CH3:23])[CH2:20][N:16]1[C:14]2=[N:15][C:10]([CH2:33][CH2:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[CH:11][CH:12]=[C:13]2[N:18]=[C:17]1[NH2:19]
Reactant: C#Cc1ccc(F)cc1
Reactant: CC(C)(C)Cn1c([NH3+])nc2ccc(Br)nc21
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)Cn1c(N)nc2ccc(CCc3ccc(F)cc3)nc21
Temperature: 72.5 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Add triethylamine (27.10 g, 267.80 mmol) to a mixture of 5-bromo-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-yl-ammonium bromide (25.00 g, 68.67 mmol) in ethanol (25 mL) and toluene (75 mL). Heat to 70-75° C. and then add Pd(OAc)2 (0.15 g, 0.69 mmol), triphenylphosphine (0.72 g, 2.75 mmol), and copper (I) iodide (0.13 g, 0.69 mmol). Add ⅔ of a solution of 4-fluorophenylacetylene (12.37 g, 103.00 mmol) in toluene (50 mL, 2.0 vol.) over 15 minutes. Add the remaining 4-fluoroacetylene solution after 1 h. After 3 h, add additional 4-fluorophenylacetylene (1.5 g, 12.86 mmol). After an additional hour, remove EtOH by distillation. Cool the reaction mixture to <40° C. and add water (25 mL). Cool to room temperature. Filter suspension and wash with water (25 mL) and 2×25 mL toluene. Dry under reduced pressure at 45-50° C. to provide 19.3 g (87%) of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:20])[CH2:13][CH2:12][N:11]([CH:14]3[CH:18]([OH:19])[CH2:17][NH:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[N:25]=[CH:24][N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:20])[CH2:13][CH2:12][N:11]([C@@H:14]3[C@@H:18]([OH:19])[CH2:17][N:16]([C:22]4[C:31]5[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=5)[N:25]=[CH:24][N:23]=4)[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC1CNCC1N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Product: O[C@H]1CN(c2ncnc3cc(Cl)ccc23)C[C@@H]1N1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared following general procedures described above from 4-(4-Chlorophenyl)-1-(4-hydroxy-pyrrolidin-3-yl)-piperidin-4-ol and 4,7-dichloroquinazoline. 1H-NMR (300 MHz, DMSO): δ 1.57 (2H, m), 1.90 (2H, m), 2.60-2.70 (3H, m), 2.96 (2H, m), 3.70 (1H, m), 3.85 (1H, m), 4.10 (2H, m), 4.36 (1H, m), 4.90 (1H, s), 5.32 (1H, d), 7.40 (4H, dd), 7.48 (1H, m), 7.73 (1H, d), 8.30 (1H, d), 8.45 (1H, s). Retention Time (LC, method, AA standard): 1.48 min MS (M+H+): 459.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Br[CH2:27][CH2:28][CH2:29][Cl:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[C:16]([CH3:25])=[N:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: ClCCCBr
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (200 mg) was dissolved in N,N-dimethylformamide (10 ml) to prepare a solution. 1-Bromo-3-chloropropane (474 mg) and potassium carbonate (416 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (203 mg, yield 83%).
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)([OH:36])[C:29]4[N:33]([CH3:34])[C:32](S)=[N:31][N:30]=4)[CH:26]=3)[N:21]([CH3:44])[C:20](=[O:45])[CH:19]=2)[CH:13]=[CH:14][CH:15]=1>O.C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)([OH:36])[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][N:30]=4)[CH:26]=3)[N:21]([CH3:44])[C:20](=[O:45])[CH:19]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Cn1c(S)nnc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(CCc1cccc(Cl)c1)cc(=O)n2C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cnnc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(CCc1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
Sodium nitrite (0.0007 mol) was added at 0° C. to a mixture of nitric acid (0.0007 mol) in water (1 ml). A solution of 4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone, obtained in Example B19 (0.0007 mol) in THF (3 ml) was added dropwise (very exothermic reaction). The mixture was stirred at room temperature for 30 minutes, poured out into ice water and extracted with DCM. The organic layer was separated, washed with K2CO3 10%, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over kromasyl (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.4; 5 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.25 g) was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.12 g (32%) of 4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone, melting point 200° C.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([CH:15]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:16])[CH:6]=[CH:5][C:4]1=2.[N:37]1[CH:42]=[CH:41][C:40]([CH:43]=O)=[CH:39][CH:38]=1>C1OCCC1>[CH3:2][C:3]1([CH3:36])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7](/[C:15](/[CH3:16])=[CH:43]/[C:40]3[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: O=Cc1ccncc1
Reactant: CC(c1ccc2c(c1)C(C)(C)CCC2(C)C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C/C(=C\c1ccncc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
378 g of [1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethyl]triphenylphosphonium bromide were suspended in 4 l of butylene oxide. After the addition of 51 ml of 4-pyridinecarbaldehyde the mixture was boiled at reflux for 1.5 hours. After cooling the majority of the solvent was evaporated in a water-jet vacuum, the residue was poured into 1.5 l of a methanol/water mixture (ratio 6:4) and extracted repeatedly with hexane. The organic phase was washed three times with water and, after drying over sodium sulphate, evaporated. After flash chromatography (eluting agent hexane/ether=2:1) and recrystallization from hexane there were obtained 216 g of 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthyl) propenyl]pyridine in colorless crystals, melting point 84°-85°.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[CH:20]([C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C=O)C.C(N(CC)CC)C>[O:15]=[C:13]1[N:12]=[C:11]([NH:16][CH2:17][C:18]#[CH:19])/[C:10](=[CH:9]/[CH:6]2[CH2:7][CH2:8][N:3]([CH2:20][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[CH2:4][CH2:5]2)/[S:14]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added triethylamine (0.35 mL) and 4-formylbenzonitrile (82 mg). The reaction mixture was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (554 mg) was added. The reaction mixture was stirred at room temperature for 3 hr, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (100 mg).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C:9]2[S:15][CH:14]3[N:11]([C:12](=[O:16])[CH2:13]3)[C:10]=2[C:17]([O:19]CC2C=CC([N+]([O-])=O)=CC=2)=[O:18])=[CH:6][CH:5]=1)=[O:3].C(=O)(O)[O-].[Na+:36]>O1CCOCC1.O.[Pd]>[CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[S:15][CH:14]3[N:11]([C:12](=[O:16])[CH2:13]3)[C:10]=2[C:17]([O-:19])=[O:18])=[CH:30][CH:31]=1)=[O:3].[Na+:36]
Reactant: CS(=O)c1ccc(OC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)CC3S2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)c1ccc(OC2=C(C(=O)[O-])N3C(=O)CC3S2)cc1
Yield: 109.8 %

Procedure:
A mixture of a solution of 70 mg of 4-nitrobenzyl 3-(4-methylsulphinylphenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 13 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes. Then, the mixture was filtered through Gelite, and lyophilized to yield 58 mg of the title compound as a pale yellow crystalline solid.