Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:25](=[O:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1>CC(O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C@@H:25]([OH:26])[CH2:24][C:23]([CH3:28])([CH3:27])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)C[C@H](O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2O1
Reaction time: 16 h

Procedure:
A solution of Example 1 (14.1 g, 32.5 mmol) and the (S,S) catalyst described by Noyori in Angew. Chem. Int. Ed. Engl. 1997, 36, 285 (998 mg, 1.62 mmol) in IPA (20 mL) and CH2Cl2 (10 mL) was stirred at rt. After 16 h, the reaction mixture was concentrated to give the product, which was taken into the next step without further purification: 1H NMR δ 1.43 (s, 3H), 1.56 (s, 3H), 1.96 (dd, J=9.7, 13.4, 1H), 2.06 (d, J=7.3, 1H), 2.28 (dd, J=6.2, 13.5, 1H), 5.00 (m, 1H), 7.03 (d, J=8.5, 2H), 7.18-7.26 (m, 5H), 7.90 (s, 1H).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:17][C:18]1[CH:41]=[CH:40][C:21]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:35][CH2:34][CH:33]([N:36]([CH3:38])[CH3:37])[CH2:32]3)=[C:27]([F:39])[CH:26]=2)=[O:23])=[C:20]([CH3:42])[CH:19]=1)[CH2:14][CH2:15][CH3:16].Cl>C1COCC1.CN(C=O)C>[CH2:13]([O:17][C:18]1[CH:19]=[C:20]2[C:21](=[CH:40][CH:41]=1)[C:22](=[O:23])[N:24]([C:25]1[CH:30]=[CH:29][C:28]([N:31]3[CH2:35][CH2:34][CH:33]([N:36]([CH3:38])[CH3:37])[CH2:32]3)=[C:27]([F:39])[CH:26]=1)[CH:1]=[CH:42]2)[CH2:14][CH2:15][CH3:16]
Reactant: [Li]CCCC
Reactant: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)c(F)c2)c(C)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CCCCOc1ccc2c(=O)n(-c3ccc(N4CCC(N(C)C)C4)c(F)c3)ccc2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (2.6M in toluene; 0.70 mL) was added to a solution of N,N-diisopropylamine (184 mg) in THF (30 mL) at −78° C. After 10 minutes, 4-butoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-2-methylbenzamide (0.30 g) was added, and the mixture was stirred at −78° C. for 30 minutes and then warmed to −20° C. DMF (53 mg) was added, and the reaction mixture was hydrolyzed after a further 30 minutes with hydrochloric acid. The reaction mixture was partitioned between sodium carbonate solution and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 423.54 (C25H30FN3O2) was obtained in this way; MS (ESI): 424 (M+H+).
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17]C)[C:13]([CH3:20])([CH3:19])[CH2:12][CH:11]=[C:10]2[CH:21]([CH3:23])[CH3:22].Cl>CN(C=O)C.O>[Br:6][C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:13]([CH3:19])([CH3:20])[CH2:12][CH:11]=[C:10]([CH:21]([CH3:22])[CH3:23])[C:9]=2[CH:8]=1
Reactant: COc1cc2c(cc1Br)C(C(C)C)=CCC2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.6 %

Procedure:
To a suspension of sodium hydride 60% w/w (0.30 g, 6.8 mmol) in 20 mL of DMF under argon atmosphere was added slowly ethanethiol 98% (0.5 mL, 6.8 mmol), and the resulting solution was stirred for 15 min. A solution of 6-bromo-4-isopropyl-1,1-dimethyl-7-methoxy-1,2-dihydronaphthalene (Compound 102, 600 mg, 1.9 mmol) in 3 mL of DMF was added, and the reaction mixture was refluxed for 5 h, then cooled to room temperature, acidified with 2 N HCl, diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed to afford 0.57 g (100%) of the title compound as a dark brown oil.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([Br:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:26]1C(OC)=C(C=CC=1CSC1C=CC=CC=1C)C(OCC)=O>>[Br:24][C:14]1[C:15]([O:22][CH3:23])=[C:16]([C:11]([CH2:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[CH3:26])(=[O:9])=[O:8])=[CH:12][CH:13]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1ccc(CSc2ccccc2C)c(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 61, starting from ethyl 3-bromo-2-methoxy-(2-methylphenylthiomethyl)benzoate (Intermediate 77).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N(CC)C(C)C)(C)C.[Cl:21][CH2:22][CH2:23][N:24]=[C:25]=[O:26]>C(#N)C>[Cl:21][CH2:22][CH2:23][NH:24][C:25]([NH:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[O:26]
Reactant: NC1Cc2ccccc2C1
Reactant: O=C=NCCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NCCCl)NC1Cc2ccccc2C1
Yield: 46.8 %

Procedure:
Synthesized according to general procedure 40. The reaction was set up with 2-aminoindan hydrochloride (5.0 g, 29.5 mmol), N,N-diisopropylethylamine (10.3 mL, 58.9 mmol), acetonitrile (100 mL), and 2-chloroethylisocyanate (2.52 mL, 29.5 mmol). Purification via silica gel chromatography using 50% EtOAc in hexanes gave the desired urea as a white solid (3.3 g, 13.8 mmol, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.23-7.18 (m, 2H), 7.15-7.11 (m, 2H), 6.38 (d, J=7.3 Hz, 1H), 6.03 (t, J=5.7 Hz, 1H), 4.36-4.28 (m, 1H), 3.57 (t, J=6.2 Hz, 2H), 3.38-3.29 (m, 2H), 3.12 (dd, J=7.1, 15.8 Hz, 2H), 2.68 (dd, J=5.5, 15.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[N:8][C:6]=2[N:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[N:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-chloro-7-morpholinothiazolo[4,5-d]pyrimidine-2-carbaldehyde 43 (1.0 g, 3.5 mmol) in MeOH (30 mL) at 0° C. was treated with NaBH4 (0.1 g, 3.5 mmol). The solution was allowed to warm to room temperature and stirred 15 min. The reaction mixture was quenched with a mixture of a saturated solution of sodium bicarbonate and water (1:1, v/v). The aqueous solution was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude (5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)methanol 56 required no further purification.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].CI.[NH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([OH:22])[C:11]=1[C:23]1[CH:31]=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1.O>CN(C)C=O>[O:27]1[C:26]2[CH:30]=[CH:31][C:23]([C:11]3[C:12]([O:22][CH3:1])=[N:13][N:14]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:10]=3[NH2:9])=[CH:24][C:25]=2[O:29][CH2:28]1
Reactant: Nc1c(-c2ccc3c(c2)OCO3)c(O)nn1Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1nn(Cc2ccccc2)c(N)c1-c1ccc2c(c1)OCO2
Reaction time: 10 h
Yield: 25 %

Procedure:
Cesium carbonate (1.05 g) and methyl iodide (0.46 g) were sequentially added at room temperature under an atmosphere of nitrogen to a solution of 5-amino-4-(1,3-benzodioxol-5-yl)-1-benzyl-1H-pyrazol-3-ol (1.0 g) (Preparation 59) in anhydrous dimethylformamide (10 ml). After 10 h, the reaction mixture was diluted water (100 ml) and the mixture was extracted with ether (3×100 ml). The organic fractions were washed with brine (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (silica, 50 g) eluted with hexane:ethyl acetate (1:1) yielding the title compound as a white solid (260 mg).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C1COCC1.CS(O)(=O)=O.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C(Cl)Cl>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)[N:3]=1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc2c(I)nn(C3CCCCO3)c2c1
Reaction time: 8 h
Yield: 24.4 %

Procedure:
An oven-dried round bottom flask under Ar was charged with 3-iodo-1H-indazole-6-carbaldehyde (50 mg, 0.184 mmol), THF (1.5 mL) and CH2Cl2 (1.0 mL). Methanesulfonic acid (1.4 uL, 0.0221 mmol) was added and the solution cooled with an ice-water bath. A solution of 3,4-dihydro-2H-pyran (41 uL, 0.460 mmol) in CH2Cl2 (0.5 mL) was then added dropwise over 15 minutes and the reaction stirred overnight. The solvents were removed in vacuo and the residue purified by column chromatography (silica gel, 99:1 to 98:2 CH2Cl2/MeOH) to give the title compound as a white powder (16 mg, 25%). 1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 8.13 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 5.84-5.77 (m, 1H), 4.07-4.02 (m, 1H), 3.83-3.75 (m, 1H), 2.62-2.51 (m, 1H), 2.20-2.10 (m, 2H), 1.86-1.70 (m, 3H); MS ESI 378.9 [M+Na]+, calcd for [C13H13IN2O2+Na]+ 378.99.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.O.NN>CCO>[F:32][C:2]([F:1])([F:31])[O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([O:19][NH2:20])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 1 h
Yield: 112.1 %

Procedure:
A mixture of 2-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (640 mg, 1.36 mmol) and hydrazine monohydrate (0.073 ml, 1.5 mmol) in EtOH (6 ml) was stirred for 1 hour. The precipitated materials were filtered off and washed with EtOH (2 ml×2), then the filtrate was evaporated under reduced pressure to give O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (519 mg, 100%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.Cl[C:21]1[N:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.C(NC(C)C)(C)C>CS(C)=O.C(Cl)Cl>[CH:16]1([N:9]2[C:10]3=[N:15][CH:14]=[CH:13][N:12]=[C:11]3[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:21]4[N:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH2:4]3)[C:8]2=[O:19])[CH2:17][CH2:18]1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Reactant: Clc1ncc2ccccc2n1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: CS(C)=O
Product: O=c1n(C2CC2)c2nccnc2n1[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Temperature: 90 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 79, 0.1099 g, 0.390 mmol), 2-chloroquinazoline (0.128 g, 0.780 mmol, Waterstone), and diisopropylamine (0.204 ml, 1.170 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO. The reaction was heated to 90° C. for 24 h. The reaction was taken up in DCM and loaded onto an Accubond SCX cartridge and washed with DCM (2×), MeOH (2×), and 2.0 ammonia in MeOH (2×). The ammonia fractions were combined and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (25 g), eluting with a gradient of 1% to 5% MeOH in CH2CL2, to provide the title compound (0.0445 g, 0.119 mmol, 30.6% yield). LCMS showed product peak at 1.511 min (m+1=374.0). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12-1.23 (m, 4 H) 2.65 (t, J=9.29 Hz, 2 H) 2.97-3.08 (m, 1 H) 3.41-3.53 (m, 2 H) 5.30-5.42 (m, 1 H) 7.36 (t, J=6.85 Hz, 1 H) 7.69 (d, J=8.41 Hz, 1 H) 7.73-7.85 (m, 2 H) 7.92-7.99 (m, 2 H) 9.11 (br. s., 1 H)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([C:14]([N:35]1[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]1)=[O:16])([CH3:17])[CH2:6][CH2:5]2
Reactant: CN1CCNCC1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N1CCN(C)CC1)O2
Yield: 83.4 %

Procedure:
Following the amide coupling procedure described in protocol A, 502 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.01 mmol), 354 mg CDI (2.18 mmol) and 220 mg N-methylpiperazine (2.2 mmol) produced 557 mg of (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-methylpiperazin-1-yl)methanone as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([CH2:12][CH2:13]O)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].C(N(CC)CC)C.C(OCC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>O>[CH3:1][C:2]1[O:3][C:4]2[C:11]([CH2:12][CH2:13][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: Cc1oc2c(CCO)cccc2c1C
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1oc2c(CCS(C)(=O)=O)cccc2c1C
Temperature: -30 °C
Reaction time: 1 h
Yield: 111.9 %

Procedure:
5.1 g (26.5 mmol) of 2,3-dimethyl-7-(2-hydroxyethyl)benzofuran, 5.91 ml (42.5 mmol) of triethylamine and 500 ml of anhydrous ethyl ether are introduced, under an inert atmosphere, into a 1 l round-bottomed flask. The mixture is cooled to -30° C. and 3.3 ml (42.5 mmol) of mesyl chloride are added dropwise. The reaction mixture is stirred for 1 h 30, while being allowed to return to 0° C. 200 ml of water are added and extraction is carried out with ethyl ether. The organic phases are combined and concentrated under vacuum. 7.48 g of 2,3-dimethyl-7-(2-(methylsulphonyl)ethyl)benzofuran are obtained in the form of an oil. 7.18 g (26 mmol) of 2,3-dimethyl-7-(2-(methylsulphonyl)ethyl)benzofuran and 200 ml of diethylamine are introduced into a 500 ml round-bottomed flask equipped with a reflux condenser. The reaction mixture is stirred for 16 h at reflux and concentrated under vacuum and the residue is purified by silica column chromatography (elution solvent: 9/1 dichloromethane/methanol).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=3[OH:24])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[F:25][C:26]([F:30])([F:29])[CH2:27]Br.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C.CCCCCC>CN(C=O)C>[C:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]=3[O:24][CH2:27][C:26]([F:30])([F:29])[F:25])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(-c3cc(C)cc(C(C)(C)C)c3O)cccc2s1
Reactant: FC(F)(F)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc2c(-c3cc(C)cc(C(C)(C)C)c3OCC(F)(F)F)cccc2s1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
A mixture of 211 mg (0.63 mmol) of 2-acetyl-4-(2-hydroxy-3-tert-butyl-5-methylphenyl)benzo[b]thiophene, 0.1 ml (132 mg, 0.81 mmol) of 1,1,1-trifluoro-2-bromoethane and 304 mg (0.94 mmol) of Cs2CO3 in 2.5 ml of dry DMF was heated at 60° C. in a pressure tube overnight. After cooling at room temperature, 10 mL of a 5/95 ethyl acetate/hexane solution was added and the remaining mixture was stirred for 5 minutes. The solution was filtrated through a silica plug (eluent: 5/95 ethyl acetate/hexane) and the solvents were removed under pressure. 188 mg (0.44 mmol, yield: 71%) of 2-acetyl-4-[2-(2,2,2-trifluoroethoxy)-3-tert-butyl-5-methylphenyl]benzo[b]thiophene was isolated as an oil. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=7.9 Hz, 1H), 7.75 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.26 (d, J=1.9 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 3.63 (m, 1H), 3.52 (m, 1H), 2.56 (s, 3H), 2.38 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[S:22]>CCOCC>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:22]
Reactant: Fc1ccccc1N=C=S
Reactant: c1cnc(N2CCNCC2)cn1
Solvent: CCOCC
Product: Fc1ccccc1NC(=S)N1CCN(c2cnccn2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 50 ml. of anhydrous ether is added a solution of 4.59 g. of 2-fluorophenyl isothiocyanate in 50 ml. of anhydrous ether over a period of 10 minutes. The mixture is stirred for 30 minutes and the resulting solid is collectedand then recrystallized from 200 ml. of ethanol, giving 7.04 g. of the desired product, m.p. 151°-153° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1ccccc1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
192 mg (0.352 mmol) of (2R*,4S*)-2-benzyl-1-(2-phenylacetyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 40 with 141 μl (0.704 mmol) of 5N sodium hydroxide solution in 1 ml of tetrahydrofuran and 1 ml of methanol. The title compound ##STR67## is obtained (73 mg, 46%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.43, FD-MS: M+ =449.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[CH3:8][O:9][CH:10]([O:26][CH3:27])[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[N:18]=[CH:17][C:16]=1[NH2:25].[OH-].[Na+]>ClCCl>[CH3:27][O:26][CH:10]([O:9][CH3:8])[CH2:11][CH2:12][CH2:13][N:14]1[C:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: COC(CCCNc1c(N)cnc2cccnc12)OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2cnc3cccnc3c2n1CCCC(OC)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Ethoxyacetyl chloride (4.2 mL, 37.4 mmol, 1.1 eq) was added dropwise over 8 minutes to a solution of N4-(4,4-dimethoxybutyl)[1,5]naphthyridine-3,4-diamine (9.50 g, 34.0 mmol) in dichloromethane (140 mL) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethanol (140 mL). Sodium hydroxide (6M) solution (8.5 mL, 51 mmol) was added to the reaction mixture, which was then heated for 60° C. for 3 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (150 mL) and water (100 mL). The pH of the mixture was adjusted to 7 and the layers were separated. The aqueous layer was back-extracted with dichloromethane (2×50 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 10.52 g of 1-(4,4-dimethoxybutyl)-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridine.
Reaction SMILES: C(C1C=[C:5](C=CC=1O)[C:6](NNC(C1OC=C(C2C=CC=CC=2)C=1C1C=CC=CC=1)=O)=[O:7])#N.[OH:33][C:34]1[CH:62]=[CH:61][C:37]([C:38]([NH:40][NH:41][C:42]([C:44]2[O:45][CH:46]=[C:47]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:48]=2[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:43])=[O:39])=[CH:36][C:35]=1[N+:63]([O-:65])=[O:64]>>[C:6]([O:33][C:34]1[CH:62]=[CH:61][C:37]([C:38]([NH:40][NH:41][C:42]([C:44]2[O:45][CH:46]=[C:47]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:48]=2[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:43])=[O:39])=[CH:36][C:35]=1[N+:63]([O-:65])=[O:64])(=[O:7])[CH3:5]
Reactant: O=C(NNC(=O)c1occ(-c2ccccc2)c1-c1ccccc1)c1ccc(O)c([N+](=O)[O-])c1
Reactant: N#Cc1cc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)ccc1O
Product: CC(=O)Oc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
A reaction and treatment was carried out in the same manner as in Example 94 except that the compound of Example 18 used in Example 94 was replaced with the compound of Example 19, thereby giving the desired compound. HPLC retention time: 15.15 minutes.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[O:40][CH3:41])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.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>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:2]3[S:6][C:5]4=[N:7][CH:8]=[C:9]([I:10])[N:4]4[N:3]=3)=[CH:27][C:26]=2[O:40][CH3:41])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Brc1nn2c(I)cnc2s1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2nn3c(I)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 115 °C
Yield: 47.5 %

Procedure:
To a suspension of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.262 g, 0.794 mmol, 1 eq) in 1,4-dioxane (13 mL), 4-[2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (0.413 g, 0.953 mmol, 1.2 eq), Cs2CO3 (0.517 g, 1.588 mmol, 2 eq), dichlorobis(triphenylphosphine)palladium(II) (0.056 g, 0.079 mmol, 0.1 eq) and water (6 ml) were added. The resulting mixture was heated at 115° C. overnight. Solvents were removed and the crude was purified in an (solute Flash Si II column (25 g silica gel, 10%-21% EtOAc in c-hexane) to give the desired product (0.21 g). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=4.98 min, [M+H]+ m/z 557.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:15])[CH3:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH:13]([OH:15])[CH3:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1c(C)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(C)O
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a solution of 1-(6-chloro-2-methyl-4-phenylquinolin-3-yl)ethanone (550 mg, 1.8 mmol) in methanol (10 ml) at room temperature was added portionwise sodium borohydride (315 mg, 8.3 mmol). After the addition the reaction was stirred for 3 hours. Most of the solvent was removed under reduced pressure, the residue diluted with ethyl acetate, and the mixture was poured into a separatory funnel. The organic layer was washed with water (2×), saturated sodium bicarbonate, then brine. The organic phase was separated and solvent removed under reduced pressure to provide 1-(6-chloro-2-methyl-4-phenylquinolin-3-yl)ethanol (460 mg, 83%) as a white powder. TLC Rf=0.4 using 1:1 ethyl acetate:hexanes as eluent. 1H NMR (CDCl3, 400 MHz) δ 7.88 (d, 1H, J=8.9 Hz); 7.54-7.42 (m, 4H); 7.18-7.08 (m, 3H); 5.05 (q, 1H, J=7.0 Hz); 2.95 (s, 3H); 1.0 (d, 3H, J=6.65 Hz). LCMS (CI) shows M+H 297.