Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([CH2:16][OH:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:18]1([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:29][CH:30]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:28]3[CH:27]=[C:26]4[C:31]([CH:32]=[CH:33][C:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:25]4)=[CH:30][CH:29]=3)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([CH2:16][OH:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@H](CO)C1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@H](CO)C1

Procedure:
Following the general procedure for the Suzuki coupling, trans-[3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol (139.2 mg, 0.4045 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (141 mg, 0.426 mmol), Na2CO3 (107 mg, 1.01 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) in DMF (10 mL)/water (2 mL). The crude material was purified by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-7)→2% MeOH in CH2Cl2 (8-22)→5% MeOH in CH2Cl2 (23-41)-7% MeOH in CH2Cl2 (42-51)], yielding the title compound. 1H NMR (CDCl3, 400 MHz) δ 2.42-2.60 (m, 3H), 2.60-2.73 (m, 3H), 3.88 (d, J=6.4 Hz, 2H), 5.19 (brs, 2H), 5.44-5.53 (m, 1H), 7.39 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.71 (dd, J=1.7, 8.3 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.94 (d, J=7.7 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.5 Hz, 1H), 8.29-8.32 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135) δ 30.62 (+), 32.16 (2C, −), 46.70 (+), 65.12 (−), 101.04 (Cquart), 116.13 (Cquart), 118.88 (+), 120.64 (+), 125.82 (Cquart), 127.27 (+), 127.45 (2C, +), 128.17 (+), 128.21 (+), 128.71 (2C, +), 129.40 (+), 136.23 (Cquart), 136.49 (+), 139.23 (Cquart), 148.28 (Cquart), 150.47 (Cquart), 151.57 (+), 157.09 (Cquart), 157.97 (Cquart). MS (ES+): m/z 422.1 (51) [MH+], 338.2 (39) [MH+-cyclobutene-CH2OH]. HPLC: tR=2.4 min (OpenLynx, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=2)=[O:10])[C:4](=[O:29])[CH:3]=1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][C:41]([F:44])([F:43])[F:42])=[C:35](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][C:41]([F:42])([F:43])[F:44])=[C:35]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:9]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:23][CH:24]=3)=[O:10])[C:4](=[O:29])[CH:3]=2)[CH:36]=1
Reactant: OB(O)c1cc(Cl)ccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CC2CC2)n2ccc(Br)cc2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CC2CC2)n2ccc(-c3cc(Cl)ccc3OC(F)(F)F)cc2=O)cc1

Procedure:
110 mg (purity 80%, 0.19 mmol) of tert-butyl 4-{[2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoyl]amino}benzoate (racemate), 46 mg (0.19 mmol) of 5-chloro-2-trifluoromethoxyphenylboronic acid and 22 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) were taken up in 2.5 ml of dioxane and 2.5 ml of saturated aqueous sodium carbonate solution and irradiated in a microwave at 130° C. for 12 min. The crude product was purified by flash chromatography (silica gel 60, cyclohexane/ethyl acetate mixtures). Yield: 77 mg (purity 92%, 64% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[Cl:18])=[O:22])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: Nc1ccc(-c2cc3ocnc3cc2Cl)cn1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2cc3ocnc3cc2Cl)cn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of 5-(5-chlorobenzoxazol-6-yl)-2-pyridylamine (31) (23 mg, 0.09 mmol) and 2 mg DMAP in 2 ml DCM was added 2-chlorobenzoyl chloride (23 μl, 0.18 mmol) followed by addition of DIEA (94 μl). The resulting brown solution was stirred at r.t. for overnight. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (135 μl) at r.t. for 30 min before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 17 mg 32 as pale yellow solid. (yield: 49%).
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.C(Cl)Cl.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(N(CC)CC)C>[CH3:23][S:24]([O:1][CH2:2][C:3]#[C:4][CH:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC#CC1c2ccccc2C=Cc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC#CC1c2ccccc2C=Cc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
This preparation illustrates methods according to step 3 of the process for preparing the compounds of formula A. In this preparation a solution containing 0.25 g. of 5-(3-hydroxy-prop-1-ynyl)-5H-dibenzo[a,d]cycloheptene in 25 ml. of anhydrous methylene chloride containing 0.25 ml. of triethylamine is stirred and cooled to maintain the temperature between 0°C and -10°C and 0.15 ml. of methanesulfonyl chloride is added. Cooling is then discontinued and the temperature of the mixture allowed to rise, with stirring, for 15 minutes. The solution is then poured into ice water, resulting in a two-phase organic-aqueous mixture. The organic layer is separated and washed successively with ice cold 1Normal aqueous hydrochloric acid, water, and saturated brine, and then dried over sodium sulfate and evaporated under vacuum yielding 5-(3-methanesulfonyloxyprop-1-ynyl)-5H-dibenzo[a,d] cycloheptene which is of sufficient purity to be used directly as starting material for subsequent examples.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@@:24]([CH3:30])([C:26](OC)=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:44]>>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@@:24]([CH3:30])([C:26]([NH2:44])=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:43])([F:1])[F:42])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@@]1(C)CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@](C)(C(N)=O)N2
Yield: 55.8 %

Procedure:
In a sealed tube a solution of methyl (2R,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-methyl-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 44, 70 mg, 0.113 mmol) in 7 N methanolic ammonia (5 mL, 35.0 mmol) was shaken at 40° C. for 5 days by PLS. Volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel using a SNAP 10 g as column and Dichloromethane/Methanol 98:2 as eluent affording the title compound (38 mg, 0.063 mmol, y=55.7%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:22]=2[N:23]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:19]([CH3:18])=[N:20][C:21]=2[CH:27]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1nc2ccc(N)cc2[nH]1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc4[nH]c(C)nc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 294.4 mg (2.0 mmol) of 2-methyl-5-aminobenzimidazol and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed for 4 hr. The work up gave 220.2 mg (61.3%) of the product as a sand color solid, m.p. 207° C. (dce.), mass (electrospray, m/e): M+H 359.9. HRCIMS: calcd 359.138 for C20H17N5O2 (M+), obsd 359.1403.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:26]/[C:27](/B(O)O)=[CH:28]/[CH3:29].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1/[C:27](/[CH3:26])=[CH:28]\[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C(/C)B(O)O
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C/C=C(/C)c1cc(C(=O)OC)ccc1OCc1ccccc1
Yield: 40.5 %

Procedure:
Methyl 4-benzyloxy-3-bromobenzoate (1.61 g, 5.0 mmol), caesium carbonate (4.89 g, 15.0 mmol), (E)-2-buten-2-yl boronic acid (600 mg, 6.0 mmol) and [1,1′-bis(diphenylphosphino)ferrocenyl]palladium (II) chloride (204 mg, 0.25 mmol) were dissolved in anhydrous tetrahydrofuran (100 ml), water (10 ml) was added and the mixture was stirred and held at reflux under an atmosphere of nitrogen for 16 hours. Upon cooling the solvent was removed in vacuo and the mixture partitioned between dichloromethane and water. The organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 5% ethyl acetate in petroleum ether afforded methyl (Z)-4-benzyloxy-3-(1-methyl-propenyl)-benzoate (600 mg, 41%) as a colourless solid. 1H NMR (DMSO-d6) 7.88 (1H, dd), 7.59 (1H, d), 7.40 (4H, m), 7.34 (1H, m), 7.23 (1H, d), 5.57 (1H, q), 5.21 (2H, s), 3.82 (3H, s), 1.94 (3H, s), 1.38 (3H, d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.CN.[C:28]([BH3-])#[N:29].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:29][CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.228 g, 0.65 mmol) and methylamine (2M in THF; 0.5 mL, 0.84 mmol) in CH2Cl2 (3.4 mL) was added sodium cyanoborohydride (0.061 g, 0.97 mmol), followed by acetic acid (1 drop). The reaction was stirred at room temperature overnight, until no starting material was seen by analytical LCMS. The solution was neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:33])[CH2:23][NH:24][C:25](=[O:32])[CH2:26][O:27]S(C)(=O)=O)[CH3:21])[C:14]=3[Cl:34])[C:5]2=[N:4][C:3]=1[CH3:35].[CH3:36][O-].[Na+].O>CO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:33])[CH2:23][NH:24][C:25](=[O:32])[CH2:26][O:27][CH3:36])[CH3:21])[C:14]=3[Cl:34])[C:5]2=[N:4][C:3]=1[CH3:35]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)COS(C)(=O)=O)c3Cl)cccn2c1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-[N-(N-mesyloxyacetylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (100 mg) in methanol (2 ml) was added sodium methoxide (317 mg), and the mixture was stirred for 1 hour. Sodium methoxide (200 mg) was added thereto, and the mixture was stirred for 3 hours. To the reaction mixture was added water, and the mixture was extracted with methylene chloride 3 times. The extracts were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride:methanol=10:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(methoxyacetylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (60 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH2:26]Br)=[CH:22][CH:21]=1)#[N:19]>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([CH2:26]/[CH:25]=[CH:24]/[C:23]3[CH:22]=[CH:21][C:20]([C:18]#[N:19])=[CH:29][CH:28]=3)[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: N#Cc1ccc(C=CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(/C=C/CN2CCc3nc(N)sc3CC2)cc1
Yield: 49 %

Procedure:
Prepared analogously to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine, potassium carbonate and 4-cyano-cinnamyl bromide (melting point: 79°-82° C.) in anhydrous dimethylformamide for one hour at 20° C. After the dimethylformamide has been distilled off in vacuo, the evaporation residue is distributed between ethyl acetate and water. After drying, filtering and evaporation of the organic phase, the evaporation residue is crystallised from acetone and the crystals are washed with ether. Yield: 49% of theory, Melting point: 199°-205° C. (decomp.).
Reaction SMILES: C([O-])(=O)C.[Na+].Br[C:7](Br)([CH3:14])[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].[F:16][C:17]1[C:30]([NH:31][NH2:32])=[CH:29][C:20]2[N:21]([CH2:26][C:27]#[CH:28])[C:22](=[O:25])[CH2:23][O:24][C:19]=2[CH:18]=1>O>[F:16][C:17]1[C:30]([NH:31][N:32]=[C:7]([CH3:14])[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:29][C:20]2[N:21]([CH2:26][C:27]#[CH:28])[C:22](=[O:25])[CH2:23][O:24][C:19]=2[CH:18]=1
Reactant: CC(Br)(Br)C(=O)C(F)(F)F
Reactant: C#CCN1C(=O)COc2cc(F)c(NN)cc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(NN=C(C)C(=O)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 8.0 g (97.2 mmol) of sodium acetate and about 50 ml of water was added under ice cooling 6.9 g (24.3 mmol) of 3,3-dibromo-1,1,1-trifluoro-butanone, and the reaction was allowed to proceed at 80° C. for 30 minutes. Then, the reaction mixture was cooled to 0° C., to which 4.4 g (18.7 mmol) of 7-fluoro-6-hydrazino-4-propargyl-2H-1,4-benzoxazin-3-one was added, and the reaction mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed twice with 10 ml of water, and dried, which afforded 6.1 g (17.0 mmol) of 1,1,1-trifluoro-2,3-butandione 3-(7-fluoro-3-oxo-4-propargyl-2H-1,4-benzoxazin-6-ylhydrazone).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][N:21](C(=O)C(F)(F)F)[CH2:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][NH:21][CH2:22]3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2ccc3c(c2)CNCC3)cc1
Yield: 44.4 %

Procedure:
4.63 g 4-(Trifluormethyl)phenylboronic acid was dissolved in 15 ml ethanol and added to a mixture of 5.0 g 1-(7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone in 150 ml toluene and 54 ml of a 2 molar sodium carbonate solution. The reaction mixture was degassed then 940 mg tetrakis(triphenylphosphine)palladium(0) was added and the mixture heated under reflux for two hours. The cooled reaction mixture was evaporated, the resulting residue was dissolved in 150 ml ethyl acetate and washed with 50 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 2.0 g 7-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-isoquinoline as its trifluoroacetate salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:21][CH2:20][C:15]4(OCC[O:16]4)[CH2:14][CH2:13]3)[C:4]=2[O:3]1.O>C(O)(=O)C>[CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH:12]3[CH2:21][CH2:20][C:15](=[O:16])[CH2:14][CH2:13]3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(CC3CCC4(CC3)OCCO4)c2O1
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)Cc2cccc(CC3CCC(=O)CC3)c2O1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 2, using 5.4 grams (0.01 8 mole) of 8-(2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)-1,4-dioxaspiro[4.5]decane and 25 mL of water in 100 mL of acetic acid, yielding 4-(2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)cyclohexanone.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][CH3:18])=[C:12]2[CH2:19][CH2:20]O)=[O:5].[Br:27]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:27][CH2:20][CH2:19][C:12]1[C:11]2[C:16](=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([Cl:1])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:26])[CH:8]=[CH:9][CH:10]=2)[N:15]=[CH:14][C:13]=1[CH2:17][CH3:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CCBr
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-3-ethyl-4-(2-hydroxyethyl)quinoline (405 mg) in dichloromethane were added N-bromosuccinimide (241 mg) and triphenylphosphine (355 mg) under water cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (dichloromethane) and crystallized from n-hexane to give 4-(2-bromoethyl)-8-(2,6-dichlorobenzoylamino)-3-ethylquinoline (424 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])[CH3:2].N1CCCCC1.[C:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([OH:29])=[O:28]>C1C=CC=CC=1>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:6](=[O:7])/[C:5](/[C:4]([O:3][CH2:1][CH3:2])=[O:20])=[CH:34]/[C:33]1[CH:36]=[CH:37][C:30]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)/C(=C\c1ccc(C(=O)O)cc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 75.8 %

Procedure:
To a solution of tert-butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (5.0 g, 17.5 mmol) in benzene (50 ml) and piperidine (0.3 ml, 3 mmol) was added 4-carboxybenzaldehyde (2.63 g, 17.5 mmol), and the mixture was refluxed for 3 h. The cooled solution was washed with 0.1 N HCl twice. The aqueous layer was extracted three times with ether. The combined organic phases were dried (Na2SO4) and concentrated to give C as a tan solid (5.54 g, 76% yield). LCMS m/z 416 (M−H), 833 (2M−H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([O:17][C:18]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:19]=3[C:20]#[N:21])[CH2:13][CH2:12]2)[CH2:5][CH2:4]1.[C:27](O)(=[O:29])[CH3:28]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:18]([O:17][CH:14]2[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C@H:6]3[CH2:7][CH2:8][C@H:3]([NH:2][C:27](=[O:29])[CH3:28])[CH2:4][CH2:5]3)[CH2:16][CH2:15]2)=[C:19]([C:20]#[N:21])[CH:22]=1
Reactant: N#Cc1cc(Cl)ccc1OC1CCN(CC[C@H]2CC[C@H](N)CC2)CC1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(Oc3ccc(Cl)cc3C#N)CC2)CC1

Procedure:
The title compound was prepared analogously to example 59.5 from 2-{1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yloxy}-5-chloro-benzonitrile hydrochloride and acetic acid. MS (m/z): 404.5 (M+H+).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12]N>C(O)C>[NH2:12][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: NN
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CCO
Product: NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 75.2 %

Procedure:
To an ice-cold suspension of 14.7 g (0.1 mole) of phthalimide in 100 ml of 95% ethyl alcohol at 5° C., with stirring, 3.6 ml (0.11 mole) of 96.8% hydrazine was added dropwise. A slight exothermic reaction was observed and the mixture was allowed to stir at 5° C. for two hours. The mixture was diluted with 200 ml of ice water, stirred, filtered, washed with water and dried to give 12.2 g (75%) of white powder, m.p. 199°-202°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[S:6]1[C:10]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1>N1C=CC=CC=1>[S:6]1[C:10]2[CH:11]=[C:12]([NH:15][S:2]([CH3:1])(=[O:4])=[O:3])[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2ncsc2c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
Methanesulfonyl chloride (4.93 mL, 63.7 mmol) was added over 5 min to a solution of benzothiazol-6-ylamine (9.58 g, 63.8 mmol) in pyridine (100 mL) at 25° C. The resulting mixture was stirred at 25° C. for 30 min, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with diethyl ether afforded a solid that was collected by vacuum filtration and dried in vacuo to afford the desired product, N-benzothiazol-6-yl-methanesulfonamide (13.3 g, 58.3 mmol, 91% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.03 (3H, s), 7.36 (1H, dd, J1=2.3 Hz, J2=8.6 Hz), 7.94 (1H, d, J=1.6 Hz), 8.02 (1H, d, J=9.2 Hz), 9.27 (1H, s), 9.95 (1H, s).