Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:22]4[CH:23]=[CH:24][C:25]([O:27]C)=[CH:26][C:21]=4[S:20][N:19]=3)=[O:17])=[CH:11][C:10]=2[C:29]([F:32])([F:31])[F:30])[CH2:4][CH2:3]1.B(Br)(Br)Br.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:22]4[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:21]=4[S:20][N:19]=3)=[O:17])=[CH:11][C:10]=2[C:29]([F:32])([F:30])[F:31])[CH2:4][CH2:3]1
Reactant: COc1ccc2c(C(=O)Nc3ccc(CN4CCN(C)CC4)c(C(F)(F)F)c3)nsc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)c3nsc4cc(O)ccc34)cc2C(F)(F)F)CC1

Procedure:
1.923 g (4.14 mMol) 6-methoxy-benzo[d]isothiazole-3-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide in 120 ml of a 1 M solution of BBr3 in CH2Cl2 are stirred for 16 h at 45° C. Then the solution is poured into water and EtOAc, the aq. layer is neutralized with Na2CO3, separated off and extracted twice with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated. Reversed phase chromatography (Gilson system) gives the title compound: MS: [M−1]=451; HPLC: tRet=11.6.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=C[C:3]=1[C:4]([N:6]([CH2:9]C)CC)=[O:5].[NH2:24]C1C(C(NC)=O)=NC(Br)=CC=1>>[NH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:9])=[O:5])=[N:24][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: CNC(=O)c1nc(Br)ccc1N
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1N

Procedure:
Prepared analogously to Compound 3C replacing Compound 3D 3-amino-6-bromo-N-methylpyridine-2-carboxamide (Compound 6D 700 mg, 3 mmol) to isolate 386 mg of the title compound as a hygroscopic foam (46%). 1H NMR (400 MHz, CDCl3) δ 8.11 (br. s., 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 5.95 (br. s., 2H), 4.34 (t, J=6.4 Hz, 2H), 3.68 (q, J=5.8 Hz, 2H), 3.02 (d, J=5.01 Hz, 3H), 2.58 (t, J=5.7 Hz, 1H), 2.11 (td, J=6, 12.3 Hz, 2H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C1(C)C(C)=CC=CC=1>[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:4])=[CH:26][CH:25]=1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1ccc(F)cc1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccc(F)cc2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 89 %

Procedure:
N-(4-Fluorophenyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 1 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 4-fluoroaniline. Yield: 89% of theory; m.p. 284°-285° C (decomp.; from xylene).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([NH:29][C:30](=[O:59])[O:31][C@@H:32]1[CH2:37][CH2:36][CH2:35][O:34][C@H:33]1[CH2:38][O:39]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)(O)[O-].[Na+]>CO>[CH2:12]([NH:29][C:30](=[O:59])[O:31][C@@H:32]1[CH2:37][CH2:36][CH2:35][O:34][C@H:33]1[CH2:38][OH:39])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCNC(=O)O[C@@H]1CCCO[C@H]1CO
Yield: 85 %

Procedure:
240.0 mg of p-toluenesulfonic acid were added to a solution of 2.753 g of (2S, 3R)-2-(triphenylmethoxymethyl)tetrahydropyran-3-yl N-heptadecylcarbamate (prepared as described in Preparation 27) dissolved in 55 ml of methanol, and the mixture was heated under reflux for 1 hour. At the end of this time, the reaction mixture was cooled, and 352.6 mg of sodium bicarbonate were added. The methanol was then removed by distillation under reduced pressure, and ethyl acetate was added. Insoluble materials were filtered off, and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 55 g of silica gel. 1.476 g of the title compound was obtained from those fractions eluted with mixtures of hexane and ethyl acetate ranging from 2:1 to 1:1 by volume in the form of crystals melting at 92.0°-93.5° C. (after recrystallisation from diethyl ether).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])=[CH:11][C:10]=1[CH3:33])C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:33][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Cc1cc(/C=C/c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1O

Procedure:
A solution of 5-{(E)-2-[4-(benzyloxy)-3-methylphenyl]ethenyl}-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole)_(intermediate 6, 1.5 g) in glacial acetic acid (30 ml) was hydrogenated over 10% palladium on carbon (0.150 g). The catalyst was filtered off, the solvent was removed and the residues dissolved in ethyl acetate. This was washed with saturated sodium bicarbonate solution and brine. Drying and removal of solvent gave an oil which was purified by SPE (Si cartridge). Elution with cyclohexane:ethyl acetate gave the title compound as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12](N)[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9])(=O)C.N([O-])=O.[Na+].[F:21][B-](F)(F)F.[H+]>>[F:21][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([OH:4])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9]
Reactant: F[B-](F)(F)F
Reactant: COc1c(N)cc(C(=O)O)cc1OC(C)=O
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: COc1c(O)cc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound of step 1 (2.0 g, 8.88 mmol) was dissolved in aqueous tetrafluoroboric acid (48%, 4.5 ml), sodium nitrite (612 mg, 8.88 mmol) was added at 0° C., and the mixture was stirred at room temperature for 60 min. The volatiles were evaporated, toluene was added to the oily residue and the mixture was heated at 100° C. for 4 h. The mixture was partitioned between EA and 2 N hydrochloric acid, the aqueous phase extracted with EA, and the combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by preparative RP HPLC (water/ACN gradient) to give 170 mg of the title compound.
Reaction SMILES: [ClH:1].[CH:2]1([O:7][C:8]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:18]([OH:20])[CH3:19]>>[ClH:1].[CH:2]1([O:7][C:8]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=2[C:10](=[NH:11])[O:20][CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C#N)c(OC2CCCC2)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2-cyclopentyloxy-4-methoxy-benzonitrile (0.12 g, 0.55 mmol) in absolute ethanol (15 mL) in a pressure tube for 1 h at 0° C. The tube was sealed and stirred at room temperature for 3 d. Evaporation of the solvents and trituration of the residue in diethyl ether gave ethyl 2-cyclopentyloxy-4-methoxy-benzimidate hydrochloride (0.17 g, 100%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][CH2:13][CH2:14][S:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=1)=[O:11].[NH2:26][OH:27].CO.[OH-].[Na+]>C1COCC1.O>[OH:27][NH:26][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([S:15][CH2:14][CH2:13][NH:12][C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[O:11])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(SCCNC(=O)c2cc3ccccc3o2)cc1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(NO)c1ccc(SCCNC(=O)c2cc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 4-{2-[(benzofuran-2-yl-carbonyl)amino]ethylsulfanyl}-benzoate in THF (2 ml) was added a solution of 50% hydroxylamine in water (4 ml). Methanol (2 ml) and 0.1 M NaOH (0.1 ml) were added. The reaction mixture was stirred for three days at room temperature. The solvents were evaporated and the residue was crystallized from dichloromethane/ethyl acetate, to give the title compound (46 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1.C(Cl)(Cl)Cl.CO>[CH3:40][O:41][C:42](=[O:43])[NH:44][C@@H:45]([C:49]([CH3:51])([CH3:50])[CH3:52])[C:46](=[O:47])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[NH:19][C:20](=[O:21])[C@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:27][C:28](=[O:31])[O:29][CH3:30]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of the product of Example 2C (1.6 g, 3.0 mmol) in THF (30 mL) was treated with the product of Example 1F (0.57 g, 3.0 mmol), DEPBT (1.35 g, 4.5 mmol), and N,N-diisopropylethylamine (2.6 mL, 14.9 mmol), stirred at 25° C. for 3 hours and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4 filtered and concentrated. The residue was chromatographed on silica gel eluting with 50% ethyl acetate in chloroform, followed by. 5% methanol in chloroform to give the title compound (1.59 g, 75% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.79 (s, 9 H), 0.82 (s, 9 H), 1.51 (m, 2 H), 2.51 (m, 1 H),2.72 (m, 3 H), 3.49 (s, 3 H), 3.55 (s, 3 H), 3.63 (m, 1 H), 3.82 (d, J=9.93 Hz, 1 H), 3.90 (d, J=9.56 Hz, 1 H), 4.04 (m, 2 H), 4.86 (d, J=5.88 Hz, 1 H), 6.60 (d, J=9.93 Hz, 1 H), 6.78 (d, J=9.19 Hz, 1 H), 7.16 (m, 7 H), 7.31 (m, 1 H), 7.54 (d, J=8.46 Hz, 1 H), 7.83 (m, 5 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:21](Cl)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[C:21]([C:28]3[CH:29]=[C:24]([CH3:23])[CH:25]=[CH:26][CH:27]=3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3nc2Cl)C1
Reactant: Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(-c2nc3ccccc3nc2C2CN(C(=O)OC(C)(C)C)C2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (46) (639 mg, 2.0 mmol, as prepared in the above Preparation 14), 3-methyl-phenylboronic acid (68) (299.2 mg, 2.2 mmol), K3PO4 (818 mg, 4.0 mmol) in dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl2 (73.2 mg, 0.1 mmol) then the reaction mixture was stirred at 90° C. under nitrogen atmosphere overnight. The reaction mixture was filtered through CELITE® and washed with EtOAc (50 mL). The filtrate was concentrated and the crude product was purified by silica gel column to give 3-(3-m-tolyl-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (69) (637 mg, 1.7 mmol, yield 85%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[C:6]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=2[O:24][CH3:25])=[CH:5]1)(=[O:3])[CH3:2].[CH:26]1([CH2:31][C:32](O)=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:32](=[O:33])[CH2:31][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:10][CH:11]=2)[C:6]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=2[O:24][CH3:25])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: O=C(O)CC1CCCC1
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C(C)=O)c2ccc(N)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(C)=O)c2ccc(NC(=O)CC3CCCC3)cc12
Yield: 13.4 %

Procedure:
A solution of 4-(1-acetyl-5-aminoindol-3-ylmethyl)-3-methoxybenzoic acid (Z) (0.31 g.), cyclopentylacetic acid (0.117 g.), 4-(dimethylamino)pyridine (0.233 g.) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.35 g.) in dichloromethane (20 ml.), under a nitrogen atmosphere, was stirred at ambient temperature for two hours. The mixture was acidified with hydrochloric acid (1N, 30 ml.), extracted with ethyl acetate (3×50 ml.), and the combined extracts dried (MgSO4) and evaporated. The residual oil was purified by flash chromatography on silica gel (100 ml.), eluting with 50:45:5 v/v/v hexane:dichloromethane:ethyl acetate, to give a product which was recrystallized from a mixture of tetrahydrofuran and ether, and then from a mixture of ethanol and water, to give the title compound (0.055 g., 14%), as a white solid, m.p. 245°-247° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2nc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)sc2c1
Yield: 47.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-6-methoxybenzothiazole (92 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 76 mg (47%) of the title compound as an amorphous solid. mp 102°-107°. FDMS: m/e=424. α[D]589 =+64.29 (c=0.71, chloroform).
Reaction SMILES: [CH:1]([C:4]1[O:5][C:6]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[C:7]([CH2:9][C:10]([O:12]CC)=[O:11])[N:8]=1)([CH3:3])[CH3:2].CO.[OH-].[K+]>O>[CH:1]([C:4]1[O:5][C:6]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1nc(C(C)C)oc1-c1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1nc(CC(=O)O)c(-c2ccco2)o1
Yield: 67.2 %

Procedure:
5.0 g of ethyl 2-[2-isopropyl-5-(2-furyl)-4-oxazolyl]acetate, 70 ml of methanol, 7 ml of water and 3.75 g of potassium hydroxide are treated in the same manner as described in Example 16. 3.0 g of 2-[2-isopropyl-5-(2-furyl)-4-oxazolyl]acetic acid are obtained. Yield: 67.1%
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=O)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[I-:23].[CH3:24][N+:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH3:35])=[CH:27][CH:26]=1.N1CCCCC1>C(O)C>[I-:23].[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17](/[CH:21]=[CH:35]/[C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N+:25]([CH3:24])=[CH:26][CH:27]=3)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: Cc1cc[n+](C)c2ccccc12
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Agent: [I-]
Solvent: C1CCNCC1
Solvent: CCO
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](C)c4ccccc34)ccc21
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution mixture of 3a (0.14 g, 0.5 mmol), 4 (0.18 g, 0.6 mmol) and piperidine (0.1 mL) in ethanol (40 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by recrystallization from methanol to afford SLM (0.24 g) as red solid in 56% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.28 (d, J=6.4 Hz, 1H), 9.14 (d, J=8.4 Hz, 1H), 8.86 (s, 1H), 8.51 (d, J=6.4 Hz, 1H), 8.42 (m, 3H), 8.28 (m, 2H), 8.13 (d, J=8.8 Hz, 1H), 8.08 (t, J=7.2 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.32 (t, J=7.2 Hz, 1H), 4.64 (t, J=5.2 Hz, 2H), 4.52 (s, 3H), 3.84 (t, J=5.2 Hz, 2H), 3.48 (m, 2H), 3.33 (m, 2H), 3.11 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.0, 147, 144.9, 142.1, 140.9, 138.8, 134.9, 129.0, 127.3, 126.7, 126.4, 126.1, 122.8, 122.2, 121.7, 120.4, 119.9, 119.3, 116.2, 115.1, 110.5, 110.4, 71.3, 69.8, 68.9, 58.1, 44.2, 42.9. HRMS (MALDI-TOF) m/z Calcd for C29H29N2O2 437.2223. Found 437.2207 [M+].
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[B:23]1[O:27]C(C)(C)[C:25](C)(C)[O:24]1)[O:6][C:7]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.[BH4-].[Na+].Cl>CO>[OH:27][B:23]1[C:22]2[CH:21]=[CH:20][C:5]([O:6][C:7]3[N:14]=[C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])[CH:12]=[CH:11][C:8]=3[C:9]#[N:10])=[CH:4][C:3]=2[CH2:25][O:24]1
Reactant: COCCNc1ccc(C#N)c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCNc1ccc(C#N)c(Oc2ccc3c(c2)COB3O)n1
Reaction time: 8 h
Yield: 31.9 %

Procedure:
To a clear solution of 2-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-6-(2-methoxy-ethylamino)-nicotinonitrile (10) (440 mg, 1.04 mmol) in MeOH (anhydrous, 100 mL) was slowly added NaBH4 (120 mg, 3.12 mmol). The reaction was stirred at room temperature for 4 hours, before the addition of HCl solution (1 M, 50 mL). The stirring was kept at room temperature overnight. Then the solution was slowly concentrated in vacuo. Purification was accomplished by preparative HPLC to afford the title compound (108 mg, 32% yield) as a white lyophilizate. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H), 7.86 (br. s., 1 H), 7.79-7.68 (m, 2 H), 7.24 (s, 1 H), 7.18-7.13 (m, 1 H), 6.30 (d, J=8.6 Hz, 1 H), 4.98 (s, 2 H), 3.20 (d, J=1.6 Hz, 2 H), 3.17-3.06 (m, 5 H); ES-MS m/z=326 (M+H)+; HPLC: 99.39% (220 nm), 99.24% (MaxPlot).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[NH2:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[NH2:31][C:32]1[N:37]=[CH:36][C:35]([C:2]2[N:6]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:4]([CH3:17])[C:3]=2[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:34][N:33]=1
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: Nc1ncc(B(O)O)cn1
Product: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(-c2cnc(N)nc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 104) was reacted with 2-amino-pyrimidin-5-yl-boronic acid to give the title compound as colorless solid. MS: 499.7 (MH+).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[S:15][C:16](Cl)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Cs+].[Cs+]>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.O.O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[S:15][C:16]([C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCC3)sc1Cl
Reactant: COc1ccc(B(O)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: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCC3)sc1-c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-chlorothiazole-4-carboxylate (1J) (0.450 g, 1.23 mmol), 4-methoxyphenylboronic acid (0.281 g, 1.85 mmol), lithium chloride (0.157 g, 3.70 mmol), tetrakis(triphenylphosphine)palladium (0) (0.142 g, 0.12 mmol), and cesium carbonate (1.2 g, 3.70 mmol) was added 1,4-dioxane (20 mL) and water (10 mL). Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was cooled to rt, diluted with EtOAc, filtered through Celite, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 80% EtOAc in hexanes to provide 0.483 g (90%) of the desired product ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-(4-methoxyphenyl)thiazole-4-carboxylate (1K): LC/MS (APCI): m/z 436.8 (M+H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][N:4]1[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1.[ClH:16]>CC(C)=O>[ClH:16].[F:15][C:2]([F:1])([F:14])[CH2:3][N:4]1[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: FC(F)(F)CN1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCN(CC(F)(F)F)CC1

Procedure:
8-(2,2,2-Trifluoroethyl)-1,4-dioxa-8-aza-spiro[4.5]decane (3.7 g, 16 mmol) was added to a solution of 5% HCl (45 ml) and acetone (8 ml). After refluxing for 12 h, the solvent was removed to give crude 1-(2,2,2-trifluoroethyl)piperidin-4-one hydrochloride which was used in the next reaction.