Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[N:6]([C:20](=[O:38])[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])=[CH:23][C:22]=3[CH3:37])[CH2:7][CH2:8][CH2:9][CH:10]([O:11][C:12]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[C:4]=2[CH:3]=1.C(=O)([O-])O.[Na+:45]>CC(C)=O>[Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[N:6]([C:20](=[O:38])[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])=[CH:23][C:22]=3[CH3:37])[CH2:7][CH2:8][CH2:9][CH:10]([O:11][C:12]([CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[O:13])[C:4]=2[CH:3]=1.[Na+:45]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CCCC(=O)O)c3cc(Cl)ccc32)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CCCC(=O)[O-])c3cc(Cl)ccc32)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
4-{7-Chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonyl}butyric acid (0.30 g, 0.53 mmol) was dissolved in acetone (2 ml). A sodium hydrogen carbonate (45 mg, 0.53 mmol) aqueous solution (2 ml) was added thereto and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was washed with ethyl acetate and then air-dried to obtain 0.14 g (45%) of sodium 4-{7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonyl}butyrate as amorphous.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[N:7][C:6]([C:14]#[N:15])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[F:24].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O.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>[F:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[NH:16][C:5]1[C:4]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[CH:3]=2)[N:8]=[N:7][C:6]=1[C:14]#[N:15]
Reactant: OB(O)c1ccncc1
Reactant: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1Br
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: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2nnc(C#N)c(Nc3ccc(C)cc3F)c2cc1-c1ccncc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 69.9 %

Procedure:
To a mixture of 6-bromo-4-(2-fluoro-4-methylphenylamino)-7-methoxycinnoline-3-carbonitrile (Method 38, 0.25 g, 0.65 mmol), pyridin-4-ylboronic acid (0.159 g, 1.29 mmol) and K2CO3 (0.357 g, 2.58 mmol) in DMA (3.0 ml) and water (0.30 ml), was added Pd(Ph3P)4 (0.224 g, 0.19 mmol). The reaction was stirred under argon at 90° C. for 12 hours, cooled, diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extract was dried (MgSO4), filtered, and the residue purified with silica chromatography (EtOAc) to give 0.175 g (64%) product. m/z 386.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1.[H-].[Na+].I[CH2:23][CH2:24][O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28]>CN(C)C=O.O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][C:15](=[O:18])[N:14]([CH2:23][CH2:24][O:25][Si:26]([CH:30]([CH3:31])[CH3:32])([CH:27]([CH3:29])[CH3:28])[CH:33]([CH3:34])[CH3:35])[C:13]=2[CH:19]=1
Reactant: CC(C)[Si](OCCI)(C(C)C)C(C)C
Reactant: O=C1COc2ccc(COC3CCCCO3)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCN1C(=O)COc2ccc(COC3CCCCO3)cc21)(C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
The solution of 5.50 g of 6-(tetrahydropyran-2-yloxymethyl)-4H-benzo[1,4]oxazin-3-one and 100 ml of N,N-dimethylformamide-tetrahydrofuran (1:1) is cooled to 0° C., admixed with 0.800 g of sodium hydride dispersion (60%) and stirred over 30 minutes. The mixture is admixed with 7.90 g of (2-iodoethoxy)triisopropylsilane and stirred at room temperature for a further 16 hours. The reaction mixture is poured onto ice-water (150 ml) and extracted with ethyl acetate (3×150 ml). The organic phases are washed successively with aqueous sodium hydrogencarbonate solution (1×100 ml), water (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.57 (1:1 EtOAc-heptane); Rt=6.71.
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=3[CH:11]=2)=[CH:3][CH:2]=1.[CH:19](=NC1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]1([CH:18]=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:2]=[CH:3][C:4]([C:7]2[O:8][C:9]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:10]=3[CH:11]=2)=[CH:5][CH:6]=1
Reactant: C(=Nc1ccccc1)c1ccccc1
Reactant: COc1ccc2cc(-c3ccc(C)cc3)oc2c1
Product: COc1ccc2cc(-c3ccc(C=Cc4ccccc4)cc3)oc2c1

Procedure:
Following the procedure given in Example 1b 2-(p-tolyl)-6-methoxybenzofuran was interacted with an equimolar quantity of benzalaniline to produce 2-(4-stilbenyl)-6-methoxybenzofuran, which, when recrystallized from toluene, melted at 223.5°-225.5° C. The wavelength of maximum excitation of this compound was 371 nm., and the wavelength of maximum emission was 446 nm.
Reaction SMILES: CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O.[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH2:38][O:39][CH2:40][C@H:41]([CH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=1)[C@@H:42]([O:46][CH2:47][CH:48]([CH3:50])[CH3:49])[C@@H:43](O)[CH3:44])[C:35]([OH:37])=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[C:26]([O:30][C:31](=[O:32])[NH:33][C@H:34]1[CH2:38][O:39][CH2:40][C@H:41]([CH2:51][C:52]2[CH:53]=[CH:54][C:55]([CH3:58])=[CH:56][CH:57]=2)[C@@H:42]([O:46][CH2:47][CH:48]([CH3:50])[CH3:49])[C@H:43]([CH3:44])[O:36][C:35]1=[O:37])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1ccc(C[C@@H](COC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](OCC(C)C)[C@H](C)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C[C@H]2COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]2OCC(C)C)cc1
Reaction time: 16 h
Yield: 87.6 %

Procedure:
To a magnetically stirred solution of DMAP (3.22 g, 26.3 mmol) and MNBA (2.07 g, 6.02 mmol) in anhydrous toluene (750 mL) was added a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(((2S,3R,4S)-4-hydroxy-3-isobutoxy-2-(4-methylbenzyl)pentyl)oxy)-propanoic acid (1.76 g, 3.76 mmol) in anhydrous toluene (60 mL) dropwise over 5.5 h (syringe pump), and the resulting turbid mixture was stirred for 16 h. The reaction mixture was filtered through paper and the filtrate was concentrated to a pale yellow solid which was purified by flash chromatography (SiO2, 0→30% acetone/hexanes) to give tert-butyl((3S,7S,8R,9S)-8-isobutoxy-9-methyl-7-(4-methylbenzyl)-2-oxo-1,5-dioxonan-3-yl)carbamate (1.48 g, 87%) as a white foam: 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J=8.2 Hz, 2H), 7.06 (d, J=8.2 Hz, 2H), 5.14 (d, J=8.2 Hz, 1H), 4.95 (dq, J=9.2, 6.4 Hz, 1H), 4.59 (q, J=7.3 Hz, 1H), 3.87 (dd, J=11.5, 7.3 Hz, 1H), 3.44 (t, J=7.4 Hz, 2H), 3.32 (tdd, J=16.8, 10.6, 5.2 Hz, 3H), 3.10 (dd, J=10.4, 6.6 Hz, 2H), 2.31 (s, 3H), 2.24 (t, J=12.7 Hz, 1H), 1.88 (dq, J=13.2, 6.6 Hz, 2H), 1.47 (d, J=6.4 Hz, 3H), 1.41 (s, 9H), 0.95 (d, J=6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 172.24, 154.95, 136.81, 135.52, 129.10, 129.01, 84.66, 80.02, 79.21, 75.57, 72.86, 72.48, 52.97, 47.40, 34.56, 29.17, 28.27, 21.01, 19.48, 18.80; ESIMS m/z 473 ([M+Na]+).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:3]=1[OH:20].Br[C:22]1C(O)=C(C)C=C2C=1C=CC(C)=N2>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[C:3]([OH:20])=[C:2]([CH3:22])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([CH3:12])=[N:9]3)=[CH:14][CH:15]=1
Reactant: Cc1ccc2c(Br)c(O)c(C)cc2n1
Reactant: Cc1ccc2c(-c3ccc(Cl)cc3)c(O)c(Cl)cc2n1
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c(O)c(C)cc2n1

Procedure:
Compound 2D was prepared following the procedure used to prepare compound 1E of Example 1, except that 5-bromo-2,7-dimethylquinolin-6-ol (2C) was used instead of compound 1D. LCMS-ESI+ (m/z): 284.2, 286.2 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23][CH3:24])=[O:22])[C:6]=1[O:25]CC1C=CC=CC=1)(=[O:3])[CH3:2]>C(O)C.[OH-].[Pd+2].[OH-]>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[C:12]=2[F:20])[N:8]=[C:7]([C:21]([O:23][CH3:24])=[O:22])[C:6]=1[OH:25])(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1O
Reaction time: 24 h
Yield: 29 %

Procedure:
The methyl 4-acetamido-3-(benzyloxy)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-picolinate produced in the first step was dissolved in ethyl alcohol (EtOH; 100 mL), and a catalytic amount of palladium hydroxide (Pd(OH)2) in carbon was added (2 spatula tips). The reaction mixture was stirred under a hydrogen atmosphere for 24 h, and the palladium was removed by filtration. The filtrate was concentrated, and the residue was purified by flash chromatography (SiO2; 0-50% EtOAc/hexane gradient) to provide the title compound as a white solid (0.431 g, 29% yield for the two steps): mp 168-172° C.; 1H NMR (400 MHz, CDCl3) δ 11.28 (s, 1H), 8.93 (d, J=1.6 Hz, 1H), 7.98 (s, 1H), 7.49 (dd, J=8.5, 7.6 Hz, 1H), 7.23 (dd, J=8.6, 1.8 Hz, 1H), 4.07 (s, 3H), 3.99 (d, J=1.1 Hz, 3H), 2.30 (s, 3H); ESIMS m/z 369 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH3:2].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(CO)cc1
Temperature: 25 °C

Procedure:
Mix 4-ethoxybenzaldehyde (3.3 g, 22 mmol), sodium borohydride (830mg, 22 mmol) and absolute ethanol (25 mL). Stir at room temperature until the reaction is complete, pour onto dilute hydrochloric acid and extract into ethyl acetate. Separate the organic phase and extract the aqueous phase with ethyl acetate (2X). Combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo and purify by silica gel chromatography to give 4-ethoxybenzyl alcohol.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[N:24]([CH3:33])[CH:23]=1>CN(C=O)C.O>[NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=2[C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[N:24]([CH3:33])[CH:23]=2)[CH2:4][CH2:3]1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ccccc2c1=O
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2O[C@H]2CC[C@@H](N)CC2)c2ccccc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To compound cis-4-aminocyclohexan-1-ol (275 mg, 1.81 mmol) in DMF (3 mL), was added NaH (127 mg, 3.17 mmol, 60% in mineral oil) in one portion at 0° C. The mixture was stirred at 0° C. for 30 min, 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (150.00 mg, 0.45 mmol) was added in one portion and the mixture stirred at 0° C. for 2 hrs. The reaction was diluted with water (20 mL) and extracted with EA (3×20 mL). The combined organic layers were washed with saturated brine (2×20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give the title compound as its hydrochloride salt (91.01 mg, 47.1%). 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, J=8.0 Hz, 1H), 8.00 (s, 3H), 7.95 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.56 (s, 1H), 7.51 (t, J=7.2 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.70 (s, 1H), 3.59 (s, 3H), 3.22 (s, 3H), 2.96-2.94 (m, 1H), 1.85-1.82 (m, 1H), 1.64-1.46 (m, 5H), 1.32-1.26 (m, 1H), 1.04-0.98 (m, 1H). LCMS (M+H)+ =427.0 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2I)[CH:5]=[CH:6][N:7]=1.C(OC([N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[C:36]1B(O)O)=O)(C)(C)C.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[C:36]2[NH:35][C:43]3[C:38]([CH:37]=2)=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: Nc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nccn2c(C3CCN(C(=O)OCc4ccccc4)CC3)nc(-c3cc4ccccc4[nH]3)c12
Temperature: 100 °C

Procedure:
A mixture of benzyl 4-(8-amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)piperidine-1-carboxylate (1.149 g, 0.002191 mol), 1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid (0.629 g, 0.00241 mol), 1,2-dimethoxyethane (9.3 mL), water (1.8 mL) and cesium carbonate (1.43 g, 0.00438 mol) was degassed three times and then treated with tetrakis(triphenyl phosphine)palladium(0) (200 mg, 0.0002 mol). The mixture was once more degassed and then heated at 100° C. overnight. The resulting reaction mixture was diluted with EtOAc (30 mL) then washed with water (2×30 mL) and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was chromatographed over silica gel eluting with hexane→EtOAc:hexane 1:1:0.05 2M NH3/MeOH to afford the desired product. 1H NMR (400 MHz, CDCl3): δ 2.02-2.06 (m, 4H), 3.03-3.17 (m, 3H), 4.29-4.33 (m, 2H), 5.16 (s, 2H), 5.66 (br, 2H), 6.79-6.80 (m, 1H), 7.11-7.16 (m, 2H), 7.20-7.25 (m, 2H), 7.31-7.45 (m, 5H), 7.44 (m, 1H), 7.64 (d, J=7.6 Hz, 1H), 8.96 (br, 1H). MS (ES+): m/z 467.12 [MH+].
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.CN(C)CCN(C)C.[Br:29][C:30]1[CH:45]=[CH:44][C:33]([CH2:34][N:35]2[C:39]([CH2:40][CH2:41][CH2:42]Cl)=[CH:38][N:37]=[CH:36]2)=[CH:32][CH:31]=1>O1CCCC1>[Br:29][C:30]1[CH:45]=[CH:44][C:33]([CH:34]2[N:35]3[CH:36]=[N:37][CH:38]=[C:39]3[CH2:40][CH2:41][CH2:42]2)=[CH:32][CH:31]=1
Reactant: ClCCCc1cncn1Cc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Brc1ccc(C2CCCc3cncn32)cc1
Reaction time: 3.5 h

Procedure:
A solution of lithium diisopropylamide, prepared at 0° from 0.12 ml of diisopropylamine and 0.33 ml of n-butyllithium (2.5M) in 2 ml of tetrahydrofuran under nitrogen, is added to a solution of 0.13 ml of N,N,N', N'-tetramethyl-ethylenediamine and 0.124 g of 1-(p-bromobenzyl)-5-(3-chloropropyl)-1H-imidazole in 2 ml of tetrahydrofuran at -78°. The reaction mixture is stirred for 3.5 h, quenched at -78° with saturated ammonium chloride solution and extracted with methylene chloride (3×10 ml). The organic extracts are dried over sodium sulfate and evaporated to yield the title compound which is purified by conversion to the hydrochloride salt, m.p. 216°.
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[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[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[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN(Cc2ccc(Cl)cc2Cl)[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: Clc1ccc(CN2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)c(Cl)c1

Procedure:
128 mg (0.218 mmol) of (2R *,4S*)-2-benzyl-1-(2,4-dichlorobenzyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 34 mg (0.920 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR40## is obtained as yellow oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.25, FD-MS: M+ =472.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:23][CH2:24][CH2:25][O:26][CH3:27])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:27][O:26][CH2:25][CH2:24][NH:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1
Reactant: COCCNc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-(2-methoxyethylamino)phenyl)-5-phenylbenzoxazole (131 mg, 0.36 mmol) and 1,2,4-benzenetricarboxylic anhydride (70 mg, 0.36 mmol) the title compound was obtained (138 mg, 72%). 1H NMR (DMSO) δ 8.61(t, 1H), 8.42(dd, 1H), 8.31(s, 1H), 8.13(d, 1H), 8.08(m, 2H), 7.83(d, 1H), 7.53(m, 3H), 7.50(m, 3H), 7.41(t, 1H), 7.08(d, 1H), 3.69(m, 2H), 3.59(m, 2H), 3.35(s, 3H). MS 534 m/z (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[S:12](=[O:14])(=[O:13])[NH:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]Br)=[C:18]([F:24])[CH:17]=1.[H-].[Na+].O>CN(C)C(=O)C.CCOC(C)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:11]2[CH2:10][CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:12]2(=[O:14])=[O:13])=[C:18]([F:24])[CH:17]=1
Reactant: O=S1(=O)NCCCC1c1ccccc1
Reactant: Fc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=S1(=O)C(c2ccccc2)CCCN1Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 6-phenyl-1,2-thiazinane 1,1-dioxide (300 mg, 1.42 mmol) and 4-bromo-1-(bromomethyl)-2-fluorobenzene (456 mg, 1.7 mmol) in N,N-dimethylacetamide (5 mL) at 0° C. was added sodium hydride (60% in mineral oil) (68 mg, 1.85 mmol) and the reaction was stirred at room temperature for 2 hours. Water was added and the reaction was diluted with EtOAc, washed with brine, dried with MgSO4, filtered and purified by silica gel column chromatography (0-60% EtOAc/heptane) to give 2-(4-bromo-2-fluorobenzyl)-6-phenyl-1,2-thiazinane 1,1-dioxide (396 mg, 70% yield). LCMS (ESI), m/z, 398 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:37])C(=O)C1>CN(C=O)C>[Br:37][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([CH3:10])[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)=CCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)=CCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 7-methyl-oct-6-en-1-ol (1.00 g, 7.04 mmol) in DMF (18 mL) was added triphenylphosphine (2.06 g, 7.85 mmol). The solution was cooled to 0° C. and NBS (1.35 g, 7.58 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 8-bromo-2-methyl-oct-2-ene (1.11 g, 77%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.10 (1H, m), 3.40 (2H, t, J=6.9 Hz), 1.98 (2H, m), 1.86 (2H, m), 1.68 (3H, d, J=0.9 Hz), 1.60 (3H, d, J=0.3 Hz), 1.42 (2H, m), 1.41 (4H, m); 13C NMR (75 MHz, CDCl3) δ 132.08, 124.81, 34.59, 33.44, 29.64, 28.49, 28.44, 26.36, 18.35.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:13])[CH:5]=1)(=[O:3])[CH3:2].[C:14](Cl)(=O)C(Cl)=O.CN(C)C=O.C(N(CC)CC)C>ClCCl.CO>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:14])=[O:9])=[C:6]([F:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(C)=O)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Acetyl-2-fluorobenzoic acid (46.1 mmol, 0.0461 mol) in dichloromethane (30 mL) was treated with oxalyl chloride (7.8 mL, 92 mmol) and N,N-dimethylformamide (0.2 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (50 mL, 0.78 mol) and cooled to 0° C. A solution of methanol (4.7 mL) and triethylamine (16 mL, 120 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 h, washed with water aqueous 1N hydrochloric acid, and brine. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to afford the desired product. (5.64 g, 62.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([CH2:13][S:14][CH3:15])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([CH2:13][S:14]([CH3:15])=[O:25])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cn(C)c2cc(Cl)ccc2c1=O
Solvent: ClCCl
Product: Cn1cc(CS(C)=O)c(=O)c2ccc(Cl)cc21

Procedure:
In a similar manner to that described in Example 4 7-chloro-1-methyl-3-methylthiomethyl-4-quinolone was oxidised with 3-chloroperbenzoic acid to give the novel 7-chloro-1-methyl-3-methylsulphinylmethyl-4-quinolone m.p. 180°-181° (from dichloromethane:petroleum ether (b.p. 60°-80°).
Reaction SMILES: [N:1]1([C:10]2([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl>[N:1]1([C:10]2([C:15]([Cl:21])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C(O)C1(n2ccc3cccnc32)CCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(n2ccc3cccnc32)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarboxylic acid (394) (1.2 g, 5.21 mmol) in dichloromethane (80 mL) was dropwise added oxalyl chloride (1 mL, 11.47 mmol) at 0° C., followed by dimethyl formamide (0.1 mL). The reaction mixture was stirred for 1 h at room temperature. After completion, the reaction mixture is concentrated under argon atmosphere tog et 1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentanecarbonyl chloride (395) (1.3 g, 100%, crude) as a yellow solid which was directly used for the next step without analysis.