Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13]O.S(=O)(=O)(O)O>O>[I:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: COc1cccc(C(=O)O)c1I
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccc(OC)c1I
Temperature: 25 °C
Yield: 90 %

Procedure:
A stirred mixture of 2-iodo-3-methoxybenzoic acid (20 g, 0.07 mol; prepared in a manner similar to that described above), methanol (300 ml) and concentrated sulphuric acid (3.5 ml) was heated under reflux for 8 hours, cooled to ambient temperature and added to water (1500 ml). The product was extracted into dichloromethane (3×500 ml), the combined extracts were washed with 5% aqueous sodium hydroxide solution (3×500 ml), then they were dried (MgSO4) and the solvent was removed in vacuo to give methyl 2-iodo-3-methoxybenzoate (18.5 g, 90%) as a solid, m.pt. 58-61° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(Nc2ccccc2)c2ccccc2n1

Procedure:
A solution of 2,4-dichloro-quinazoline (15 g), N,N-diisopropyl-ethylamine (24.9 ml) and aniline (7.5 ml) in isopropanol (75 ml) is heated to reflux for 45 min. The cold reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is crystallized from diethylether-toluene (1:1) to give 2-chloro-4-phenylamino-quinazoline, m.p. 194-196° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=O)=[CH:16][CH:15]=3)=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:30])[CH3:2].[CH2:31]([CH2:33][NH2:34])[OH:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][NH:34][CH2:33][CH2:31][OH:32])=[CH:16][CH:15]=3)=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:30])[CH3:2]
Reactant: NCCO
Reactant: CCc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCc1ccc(-c2cc3cc(CNCCO)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 95.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-ethyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (68.0 mg, 0.168 mmol) was dissolved in acetonitrile (5.4 mL), and the solution was treated with ethanolamine (0.041 mL, 0.67 mmol), acetic acid (0.192 mL, 3.36 mmol) and sodium triacetoxyborohydride (71.0 mg, 0.336 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-ethyl-7-{1-(tert-butoxycarbonyl)-5-[(2-hydroxyethylamino)methyl]indol-2-yl}isoindolinone (72.0 mg, yield 95%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([I:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4]([C:3]([OH:2])=[C:14]([C:15]3[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=3)[C:13](=[O:23])[NH:12]2)=[CH:9][C:8]=1[I:10]
Reactant: COC(=O)c1cc(I)c(Cl)cc1NC(=O)Cc1cc(C)cc(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2c(O)c3cc(I)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
To a solution of 4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-5-iodo-benzoic acid methyl ester (EXAMPLE 4.1B, 10.9 g in 180 mL dry tetrahydrofuran) at 0° C. was added dropwise 59.5 mL of a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran and the mixture allowed to warm to room temperature. After 1.5 hours, the mixture was cooled to 0° C. and the reaction quenched by the addition of 400 mL ice:6N hydrochloric acid (1:1). This was stirred for 15 minutes then filtered to collect the solid product. The solids were washed with ice-water then cold acetonitrile and dried to give the title compound (9.8 g).
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]([CH3:30])[C:6]2[C:11]([N:12]=1)=[C:10]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:9]=[C:8]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH2:28][CH3:29])[N:7]=2.[CH3:31][S:32]([N:35]1[CH2:40][C@@H:39]([CH3:41])[NH:38][C@@H:37]([CH3:42])[CH2:36]1)(=[O:34])=[O:33].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:42][C@@H:37]1[CH2:36][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:40][C@H:39]([CH3:41])[N:38]1[CH2:3][C:4]1[N:5]([CH3:30])[C:6]2[C:11]([N:12]=1)=[C:10]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:9]=[C:8]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH2:28][CH3:29])[N:7]=2
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: C[C@@H]1CN(S(C)(=O)=O)C[C@H](C)N1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3[C@H](C)CN(S(C)(=O)=O)C[C@@H]3C)n(C)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8-bromomethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine hydrobromide (200 mg, 0.37 mmol), (3S,5R)-1-methanesulfonyl-3,5-dimethylpiperazine (88 mg, 0.46 mmol) and K2CO3 (150 mg, 1.09 mmol) in DMF (1 mL) was allowed to stir at r.t. for 24 h. The reaction mixture was partitioned between EtOAc and H2O, the organic phase dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) followed by recrystallisation from EtOAc affording 737 (57 mg, 28%). LCMS (method I): RT 3.05 min, [M+H]+ 568.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.98 (1 H, m), 7.76-7.75 (1 H, m), 7.26-7.25 (2 H, m), 4.34 (4 H, s), 4.18 (2 H, s), 3.87 (4 H, t, J=4.70 Hz), 3.84 (3 H, s), 3.54-3.51 (2 H, m), 3.35 (2 H, q, J=7.48 Hz), 3.29-3.23 (2 H, m), 2.80 (3 H, s), 2.68-2.66 (2 H, m), 1.45 (3 H, dd, J=7.69, 7.26 Hz), 1.17 (6 H, d, J=6.36 Hz)
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:11]=1[CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[C:41]([O:45][C@@H:46]([C:52]1[C:53]([CH3:95])=[N:54][C:55]2[N:56]([N:90]=[C:91]([CH:93]=O)[CH:92]=2)[C:57]=1[N:58]1[CH2:63][CH2:62][C:61]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([O:72][Si:73]([C:86]([CH3:89])([CH3:88])[CH3:87])([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[CH3:71])([CH3:64])[CH2:60][CH2:59]1)[C:47]([O:49][CH2:50][CH3:51])=[O:48])([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[CH2:2]([O:9][C:10]1[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:11]=1[CH2:12][CH:13]=[CH:93][C:91]1[CH:92]=[C:55]2[N:54]=[C:53]([CH3:95])[C:52]([C@H:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:57]([N:58]3[CH2:63][CH2:62][C:61]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][C@H:70]([O:72][Si:73]([C:86]([CH3:87])([CH3:88])[CH3:89])([C:74]4[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=4)[C:80]4[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=4)[CH3:71])([CH3:64])[CH2:60][CH2:59]3)[N:56]2[N:90]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Fc1cc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(OCc2ccccc2)cc1F
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3cc(F)c(F)cc3OCc3ccccc3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.7 %

Procedure:
To a suspension of (2-(benzyloxy)-4,5-difluorophenethyl)triphenylphosphonium iodide salt (289 mg, 0.454 mmol) in THF (4 ml) at 0° C. was added NaH (18.61 mg, 0.465 mmol) and the resulting mixture was stirred at rt for 45 min. The mixture was cooled to 0° C. and (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (175 mg, 0.227 mmol) dissolved in THF (4 ml) was added dropwise and the mixture was stirred at 0° C. for 1 h then warmed to rt and stirred 2 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-30% EtOAc/hexane) to afford (S)-ethyl 2-(2-(3-(2-(benzyloxy)-4,5-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (190 mg, 0.190 mmol, 84% yield) as mixture of E and Z isomers. LCMS (M+H)=1002.0.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH3:13]>>[I:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: O=S(=O)(Cl)Cc1cccc(I)c1
Product: NS(=O)(=O)Cc1cccc(I)c1

Procedure:
A stirred solution of (3-iodophenyl)methanesulfonyl chloride (1 g) in TKF (20 ml) was treated with 0.88 ammonia (25 ml) at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was triturated in ether to give the title compound (0.35 g).
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][CH:44]=[CH:45][C:46](N2CCSC2)=[O:47])[CH:30]=[C:31]([O:40][CH3:41])[C:32]=1[O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39]>CN(C)C=O>[CH3:41][O:40][C:31]1[CH:30]=[C:29]([CH:42]=[CH:43][CH:44]=[CH:45][C:46]([N:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][O:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH3:8])[CH2:17][CH2:16]2)=[O:47])[CH:28]=[C:27]([O:26][CH3:25])[C:32]=1[O:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH3:39]
Reactant: CC(OCCN1CCNCC1)(c1ccccc1)c1ccc(Cl)cc1
Reactant: COCCOCOc1c(OC)cc(C=CC=CC(=O)N2CCSC2)cc1OC
Solvent: CN(C)C=O
Product: COCCOCOc1c(OC)cc(C=CC=CC(=O)N2CCN(CCOC(C)(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1OC
Yield: 60.7 %

Procedure:
To a solution of 527 mg (1.53 mmol) of N-[2-[1-phenyl-1-(p-chlorophenyl)ethoxy]ethyl]piperazine in dry dimethylformamide (10 ml) was added, under argon atmosphere, 760 mg (1.73 mmol) of N-[5-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]thiazolidine, and the mixture was allowed to react at room temperature for 67 hours. The reaction mixture was concentrated by evaporation under reduced pressure and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (100:1), to give 618 mg (0.929 mmol) of N-[5-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]-N'-[2-[1-phenyl-1-(p-chlorophenyl)ethoxy]ethyl]piperazine.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:16][C:17]1[N:18]=[N:19][C:20]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH2:32])=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.O1CCCC1>[CH2:9]([O:16][C:17]1[N:18]=[N:19][C:20]([C:31]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:4][CH2:32]2)=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: c1ccc(COc2cc(C3(c4ccccc4)CC3)nnc2OCc2ccccc2)cc1
Yield: 23 %

Procedure:
To a suspension of sodium hydride (0.487 g, 12.17 mmol, 60% in mineral oil) in DMSO (33.8 ml) stirring under nitrogen was added trimethyl sulfoxonium iodide (2.68 g, 12.17 mmol) in 4 portions over 20 minutes. A solution of 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 25; 3.2 g, 8.11 mmol) in tetrahydrofuran (50.7 ml) was added via a dropping funnel over 90 minutes before the reaction was left to stir at room temperature for 18 hours. The resulting mixture was concentrated, poured into ice water and extracted with ethyl acetate (×3). The organics portion was dried (MgSO4), filtered and concentrated to give a brown oil. The crude oil was purified by silica chromatography (eluting with 0-50% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-(1-phenylcyclopropyl)pyridazine as a yellow oil (yield=23%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH2:26]([O:28][CH2:29][CH2:30][C:31](O)=[O:32])[CH3:27]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:31](=[O:32])[CH2:30][CH2:29][O:28][CH2:26][CH3:27])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CCOCCC(=O)O
Agent: Cl
Product: CCOCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (23 mg, 68.2%), MS (ISP) m/z=431.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0744 mmol) and 3-ethoxypropanoic acid.
Reaction SMILES: Cl.[Br:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[NH:15])[NH2:14])=[CH:9][CH:8]=1.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(=O)([O-])[O-].[Na+].[Na+].O.C(Cl)Cl>[Br:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[NH:14])[NH:15][C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])=[CH:9][CH:8]=1
Reactant: N=C(N)c1ccc(OCCCBr)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCBr)cc1
Reaction time: 0.5 h

Procedure:
In a mixed solvent of 175 ml of a saturated aqueous sodium carbonate solution, 90 ml of water and 350 ml of methylene chloride was dissolved 17.5 g of 1-bromo-3-(4-amidinophenoxy)propane hydrochloride, and 8.5 ml of benzyloxycarbonyl chloride was added thereto under ice-cooling. The resulting mixture was vigorously stirred at the same temperature for 30 minutes and then at room temperature for 4 hours, after which the organic layer was separated and the aqueous layer was extracted with 150 ml of methylene chloride. The combined organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Hexane was added to the resulting residue and the crystals were collected by filtration and dried to obtain 19.6 g of 1-bromo-3-(4-benzyloxycarbonylamidinophenoxy)propane as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:22]1([CH2:28][CH2:29][C:30]2[N:35]=[C:34]3[CH2:36][O:37][C:38](=O)[C:33]3=[CH:32][CH:31]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:38]1[C:33]2[C:34](=[N:35][C:30]([CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:31][CH:32]=2)[CH2:36][O:37]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1OCc2nc(CCN3CCOCC3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CCN3CCOCC3)ccc21
Reaction time: 0.17 h
Yield: 27 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (70 mg, 0.46 mmol) in THF (0.6 mL) is placed under an Argon atmosphere and cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (1.2 mL of a 1.0 M solution in THF, 1.2 mmol) is added slowly at 0° C. and the resulting solution is stirred for 10 min. The ice-bath is then removed and a solution of 2-(2-morpholin-4-yl-ethyl)-7H-furo[3,4-b]pyridin-5-one (80 mg, 0.32 mmol) in THF (2 mL) and added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and then poured into an aqueous 10% HCl solution (40 mL). The resulting suspension is stirred at room temperature for 48 h. The yellow solid which precipitated from solution is collected by filtration and washed with 10% HCl, MeOH (3×5 mL) and Et2O (3×5 mL), and dried under vacuum overnight to give the title compound (33 mg, 27%).
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]([OH:5])=[O:4].CO.[N+](=C)=[N-].[CH3:23][CH2:24]OCC>>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:3]([O:5][CH2:23][CH3:24])=[O:4]
Reactant: CCOCC
Reactant: O=C(O)C(Br)CCCCCc1ccc(Cl)cc1
Agent: C=[N+]=[N-]
Solvent: CO
Product: CCOC(=O)C(Br)CCCCCc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 31.0 g (0.097 mol) of 2-bromo-7-(4-chlorophenyl)heptanoic acid in 250 ml of absolute ether which contains 0.5 ml of methanol, a solution of about 0.16 mol of diazomethane in 300 ml of absolute ether is added drop by drop, with stirring, at room temperature, until the evolution of nitrogen ceases. Then the reaction mixture is concentrated by evaporation and the concentrate is chromatographed with toluene on silica gel. 18.1 g (56% of theory) is obtained of ethyl 2-bromo-7-(4-chlorophenyl)heptanoate, a colorless oil.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:16]([CH:25]3[CH2:27][CH2:26]3)=[CH:15][N:14]=2)=[O:12])([CH3:9])[C:6]([OH:8])=O)[CH2:3][CH2:2]1.[Cl-].[NH4+:29]>>[NH2:29][C:6](=[O:8])[C:5]([NH:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:23])([F:24])[F:22])[C:16]([CH:25]2[CH2:27][CH2:26]2)=[CH:15][N:14]=1)=[O:12])([CH3:9])[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Agent: [Cl-]
Product: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 112e, using 3-cyclopropyl-2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-methyl-propanoic acid (example 186d) and ammonium chloride as starting materials and isolated (16 mg, 32%); MS (ESI, m/z): 386.6 (M+H+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[F:27][C@H:28]1[C@@H:33]([CH2:34][OH:35])[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:29]1>CN(C)C=O>[F:27][C@H:28]1[C@@H:33]([CH2:34][O:35][C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[N:11]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=3)=[CH:4][CH:3]=2)[CH2:32][CH2:31][N:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](F)C1
Reactant: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(OC[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
4-fluoro-N-isobutyl-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (30 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (DMF) (3 mL) and to this solution was added sodium hydride (2 mg, 0.10 mmol, 60% wt in mineral oil) followed by tert-butyl cis-3-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (24 mg, 0.10 mmol). The reaction was stirred for 3 hours at room temperature, under nitrogen, then quenched with water and concentrated in vacuo. The crude product was extracted to the organic phase of an aqueous workup between ethyl acetate and water. The organic phase was then passed through a hydrophobic frit and concentrated in vacuo to give the title compound (47 mg). LCMS (2 min, formic) Rt 1.50 min, m/z (ES+) 564 (M+H).
Reaction SMILES: [Si:1]([O:8][C:9]1([CH3:30])[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][N:25]=[N+]=[N-])[O:21][C:20]3=[O:28])=[CH:15][C:14]=2[F:29])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N#N.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(OCC)(=O)C.[Pd].CO.C(Cl)(Cl)Cl>[Si:1]([O:8][C:9]1([CH3:30])[CH2:12][N:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:39](=[O:41])[CH3:40])[O:21][C:20]3=[O:28])=[CH:15][C:14]=2[F:29])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(O[Si](C)(C)C(C)(C)C)CN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Agent: [Pd]
Agent: N#N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC(C)(O[Si](C)(C)C(C)(C)C)C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
A solution of (R)-[[3-[4-[3-[(tert-butyldimethylsilyl)oxy]-3-methyl-1-azetidinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]azide (0.750 g, 1.72 mmol) in ethyl acetate (20 mL) was degassed by repeated evacuation and filling with N2. The solution was then treated with 10% palladium/carbon (0.075 g) under a N2 stream. The atmosphere was replaced with H2 (balloon) by repeated evacuation and filling and the reaction mixture stirred at ambient temperature. TLC analysis (5% methanol/chloroform) after 6 h revealed the reduction to be complete. The reaction mixture was filtered through Celite® and the filtrate concentrated under reduced pressure. The residue was dissolved in dry dichloromethane (10 mL), cooled to 0° C. with an ice bath, and treated with pyridine (0.680 g, 0.696 mL, 8.60 mmol) and acetic anhydride (0.263 g, 0.243 mL, 2.58 mmol). The cooling bath was removed and the reaction mixture stirred at ambient temperature under N2. After 3 h the reaction mixture was transferred to a separatory funnel along with dichloromethane (100 mL). The mixture was washed with 10% hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Radial chromatography over silica gel, eluting with 3% and then 5% methanol/chloroform, afforded, after concentration of appropriate fractions, 0.643 g (83%) of the title compound as a white solid with mp 137°-138° C. and MS(EI) 451 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]2)=[CH:10][CH:9]=1.[CH:19]12[CH:24]([C:25](O)=[O:26])[CH:23]1[CH2:22][O:21][CH2:20]2>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH:18][C:25]([CH:24]3[CH:23]4[CH:19]3[CH2:20][O:21][CH2:22]4)=[O:26])[N:14]=[CH:15]2)=[CH:10][CH:9]=1
Reactant: O=C(O)C1C2COCC21
Reactant: Cc1ccncc1-c1ccc2cc(N)ncc2c1
Product: Cc1ccncc1-c1ccc2cc(NC(=O)C3C4COCC43)ncc2c1

Procedure:
The title compound was prepared following a procedure similar to example 98 using 7-(4-methylpyridin-3-yl)isoquinolin-3-amine and 3-oxabicyclo[3.1.0]hexane-6-carboxylic acid.