Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([F:21])[CH:8]=1)[OH:6])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[NH2:1][CH2:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:9]([F:21])[CH:8]=1)[OH:6]
Reactant: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H](O)c1ccc(OCc2ccccc2)c(F)c1
Reaction time: 1 h
Yield: 69.7 %

Procedure:
A solution of (1R)-2-azido-1-[4-(benzyloxy)-3-fluorophenyl]ethanol (410 mg) in THF (8 mL) and water (2 mL) was treated with PPh3 (410 mg) and stirred for 1 h prior to addition of a further portion of PPh3 (220 mg). After stirring for a further 4 h the reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The organic phase was washed three times with 5% NaHCO3(aq), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with DCM, 1% MeOH in DCM, 2% MeOH in DCM, 5% MeOH containing 0.5% Et3N in DCM, and finally 20% MeOH containing 1% Et3N in DCM) to give the title compound (260 mg). LCMS RT=2.16 min.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=[O:15])[NH:14][C:10]=2C(C#N)=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[OH-].[K+].O.[C:22]([O:28]C)([O:26][CH3:27])(OC)[CH3:23]>C1(C)C=CC=CC=1.C(O)C>[CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=[O:15])[NH:14][C:10]=2[C:23]([C:22]([O:26][CH3:27])=[O:28])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1ccc(C#N)c2[nH]c(=O)n(C)c12
Reactant: COC(C)(OC)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(CC)c1ccc(C(=O)OC)c2[nH]c(=O)n(C)c12
Temperature: 100 °C
Yield: 77 %

Procedure:
A mixture of 7-(1-ethylpropyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carbonitrile (1.50 g, 6.17 mmol), potassium hydroxide (20.0 g, 356 mmol), water (30 ml) and ethanol (30 ml) was heated under reflux for 48 h. The reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and 2N hydrochloric acid was added and extracted. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to give crude carboxylic acid. Trimethyl orthoacetate (10 ml) and toluene (10 ml) were added to the residue and heated at 100° C. for 6 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 35% ethyl acetate/n-hexane to give 1.31 g (4.74 mmol, 77%) of the title compound as a white powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:35]([Cl:36])=[CH:34][C:8]([CH2:9][NH:10]/[C:11](=[N:26]\C(=O)OC(C)(C)C)/[NH:12][C:13](=[O:25])[CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=O)=[CH:7][C:6]=1[Cl:37])(=[O:3])[CH3:2].Cl.[CH2:39]([O:43][NH2:44])[CH:40]([CH3:42])[CH3:41]>C(O)C>[C:1]([NH:4][C:5]1[C:35]([Cl:36])=[CH:34][C:8]([CH2:9][NH:10][C:11]([NH2:26])=[N:12][C:13](=[O:25])[CH2:14]/[C:15](=[N:44]\[O:43][CH2:39][CH:40]([CH3:42])[CH3:41])/[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:7][C:6]=1[Cl:37])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)CC(=O)N/C(=N/C(=O)OC(C)(C)C)NCc2cc(Cl)c(NC(C)=O)c(Cl)c2)cc1
Reactant: CC(C)CON
Agent: Cl
Solvent: CCO
Product: COc1ccc(/C(CC(=O)N=C(N)NCc2cc(Cl)c(NC(C)=O)c(Cl)c2)=N/OCC(C)C)cc1
Temperature: 80 °C

Procedure:
A mixture of (E)-tert-butyl (4-acetamido-3,5-dichlorobenzylamino)(3-(4-methoxyphenyl)-3-oxopropanamido)methylenecarbamate (6 mg) and O-isobutylhydroxylamine hydrochloride (3 mg) in ethanol (0.1 mL) was heated at 80° C. for 2 h. Ethanol was removed in vacuo and the crude mixture was purified by reverse phase HPLC (30×100 mm PHENOMENEX-LUNA S10 column, 10-90% methanol/H2O/0.1% TFA) to give the title compound as a clear sticky oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.N1C=CN=C1.[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)Cl)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O.CN(C1C=CN=CC=1)C.O>[Si:18]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1NC[C@@H](CO)O1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OC[C@@H]1CNC(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 79 %

Procedure:
(S)-5-(hydroxylmethyl)oxazolidin-2-one (1.61 g, 13.7 mmol) was dissolved in dried N,N-dimethyl formamide. Imidazole (1.87 g, 27.4 mmol) and DMAP (168 mg, 1.37 mmol) were added. The resulting mixture was cooled to 0° C., and then tert-butyldiphenylchlorosilane (5.66 g, 20.6 mmol) was added. The mixture was raised to room temperature to react for 4 hrs. The reaction was measured by TLC. After the reaction completed, the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was combined, washed sequentially with water and saturated saline solution, dried over anhydrous sodium sulfate, and filtered. Column chromatography afforded 3.85 g of white solid (compound 25a), yield 83%.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH2:7][CH2:6][S:5]1(=[O:10])=[O:9])[C:2]#[CH:3].C(Cl)Cl.[CH2:14]([O:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:23]=1[N:29]1[S:33](=[O:35])(=[O:34])[N:32](CC[Si](C)(C)C)[C:31](=[O:42])[CH2:30]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(COC)OC.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].Cl[Cu].CCOC(C)=O>[CH2:14]([O:21][C:22]1[CH:27]=[C:26]([C:3]#[C:2][CH2:1][CH:4]2[CH2:8][CH2:7][CH2:6][S:5]2(=[O:10])=[O:9])[CH:25]=[CH:24][C:23]=1[N:29]1[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:42])[CH2:30]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C#CCC1CCCS1(=O)=O
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CN(c2ccc(C#CCC3CCCS3(=O)=O)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 120 °C

Procedure:
To a solution of 2-prop-2-ynyl-tetrahydrothiophene 1,1-dioxide (53 mg, 0.34 mmol) in 1 mL glyme/water (9:1) is added Pd(dppf)Cl2.CH2Cl2 (14 mg), a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (164 mg, 0.37 mmol) in 1 mL glyme/water (9:1), triethylamine (68 mg, 0.67 mmol) and CuCl (13 mg, 0.13 mmol). The mixture is heated at 120° C. in a microwave apparatus for 5 min then is poured into EtOAc. The mixture is washed with 1N HCl and the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:26](O)=O)[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:51][C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][C:62]([C:65]#[N:66])=[C:61]([F:67])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[NH2:58]>C(#N)C>[C:65]([C:62]1[CH:63]=[CH:64][C:59]([C:54]2[CH:55]=[CH:56][C:57]3[NH:58][C:26]([C@@H:2]([NH:1][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[N:51][C:52]=3[CH:53]=2)=[CH:60][C:61]=1[F:67])#[N:66]
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc2cc(-c3ccc(C#N)c(F)c3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a solution of Boc-Asn(Trt)-OH (100.4 mg, 0.2116 mmol) in acetonitrile (2.0 mL) cooled in an ice water bath was added 4-methylmorpholine (0.059 mL, 0.53 mmol) and isobutyl chloroformate (0.027 mL, 0.21 mmol). After stirring for 60 minutes, 3′,4′-diamino-3-fluoro-[1,1-biphenyl]-4-carbonitrile (Preparation 81, 42.7 mg, 0.188 mmol) was added and the mixture allowed to warm to room temperature. After stirring for 18 hours the reaction mixture was concentrated in vacuo and redissolved in acetic acid. After stirring at room temperature for 6.5 hours, the mixture was concentrated in vacuo, redissolved in ethyl acetate, washed with water, 0.5M HCl, and brine. The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (75 mg, 60%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].C(O)C>CC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[O:8])[CH:9]=[CH:10][C:11]=1[O:12][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1ccc(C=O)cc1OCC
Yield: 63.6 %

Procedure:
The compound was prepared according to general procedure E with 3-ethoxy-4-hydroxybenzaldehyde (2.4 mmol) in dry acetone (15 ml), anhydrous K2CO3 (3.1 mmol), and ethylbromoacetate (3.6 mmol) at reflux for 1 h30. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 565 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 385 mg of purified compound were obtained (63% yield). 1H NMR (250 MHz, CDCl3): δ 1.31 (t, J=7.0 Hz, 3H), 1.49 (t, J=7.0 Hz, 3H), 4.18 (q, J=7.0 Hz, 2H), 4.31 (q, J=7.0 Hz, 2H), 4.79 (s, 2H), 6.91 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.45 (s, 1H) 9.86 (s, 1H) 13C NMR (63 MHz, CDCl3): δ 14.0, 14.5, 61.2, 64.4, 65.9, 111.2, 113.0, 125.5, 131.0, 149.1, 152.7, 168.1, 191.5. MS (ESI): m/z 253.0 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH:29]=[O:30])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH2:37][CH2:38][CH2:39][Mg]Br)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(CCCC(O)CCCC2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH:29]([OH:30])[CH2:39][CH2:38][CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:22][CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1ccc(CCCC=O)cc1)(c1ccccc1)c1ccccc1
Reactant: Br[Mg]CCCc1ccccc1
Agent: OC(CCCc1ccccc1)CCCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1ccc(CCCC(O)CCCc2ccccc2)cc1)(c1ccccc1)c1ccccc1
Yield: 122.9 %

Procedure:
The alcohol 173 was prepared from 2.12 g (5.0 mmol) of 172 and 9.0 mL (9 mmol) of 120 in 50 mL of THF as described for the synthesis of 121 in Example 1. Flash chromatography (elution with 10% ethyl acetate in hexane) gave 3.3 g of the alcohol 173. 1H NMR consistent with the product.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[F:26][C:27]1[CH:28]=[C:29]([NH:37][CH:38]=[C:39]([C:45]([O:47]CC)=O)[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34].C([O-])(=O)CC([O-])=O.FC1C(OC)=C(OC)C=C2C=1C(=O)C(C(OCC)=O)=CN2>CCCCCC>[F:26][C:27]1[CH:28]=[C:29]2[C:30]([C:45](=[O:47])[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][NH:37]2)=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34]
Reactant: CCOC(=O)C(=CNc1cc(F)c(OC)c(OC)c1)C(=O)OCC
Agent: CCOC(=O)c1c[nH]c2cc(OC)c(OC)c(F)c2c1=O
Agent: O=C([O-])CC(=O)[O-]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2cc(F)c(OC)c(OC)c2c1=O
Temperature: 250 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To Dowtherm (150 mL) heated at 250° C. was added diethyl 2-(((3-fluoro-4,5-dimethoxyphenyl)amino)methylene)malonate (30 g, 87 mmol). The mixture was stirred at 250° C. for 30 min. LCMS indicated completion of the reaction. The reaction mixture was allowed to cool a bit and was then added to cold hexane, the precipitates were collected by filtration, washed with hexane and then allowed to dry in the air. Similar scale reactions were repeated several times. From a total amount of the malonate (148 g, 434 mmol), a mixture of ethyl 5-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate and ethyl 7-fluoro-5,6-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate was obtained as brown solid without further purification (103 g, 349 mmol, 80% yield). LCMS: (M+H)+: 296.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.[CH3:30][S:31]([CH2:34][CH2:35][NH2:36])(=[O:33])=[O:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:36][CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])=[O:25])=[CH:27][CH:28]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: CS(=O)(=O)CCN
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)cc1

Procedure:
In analogy to example 207, step 2, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzoic acid (example 332, step 2) was coupled with 2-(methylsulfonyl)ethanamine using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=515.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:24])[CH2:16][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:24])[CH2:16][S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CSc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CSc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(1-methyl-2-phenylsulfanyl-ethyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH:45](I)([CH3:47])[CH3:46]>CN(C=O)C>[CH:45]([N:21]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:20][CH2:19][CH2:18][N:17]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:16]/[CH:15]=[CH:14]/[CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)NCCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 1.5 g (2.5 mmol) of (E)-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec7-ene in 20 ml of DMF there are added, with stirring, 0.4 g (10 mmol) of sodium hydride dispersion (approx. 60%) and, after 15 min., 1 ml (10 mmol) of isopropyl iodide. The reaction mixture is stirred for 16 h at room temperature; a further 0.4 g (10 mmol) of sodium hydride dispersion (approx. 60%) and 1 ml (10 mmol) of isopropyl iodide are added, and the mixture is stirred for a further 24 h at 20° C. and for 24 h at 50° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a), using ethyl acetate-hexane (1:3) and ethyl acetate-hexane (1:2) in the flash chromatography, yields the title compound, Rf value=0.37 (silica gel/ethyl acetate:hexane (2:3)).
Reaction SMILES: [CH3:1][S:2]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[N:4]S(CC[Si](C)(C)C)(=O)=O)=[O:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([S:2]([CH3:1])(=[NH:4])=[O:3])=[CH:19][CH:18]=1
Reactant: COc1ccc(S(C)(=O)=NS(=O)(=O)CC[Si](C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COc1ccc(S(C)(=N)=O)cc1
Temperature: 120 °C
Yield: 95 %

Procedure:
A mixture of S-methyl-S-(4-methoxyphenyl)-N-[[2-(trimethylsilyl)ethyl]sulfonyl]-sulfoximine (2.9 g, 8.3 mmol) and 1.0 M of TBAF (12.5 mL, 12.5 mmol, 1.5 eq.) was heated in a microwave at 120° C. for 20 minutes. After cooling to room temperature, the solvent was evaporated and the resulting mixture was purified by silica gel column chromatography (elution with 100% EtOAc) to provide the title compound (1.46 g, yield 96%). 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J=9.0 Hz, 2H), 6.99 (d, J=9 Hz, 2H), 3.87 (s, 3H), 3.08 (s, 3H); ESI-MS m/z 186.1 (M+H)+.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([OH:17])[CH:8]=1.Cl[C:19]([F:25])([F:24])C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:17][CH:19]([F:25])[F:24])[CH:8]=1
Reactant: COC(=O)C(F)(F)Cl
Reactant: COC(=O)c1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1OC(F)F
Temperature: 60 °C
Reaction time: 60 h
Yield: 23 %

Procedure:
To a 70 ml dimethylformamide solution of 5.0 g (21.7 mmol) of methyl 4-bromo-2-hydroxybenzoate, 3.4 ml (32.6 mmol) of methyl chlorodifluoroacetate and 3.0 g (21.7 mmol) of potassium carbonate were added. The mixture was stirred at 60° C. for 6 hours and at room temperature for 60 hours. Then, water was added to the reaction mixture, and the mixture was extracted with ether. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/1) to obtain 1.4 g (23%) of the captioned compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:18]1([CH2:21][O:22][C:23]2[N:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=2)[CH2:20][CH2:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[N:24][C:23]([O:22][CH2:21][CH:18]4[CH2:20][CH2:19]4)=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1cnc(OCC2CC2)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCC4CC4)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=418.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6](=[O:7])[O:5][C:4]2[CH:8]=[CH:9][C:10]3[C:15]([C:3]1=2)=[CH:14][C:13]([CH3:16])=[C:12]([C:17]#[N:18])[CH:11]=3.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[CH:8][C:4]3[O:5][C:6](=[O:7])[C:2]([CH3:19])([CH3:1])[C:3]=32)=[CH:11][C:12]=1[C:17]#[N:18]
Reactant: Cc1cc2c3c(ccc2cc1C#N)OC(=O)C3(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(=O)Oc2ccc3cc(C#N)c(CBr)cc3c21

Procedure:
A mixture of 1,2-dihydro-1,1,8-trimethyl-2-oxonaphtho[2,1-b]furan-7-carbonitrile, (0.25 g), N-bromosuccinimide (0.2 g), benzoyl peroxide (0.01 g) and carbon tetrachloride (40 ml) was stirred under reflux for 24 h. The reaction mixture was cooled, washed with water, dried and evaporated to dryness under reduced pressure, to give the required starting material, 8-bromomethyl-1,2-dihydro-1,1-dimethyl-2-oxonaphtho[2,1-b]furan-7-carbonitrile, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCCNCCC
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.0 g, 0.021 mole) and 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 2 hours with a stream of nitrogen bubbling through it. A solution of di-n-propylamine (1.94 g, 0.063 mole) in tetrahydrofuran was added dropwise at room temperature to the stirred solution and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated and the solid residue was triturated with water. The solid was collected by filtration and dried under high vacuum overnight. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum at room temperature over the weekend to give 3.79 g (59%) in 2 crops, mp 156°-57° C.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[Cl:14])[NH:7][C:6]=1[CH3:15].[H-].[Na+].[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C=O)C.O>[Cl:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[N:7]([CH2:27][C:26]3[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:30][CH:29]=3)[C:6]([CH3:15])=[C:5]([CH2:4][C:3]([OH:2])=[O:16])[C:13]=12
Reactant: COC(=O)Cc1c(C)[nH]c2nccc(Cl)c12
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2c(Cl)ccnc2n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a cooled (0° C.) stirred solution of (4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.1 g, 0.42 mmol) in dry DMF (2.5 ml) is added sodium hydride (0.019 g of a 60% dispersion in mineral oil, 0.47 mmol). After stirring at room temperature for 5 hours, the reaction mixture is re-cooled to 0° C. and treated with 4-methylsulfonylbenzyl bromide (0.105 g, 0.42 mmol). The resulting mixture is stirred and allowed to warm to room temperature overnight. The reaction mixture is diluted with water (3 ml) and extracted with ether (3×15 ml). The organic portions are combined, washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting crude residue is loaded on a pre-packed Isolute™ silica column and eluted with iso-hexane:ethyl acetate (1:8) to yield the titled compound as a white powder. (MH+ 407).