Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:21][C@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:23][CH2:24][OH:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[CH2:14]([O:21][C@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:23][C:24]([OH:3])=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCCCCCCC[C@H](CCO)OCc1ccccc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccccc1

Procedure:
Jones reagent was added in portions to a mixture of alcohol 46 (3.23 g, 10.1 mmol) in acetone (50 mL) at 0° C. until the alcohol was consumed. The mixture was partitioned between 0.1M HCl (100 mL) and ethyl acetate (400 mL), and the organic phases were washed with brine (100 mL), dried, and concentrated in vacuo. The product was purified by flash chromatography to give compound 47 as an oil (Rf 0.38, silica, 25% ethyl acetate in hexane, 2.09 g, 62%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[CH2:14]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH3:15]>>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([N:16]([CH2:14][CH3:15])[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCNc1cccc2ccccc12
Reactant: CCc1cccc(N(C)C#N)c1
Agent: Cl
Product: CCc1cccc(N(C)C(=N)N(CC)c2cccc3ccccc23)c1
Reaction time: 14 h
Yield: 71 %

Procedure:
In a 5 ml round bottom flask was placed N-(3-ethylphenyl)-N-methylcyanamide (626 mg, 3.91 mmol), N-ethyl-N-(1-naphthyl)amine hydrochloride (859 mg, 4.15 mmol) and a stir bar. The flask was evacuated via aspirator and flushed with N2. This was immediately placed in a preheated 160° C. oil bath and allowed to stir under N2 for 14 h. The resultant brown glass was dissolved in methanol (6 ml) and diluted with hot distilled water (20 ml). This solution was basified with 0.1N NaOH (25 ml) and extracted with CHCl3 (5×20 ml) to yield a brownish green oil (920 mg). A TLC of this oil showed a mixture of reactants and product. Reactants were eluted by column chromatography with benzene. The product was eluted with benzene/EtOH 20:1 (TLC Rf =0.064, CHCl3 :EtOH, 1:1) to afford a pale greenish viscous oil, 460 mg (35.5%). IR (neat) 3484, 3394 (--NH), 1635 (--C=NH). 1H-NMR (CDCl3) δ 1.00 (t, 3H, J=7.5), 1.14 (t, 3H, J=6.6), 2.32 (q, 2H, J=7.5), 2.91 (s, 3H), 3.72 (q, 2H, J=6.6), 5.62 (s, 1H), 6.34-7.73 (m, 11H, H-aromat). 13C-NMR (CDCl3) CN3, 162.2; Ar, 145.9, 144.0, 140.3, 133.7, 130.3, 127.9, 127.5, 125.5, 125.1, 125.0, 124.5, 124.4, 122.7, 122.6, 122.4, 120.4; NCH2, 46.2; NCH3, 39.1; CH2, 27.9; CH3, 14.8; CH3, 12.5. Mass Spec. m/e calcd for C22 H25N3, 331.2048, Found, 331.2046.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl[CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1>CN(C)C=O>[NH:28]1[CH:29]=[C:25]([CH2:24][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)[C:8]#[N:9])[N:26]=[CH:27]1
Reactant: N#CC(c1ccccc1)c1ccc(C(F)(F)F)cc1
Reactant: ClCc1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(Cc1c[nH]cn1)(c1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A 3.84 g. portion of 2-phenyl-2-(4-trifluoromethylphenyl)acetonitrile was reacted with 1.42 g. of 50% sodium hydride and 2.25 g. of 4-chloromethylimidazole hydrochloride in 50 ml. of dimethylformamide, as described in Example 1. The mixture was stirred for 2 hours at 60° C., and for 20 hours at ambient temperature. The reaction mixture was then worked up as described in Example 1 to obtain 3.6 g. of the desired product as the free base, a sample of which was analyzed as follows.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:17]3[C:18]4[C:19]([NH:25][C:16]=3[C:15](=O)[N:14](CC3C=CC(OC)=CC=3)[CH:13]=2)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=4)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].O=P(Cl)(Cl)[Cl:38]>[Cl-].C[N+](C)(C)C>[Cl:38][C:15]1[C:16]2[NH:25][C:19]3[C:18]([C:17]=2[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)=[CH:13][N:14]=1)=[CH:23][C:22]([CH3:24])=[CH:21][N:20]=3
Reactant: CCS(=O)(=O)c1cccc(-c2cn(Cc3ccc(OC)cc3)c(=O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: CCS(=O)(=O)c1cccc(-c2cnc(Cl)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A 500 mL round bottom flask equipped with an N2 inlet and reflux condenser was charged with 5-[3-(ethylsulfonyl)phenyl]-7-(4-methoxybenzyl)-3-methyl-7,9-dihydro-8H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-8-one (19.3 g, 39.6 mmol), tetramethylammonium chloride (4.77 g, 43.542 mmol), and POCl3 (249.5 g, 1626.9 mmol) at room temperature, transferred to an oil bath and heated at 100° C. The reaction was monitored by HPLC, and determined to be complete after 2 h. The mixture was allowed to cool to ambient temperature. A separate 3 neck, 3 L flask was fitted with a cold thermometer, and two addition funnels. To this flask was added a solution of 33% by weight aqueous K3PO4 (1500 mL), cooled in a dry ice/acetone bath, followed by the drop-wise addition of the aryl chloride suspension. The internal temperature was kept between 5 to 20° C. and the pH was carefully monitored and maintained at 11.5 during the quench using a slow addition of 10M KOH when necessary. The suspension was allowed to stir for 10 min at 5° C. after the addition was complete, and at ambient temperature for 2 h. The crude product was extracted from the aqueous layer with DCM (5×500 mL), dried with MgSO4, filtered and concentrated in vacuo to a total volume of about 500 mL. The solution was allowed to sit at ambient temperature overnight. The precipitate was collected by filtration, washed with additional DCM and dried, affording a light grey solid (9.79 g) which was confirmed by analytical LCMS and 1H-NMR as the free base. The DCM mother liquor was concentrated and taken up with a methanol/DCM mixture (300 mL, 15/85). To the light green solution was slowly added 30 mL 4N HCl in dioxane and the mixture were stirred for one hour at ambient temperature. 1200 mL of MTBE was slowly added and the resultant suspension was filtered. Chromatography on silica gel plug with methanol/DCM (3/97) afforded a yellow solid. The solid was washed with warm methanol (30 mL) and the resulting product was collected by filtration and washed with diethyl ether, affording an additional 1.7 g of the product as a free base. (9.79+1.7=11.49 g, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (t, J=7.33 Hz, 3H) 2.32 (s, 3H) 3.44 (q, J=7.33 Hz, 2H) 7.70 (d, J=1.26 Hz, 1H) 7.93 (t, J=7.71 Hz, 1H) 8.04-8.15 (m, 2H) 8.21 (d, J=10.61 Hz, 2H) 8.53 (d, J=1.52 Hz, 1H) 12.78 (br. s., 1H). ESI-MS: m/z 386.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10](Cl)=[O:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][C:10]2=[O:11]
Reactant: O=C(Cl)CCc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1CCc2c(F)cccc21
Temperature: 0 °C

Procedure:
To a mixture of 3-(2-fluorophenyl)propionic acid (18.64 g, 0.111 mol) and dimethylformamide (5 drops) at room temperature was added dropwise oxalyl chloride (60 mL). The mixture was stirred at room temperature until gas evolution had ceased. The excess oxalyl chloride was removed by distillation to give 3-(2-fluorophenyl)propionyl chloride. A solution of the 3-(2-fluorophenyl)propionyl chloride in dichloromethane (230 mL) was added dropwise to a mixture of aluminum chloride (16.25 g, 0.12 mol) in dichloromethane (230 mL), and the mixture was refluxed for 3.5 h. The reaction mixture was poured into ice water (1200 mL), and the two phases were separated. The dichloromethane phase was washed successively with 0.1N aqueous sodium hydroxide (2×100 mL), water (200 mL), and brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residual oil was chromatographed on silica gel eluting with hexane:dichloromethane (9:1) to give 11.0 g of crude 4-fluoro-1-indanone as a yellow solid. Recrystallization from acetone: water mixtures gave 8.02 g (48%) of 4-fluoro-1-indanone as a pale yellow solid: m.p., 71°-72° C.; NM (DMSO-d6): d 7.51 (m, 3H, Ar), 3.13 (t, 2H, CH2), 2.74 (t, 2H, CH2).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.[Br:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1>>[Br:16][C:17]1[N:18]=[CH:19][N:20]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:15])[N:3]=2)[CH:21]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: Brc1c[nH]cn1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example A.11) (1.91 g, 8.0 mmol) and commercially available 4-bromo-imidazole (1.76 g, 12.0 mmol) according to the general procedure IVa. Obtained as a light brown solid (2.76 g, 98%). MS (ISP) 349.1 [(M+H)+]; mp 176-178° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:11][S:12]C(=O)C)=[CH:4][CH:3]=1.CN>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:11][SH:12])=[CH:4][CH:3]=1
Reactant: CC(=O)SCCN(Cc1ccc(Cl)nc1)CC(C)C
Agent: CN
Solvent: CCO
Product: CC(C)CN(CCS)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.25 gram (0.00083 mole) of 1-(2-{[(6-chloro(3-pyridyl))methyl](2-methylpropyl)-amino}ethylthio)ethan-1-one and 0.78 gram of a 33% solution of methylamine in ethanol (0.0083 mole of methylamine) in 50 mL of ethanol was stirred at ambient temperature two hours. The reaction mixture was concentrated under reduced pressure to a residue. This residue was use without further purification in Step E.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@H:13]1[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16][N:15](C(OCC2C=CC=CC=2)=O)[CH2:14]1.[H][H].N#N>CCO.[Pd]>[CH3:20][O:19][C@H:17]1[CH2:16][NH:15][CH2:14][C@@H:13]([CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH2:18]1
Reactant: CO[C@@H]1C[C@H](CN2C(=O)c3ccccc3C2=O)CN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CO[C@H]1CNC[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Reaction time: 3 h
Yield: 89.3 %

Procedure:
To cis-phenylmethyl (3RS,5SR)-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-5-(methyloxy)-1-piperidinecarboxylate (210 mg, 0.51 mmol) in EtOH (20 mL) was added Pd/C (50 mg; 10%). The reaction was hydrogenated on a Parr apparatus at 45 psi of H2 for 3 h. The hydrogen was displaced with N2 and the solution was filtered through a pad of Celite® to remove the catalyst which was washed with additional EtOH (50 mL). The filtrate was then concentrated under reduced pressure to give the desired compound (125 mg; 90%) as a colorless oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[H-].[Na+].[N+:11]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1Cl)([O-:13])=[O:12].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:8])[CH:5]([C:6]#[N:7])[C:19]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:11]([O-:13])=[O:12])[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)c1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
Ethylcyanoacetate (3.75 g, 38 mmol) in 3 mL DMF was added dropwise at 0° C. to a suspension of sodium hydride (1.5 g, 60% in mineral oil, 38 mmol) in DMF (9 mL). The reaction mixture was stirred at room temperature for 30 minutes then cooled to ° C. and 3-nitro-4-chloropyridine (2.63 g, 19 mmol, 1 eq) in DMF (3 mL) added slowly. 2 M HCl (20 mL) and ethyl acetate (20 mL) were added after 2 hours stirring at room temperature and the organic layer was washed with water and brine, before being dried over sodium sulphate and concentrated to give a red/orange oil. The crude oil was triturated with ethyl acetate and the resultant solid collected by filtration to give the title compound (2.88 g, 48%). 1H NMR (d6-DMSO) δ 13.2 (s, br), 8.70 (1H, s), 7.88 (1H, dd, J=7.1, 1.0), 4.06 (2H, q, J=7.1), 1.18 (3H, t, J=7.1); LC-MS (1) Rt 1.13 min; m/z (ES−) 190, 234.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[C:34]([O-])(=[O:38])[C@H:35]([CH3:37])[OH:36].[Na+].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([C:34](=[O:38])[C@@H:35]([OH:36])[CH3:37])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: C[C@H](O)C(=O)[O-]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C(=O)[C@H](C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.3 %

Procedure:
To a mixture of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol) and sodium L-lactate (38 mg, 0.34 mmol) in DCM (2 mL) was added HOBt (33 mg, 0.25 mmol) and EDCI (64 mg, 0.34 mmol). The resulting mixture was allowed to stir at r.t. for 18 h then partitioned between DCM and sat. aq. NH4Cl. The organic phase was dried (phase separator), concentrated in vacuo and the resulting residue purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-25%). The resulting residue was triturated with Et2O and further purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient MeOH 45-60%) affording 840 (29 mg, 23%). LCMS (method I): RT 3.10 min, [M+H]+ 521.3. 1H NMR (DMSO, 400 MHz): δ 8.44 (1 H, brd s), 8.07-8.03 (1 H, m), 7.64-7.63 (1 H, m), 7.25-7.24 (2 H, m), 5.24 (1 H, brd s), 4.94 (1 H, dd, J=21.10, 10.14 Hz), 4.59-4.58 (2 H, m), 4.46-4.12 (4 H, brd s), 4.18-4.17 (2 H, m), 3.79 (4 H, t, J=4.51 Hz), 3.72 (3 H, s), 3.34-3.32 (2 H, m), 3.09 (3 H, s), 1.34 (3 H, t, J=7.43 Hz), 1.20 (3 H, d, J=6.71 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]#[C:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[N:43]([C:6]([C:7]3[CH:16]=[CH:15][C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C#Cc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1ccc2ccccc2c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 88 %

Procedure:
The title compound was synthesized from naphthalene-2-yl-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 88% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) δ 7.85 (m, 4H), 7.50 (m, 2.6H), 7.33 (m, 1.6H), 7.12 (m, 1.8H), 6.95 (m, 1.4H), 6.74 (m, 1.6H), 6.61 (d, 0.6H, J=0.4 Hz), 6.50 (d, 0.4H, J=0.4 Hz), 6.35 (s, 0.6H), 6.23 (s, 0.4 Hz), 4.36 (t, 2H, J=8.0 Hz), 4.05 (m, 2H), 3.76 (m, 2H), 3.20 (t, 2H, J=8.0), 2.73 (t, 2H, J=8.0 Hz), (m, 2H), 1.51 (s, 9H), 1.07 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:5](=[CH:7][S:8][CH:9]=2)[N:6]=1.C(=O)=O.[Br:13]N1C(=O)CCC1=O.[Cl-].[Na+]>O1CCCC1>[Br:13][C:9]1[S:8][CH:7]=[C:5]2[C:4]=1[S:3][C:2]([CH3:1])=[N:6]2
Reactant: Cc1nc2cscc2s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2csc(Br)c2s1

Procedure:
1 mmol of 2-methylthieno[3,4-d][1,3]thiazole represented by formula (12) was dissolved in 10 ml of tetrahydrofuran and kept at −78° C. in a methanol-bath cooled by dry ice. Into this solution, a solution comprised of 1.05 mmol of N-bromosuccinimide and 5 ml of tetrahydrofran was gradually added dropwise. After two hours reaction, an excess amount of a saturated sodium chloride aqueous solution was added to stop the reaction. The reacted liquid was washed with water, and the organic layer was recovered and dried under sodium sulfate. The solvent was evaporated out and then purification was carried out using column separation method with solvents of ethylacetate and hexane, obtaining 6-bromo-2-methylthieno[3,4-d][1,3]thiazole represented by formula (13).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([Cl:23])[CH:14]=1)[CH2:5][C@H:6]1[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7]1.O.[OH-].[Li+]>C(O)C.O>[Cl:23][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][C@H:6]2[CH2:10][CH2:9][C:8]([F:12])([F:11])[CH2:7]2)[C:3]([OH:24])=[O:2])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:20])=[O:21]
Reactant: COC(=O)[C@H](C[C@H]1CCC(F)(F)C1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)O)cc1Cl
Temperature: 25 °C
Yield: 85.7 %

Procedure:
(R)-2-(3-Chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionic acid methyl ester (294 mg, 0.77 mmol) was dissolved in ethanol (8 mL) and treated with a solution of lithium hydroxide monohydrate (81 mg, 1.9 mmol) in water (2 mL) at 25° C. It was stirred at 25° C. until the starting material was all consumed by TLC (˜1 hr). The reaction was then concentrated in vacuo to remove the ethanol. The remaining aqueous layer was then acidified to pH=2 with an aqueous 1N hydrochloric acid solution. This was then extracted with ethyl acetate (3×20 mL), the organic layers combined and dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionic acid (242 mg, 86%) as a mixture of two diastereomers as a light yellow foam: ES-HRMS m/e calcd for C15H17O4SClF2 (M+Na)+ 389.0396, observed 389.0394; 1H NMR (300 MHz, CDCl3) δ 1.06-2.38 (m, 9H, CH and 4×CH2), 3.28 (s, 3H, SO2CH3), 3.65 (m, 1H, ArCH), 7.42 (m, 1H, Ar), 7.54 (m, 1H, Ar), 8.14 (m, 1H, Ar).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[N:8]2[CH3:12])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=1>>[F:11][C:10]1[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([CH3:16])=[N:18][CH:19]=2)=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH3:12])[C:7](=[O:13])[C:6]2([CH3:15])[CH3:14]
Reactant: CN1C(=O)C(C)(C)c2ccc(N)c(F)c21
Reactant: Cc1ccc(C(=O)O)cn1
Product: Cc1ccc(C(=O)Nc2ccc3c(c2F)N(C)C(=O)C3(C)C)cn1

Procedure:
Prepared in analogy to example 1b from 6-amino-7-fluoro-1,3,3-trimethylindolin-2-one (example 13d) and 6-methylnicotinic acid. The title compound was obtained as dark red foam.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[CH2:8]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C1COCC1>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([CH:4]([C:3]#[N:7])[C:5]#[N:6])=[O:21])=[CH:23][CH:24]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: N#CCC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C#N)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.7 %

Procedure:
NaH (1.657 g, 60%, 41.4 mmol) was suspended in THF (10 mL). To this suspension was added malononitrile (1.368 g, 20.71 mmol) in THF (10 mL) at 0° C. dropwise over 10 minutes. The suspension was stirred for additional 20 minutes. To this solution was added compound 31A (5.11 g, 20.71 mmol) in THF (40 mL) portion wise. Afterwards, the solution was warmed to rt and stirred for 30 minutes. The pH of the solvent was adjusted to 1 with concentrated HCl. The reaction mixture was concentrated, and partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was triturated with 1:1 Hex/EtOAc (50 mL) to give a solid which was collected by filtration to provide 3.7 g of the desired product 31B: 1H NMR (DMSO-d6): δ 7.60-7.63 (m, 2H), 7.32-7.47 (m, 5H), 7.03-7.07 (m, 2H), 5.16 (s, 2H). MS (DCI(+)): m/z 294 (M+NH4).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11])(=[O:5])=[O:4].[C:15]([O:19][C:20](=[O:48])[NH:21][C:22]([C:24]1[S:25][C:26]([S:46][CH3:47])=[C:27]([S:29]([C:32]2[CH:33]=[C:34]([C:38]3[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:39]=3[NH2:45])[CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH:28]=1)=[NH:23])([CH3:18])([CH3:17])[CH3:16]>ClCCl>[C:15]([O:19][C:20](=[O:48])[NH:21][C:22](=[NH:23])[C:24]1[S:25][C:26]([S:46][CH3:47])=[C:27]([S:29]([C:32]2[CH:33]=[C:34]([C:38]3[C:43]([CH3:44])=[CH:42][CH:41]=[CH:40][C:39]=3[NH:45][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][NH:6][S:3]([C:2]([F:14])([F:13])[F:1])(=[O:5])=[O:4])[CH:35]=[CH:36][CH:37]=2)(=[O:30])=[O:31])[CH:28]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: O=C(Cl)CCCNS(=O)(=O)C(F)(F)F
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCNS(=O)(=O)C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
A solution of 4-trifluoromethanesulfonylamino-butyryl chloride (0.015 g, 0.058 mmol) [example 212, step b] in dichloromethane [1 mL] was added to a solution of {[4-(2′-amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.025 g, 0.049 mmol) [example 25, step c] in dichloromethane [1 mL] at room temperature with vigorous stirring for 0.5 hours. The reaction mixture was evaporated and column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.020 g, 57%) as a solid. ESI-MS (m/z): Calcd. for C29H33F3N4O7S4: 734.12; found: 734.7.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4].O.C([O-])=[O:15].[Na+].Cl>C(O)=O>[OH:15][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Reactant: O=C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: O=C(CO)c1ccc(O)c(O)c1
Temperature: 100 °C
Yield: 98.9 %

Procedure:
A 0.1 liter reactor equipped with a reflux condenser and magnetic stirring bar was charged under argon with 5.05 g of 4-chloroacetyl-catechol of a purity of ca. 99%, 50 ml of water, 2.8 g of sodium formate and 1.55 ml (˜1.9 g) of formic acid. The stirred mixture was heated under reflux (˜100° C.) for 22 hours. The solution was cooled to about 25° C. and acidified by addition of 2 g of conc. hydrochloric acid (37%) resulting in a pH of about 0.5. The mixture was extracted with ethyl acetate, once with 100 ml then 3 times with 50 ml each. The organic extracts have been back washed 3 times with 30 ml 10% brine. The combined organic phases were dried with sodium sulfate, filtered and evaporated at reduced pressure at 40° C. This resulted in a light tan solid crystalline product of 4.56 g of 97.4% purity corresponding to a yield of 98.9%.