Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC[N:3](C(C)C)C(C)C.[CH3:10][C:11]([C:15]1[N:19]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:18]2[CH:27]=[CH:28][C:29]([S:31]([N:34]3[CH:38]=[C:37]([C:39]([OH:41])=O)[CH:36]=[N:35]3)(=[O:33])=[O:32])=[CH:30][C:17]=2[N:16]=1)([CH3:14])[CH2:12][CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CN(C=O)C>[CH3:14][C:11]([C:15]1[N:19]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:18]2[CH:27]=[CH:28][C:29]([S:31]([N:34]3[CH:38]=[C:37]([C:39]([NH2:3])=[O:41])[CH:36]=[N:35]3)(=[O:32])=[O:33])=[CH:30][C:17]=2[N:16]=1)([CH3:10])[CH2:12][CH3:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(N)=O)cn3)ccc2n1CC1CCOCC1
Yield: 18.5 %

Procedure:
Following the same procedure in Example 24, Step A, using DIPEA (105 uL, 78 mg, 0.60 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.20 mmol), HATU (114 mg, 0.30 mmol) and saturated ammonia in DMF (5 mL). The crude product was purified by MPLC using CH2Cl2/MeOH (20:1) on silica gel to give 17 mg (18%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.78 (t, J=7.52 Hz, 3 H), 1.41-1.57 (m, 4 H), 1.59 (s, 6 H), 1.95 (q, J=7.42 Hz, 2 H), 2.20-2.37 (m, 1 H), 3.22-3.38 (m, 2 H), 3.90 (dd, J=11.82, 3.22 Hz, 2 H), 4.42 (d, J=7.42 Hz, 2 H), 7.94 (d, J=8.8 Hz, 1 H), 8.01 (dd, J=8.8, 1.8 Hz, 1 H), 8.05 (s, 1 H), 8.36 (d, J=1.56 Hz, 1 H), 8.79 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=460.3.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([C:18]1[S:22][C:21]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:25])=[N:20][CH:19]=1)[CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10].Cl[C:38]1[C:39]2[S:46][CH:45]=[CH:44][C:40]=2[N:41]=[CH:42][N:43]=1>C1COCC1>[N:41]1[C:40]2[CH:44]=[CH:45][S:46][C:39]=2[C:38]([O:3][CH2:4][CH:5]([C:18]2[S:22][C:21]([NH:23][C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)=[O:25])=[N:20][CH:19]=2)[CH2:6][O:7][Si:8]([CH:15]([CH3:16])[CH3:17])([CH:12]([CH3:13])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[N:43][CH:42]=1
Reactant: Clc1ncnc2ccsc12
Reactant: CC(C)[Si](OCC(CO)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](OCC(COc1ncnc2ccsc12)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (0.12 mmol as a 60% oil dispersion) in THF (0.20 mL) was added a solution of compound 73.3 (0.04 mmol) in THF (1.0 mL) at room temperature. After stirring for 1 hour, 4-chlorothieno[3,2-d]pyrimidine (0.04 mmol) was added and the reaction mixture was heated at 60° C. for 1 hour. The reaction was cooled and quenched with the addition of saturated NH4Cl. The reaction mixture was extracted with EtOAc, dried and concentrated to give a residue that was purified by preparative TLC (20% hexanes in EtOAc) to afford 1-{5-[2-(thieno[3,2-d]pyrimidin-4-yloxy)-1-triisopropylsilanyloxymethyl-ethyl]-thiazol-2-yl}-3-(3-trifluoromethyl-phenyl)-urea (compound 73.4).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.[CH2:26]([Li])CCC.IC>>[ClH:1].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14]([CH3:26])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Li]CCCC
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: Cl
Agent: [Li]C
Solvent: CI
Product: Cc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Yield: 11.4 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1; 0.350 g, 0.930 mmol), MeLi (0.639 mL, 1.02 mmol), butyllithium (0.409 mL, 1.02 mmol), and iodomethane (0.165 g, 1.16 mmol) were reacted according to the method of Example 7 to provide 3-(benzyloxy)-5-methyl-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.037 g, 12.8% yield). 1H NMR (DMSO-d6) δ 7.83 (s, 1H), 7.60 (m, 2H), 7.54 (s, 1H), 7.42 (m, 2H), 7.37 (m, 1H), 6.84 (s, 1H), 5.32 (s, 2H), 2.32 (s, 3H), 2.29 (s, 3H). Mass spectrum (apci) m/z=312.1 (M+H-HCl).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH:7]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[CH:23]1[O:28][CH2:27][CH2:26][CH2:25][O:24]1.C(N(CC)CC)C.Cl.[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:37][O:38][C:39](=[O:43])[CH2:40][CH2:41][NH:42][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH:7]([O:6][C:5]2[CH:21]=[CH:22][C:2]([Br:1])=[C:3]([CH:23]3[O:28][CH2:27][CH2:26][CH2:25][O:24]3)[CH:4]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=1
Reactant: CC(C)CC(Oc1ccc(Br)c(C2OCCCO2)c1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(Br)c(C3OCCCO3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[1-(4-bromo-3-[1,3]dioxan-2-yl-phenoxy)-3-methyl-butyl]-benzoic acid (940 mg, 2.09 mmol) in methylene chloride (21 mL) is added triethyl amine (0.88 mL, 6.28 mmol), DMAP (5.0 mg), 3-Amino-propionic acid methyl ester hydrochloride (438 mg, 3.14 mmol) and EDCI (1207 mg, 6.28 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving the titled compound (670 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=[O:14].[C:16]1([C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N+]=[N-])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(Cl)Cl>[C:16]1([CH:22]([O:14][C:13](=[O:15])[CH2:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: COc1ccc([N+](=O)[O-])cc1CC(=O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1CC(=O)OC(c1ccccc1)c1ccccc1
Yield: 21 %

Procedure:
Using 2-methoxyphenylacetic acid (5.00 g) as a starting material, the same procedure of Example 188 gave 2-methoxy-5-nitrophenylacetic acid. To a solution of the resulting nitro compound in methylene chloride (140 ml), a solution of diphenyldiazomethane in methylene chloride was added at room temperature until the reaction mixture turned purple and then acetic acid was added until the purple color of the reaction mixture disappeared. The reaction mixture was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 2.34 g of the titled compound (yield, 21%).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:29]=[CH:28][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:21]4=[N:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25][N:20]4[CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([F:4])[CH3:3]>C1COCC1.CO.[Pt](=O)=O>[F:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]3[C:21]4=[N:22][S:23](=[O:27])(=[O:26])[CH2:24][CH2:25][N:20]4[CH2:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)=[CH:28][CH:29]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(F)(F)c1ccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
Platinum(IV) oxide (15 mg) was added to a mixture of 9-{4-[4-(1,1-difluoroethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (300 mg) in THF (dry) (10 mL) and MeOH (10 mL). The mixture was stirred at room temperature under hydrogen overnight. The insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (77.7 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[CH:14]1([NH2:17])[CH2:16][CH2:15]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:14]1([NH:17][C:11]([C:8]2[N:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NC2CC2)nc1
Yield: 42.4 %

Procedure:
5-(Methoxycarbonyl)pyridine-2-carboxylic acid (1.50 g, 8.28 mmol) was dissolved in DMF (25 mL) and cyclopropylamine (689 uL, 9.94 mmol), Et3N (4.66 mL, 33.1 mmol) and HBTU (3.30 g, 8.69 mmol) were added. The reaction mixture was stirred for 3d and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with sat aq Na2CO3 (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (774 mg, 42.4%) as a white solid. LCMS (ES+): 221.2 [MH]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:20]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([O-:16])=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[Na+:20]
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution consisting of ethyl 1-benzylpiperidine-4-carboxylate (500 mg, 2.02 mmol) in ethanol (10 mL) was added 1 N sodium hydroxide (2.02 mL, 2.02 mmol) and the reaction mixture was stirred at room temperature overnight. Most of the ethanol was removed under reduced pressure and stirring was continued for six hours. Toluene was added to remove most of the water by azeotrope and the material was dried under high vacuum overnight to provide the title intermediate as a white solid.
Reaction SMILES: C([CH:3]([C:26]([OH:28])=[O:27])[N:4]([C:19](OC(C)(C)C)=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:7]([C:17]#[N:18])[CH:6]=1)C.F[C:30](F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:19]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:7]([C:17]#[N:18])[CH:6]=1)[CH2:3][C:26]([OH:28])=[O:27])[CH3:30]
Reactant: CCC(C(=O)O)N(C(=O)OC(C)(C)C)c1ccc(OCC(C)(C)C)c(C#N)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN(CC(=O)O)c1ccc(OCC(C)(C)C)c(C#N)c1
Reaction time: 1 h

Procedure:
To dimethylformamide solution (240 ml) containing N-(3-cyano-4-neopentyloxyphenyl)-tert-butoxycarboxamide (24.5 g) was added sodium hydride (60% content, 1.15 g) under ice-cooling and the mixture was stirred for 30 min. The mixture was warmed to room temperature and stirred further for 1 h. The reaction mixture was ice-cooled and ethyl bromoacetate (24.5 g) was added, which was followed by stirring for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give ethyl N-tert-butoxycarbonyl-N-(3-cyano-4-neopentyloxyphenyl)glycine (36.5 g) as an oily substance. The obtained ethyl N-tert-butoxycarbonyl-N-(3-cyano-4-neopentyloxyphenyl)glycine (8.2 g) was added to trifluoroacetic acid (24 ml) at room temperature and the mixture was stirred for 1 h. The reaction mixture was poured into an aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (5.9 g), melting point: 78° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7]O)(=[O:4])[CH:2]=[CH2:3].[C:9]1([C:19]([OH:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][CH:6]([O:20][C:19]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[O:21])[CH3:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCO
Reactant: O=C(O)c1cccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C=CC(=O)OC(C)OC(=O)c1cccc2ccccc12
Yield: 82.3 %

Procedure:
To a solution of 2-hydroxyethyl acrylate (1.01 g, 8.7 mmol) and 1-naphthoic acid (1.00 g, 5.8 mmol) in 10 ml of freshly distilled CH2Cl2 was added EDC (1.60 g, 8.7 mmol) and DMAP (cat. amount) at room temperature. The resultant mixture was stirred at room temperature until TLC indicated the disappearance of starting material. The reaction was quenched with a 5% solution of NH4Cl and the mixture was washed with water. After extraction with EtOAc (3×20 ml), the organic layers were dried over anhydrous MgSO4 and purified with column chromatography on silica gel (1:4, EtOAc:hexanes) to give 1.29 g (82%) of naphthalene-1-carbonyloxy-2-ethyl acrylate as a colorless oil. 1H NMR (250 MHz) δ 8.91 (d, J=8.4 Hz, 1H), 8.21 (d, J=7.1 Hz, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.57 (m, 3H), 6.49 (d, J=17.3 Hz, 1H), 6.19 (dd, J=17.3, 10.4 Hz, 1H), 5.71 (d, J=10.4 Hz, 1H), 4.66 (m, 2H), 4.58 (m, 2H). 13C NMR (63 MHz) δ 167.2, 165.9, 133.8, 133.6, 131.5, 131.3, 130.5, 128.6, 128.0, 127.8, 126.6, 126.2, 125.7, 124.5, 62.7, 62.3.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([OH:14])=O)[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:44][C@@H:45]([CH3:48])[CH2:46][OH:47]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:44][C@@H:45]([CH3:48])[CH2:46][OH:47])=[O:14])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: C[C@H](N)CO
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a cooled (0° C.) solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 1) (0.80 g, 1.77 mmol) in DMA (3.2 mL) was added isobutyl chloroformate (0.28 mL, 2.13 mmol) and 4-methylmorpholine (0.25 mL, 2.30 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added (S)-(+)-2-amino-1-propanol (0.21 mL, 2.66 mmol) and DMAP (0.02 g, 0.18 mmol). Stirred at ambient temperature overnight. Purified crude product by preparatory HPLC using a 10-90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=509) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a pale yellow foam (0.61 g, 67%). 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.92 (m, 1H), 7.76 (s, 1H), 7.61 (q, 1H, J=8.0 Hz), 7.52 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.60 (m, 2H), 4.16 (m, 1H), 3.57 (m, 2H), 2.19 (s, 3H), 1.22 (d, 3H, J=5.6 Hz). ESHRMS m/z 508.0666 (M+H calculated for C22H21BrF2N3O4 requires 508.0678).
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[O:1]([C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc([C@@H](C)O)cc1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)Oc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 54.6 %

Procedure:
To a solution of (R)-methyl 4-(1-hydroxyethyl)benzoate (0.9 g, 5 mmol), phenol (525 mg, 5.6 mmol), triphenylphosphine (2198 mg, 8.4 mmol) in tetrahydrofuran (30 mL) was added diisopropyl azodicarboxylate (1695 mg, 8.4 mmol) at 0° C. The mixture was stirred at 20° C. for 12 hours. Water (15 mL) was added to the mixture and then extracted with ethyl acetate (35 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give (S)-methyl 4-(1-phenoxyethyl)benzoate (700 mg, 54%). 1H NMR (300 MHz, d6-DMSO): δ 8.02-7.98 (m, 2H), 7.46-7.43 (m, 2H), 7.23-7.16 (m, 2H), 6.91-6.80 (m, 3H), 5.36 (q, J=6.0 Hz, 1H), 3.90 (s, 3H), 1.64 (d, J=6.6 Hz, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH:33][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([S:15](=[O:16])(=[O:17])[NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:26][CH:25]=1)[CH3:29]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1

Procedure:
The title compound was prepared from 4-(2-phenoxy-phenylsulfamoyl)-benzoic acid and glycine ethyl ester hydrochloride (Aldrich) according to the method described in Example 1.1/d. MS (EI) 455.2 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH3:11])[C:7](=[O:9])[CH:8]=1.CO[CH:14]=[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([Br:25])[CH:23]=2)[C:18](=[O:26])[NH:17][C:16]1=[O:27]>CN(C)C=O>[Br:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:26])[NH:17][C:16](=[O:27])[C:15]2=[CH:14][NH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH3:11])[C:7](=[O:9])[CH:8]=1
Reactant: COc1coc(CN)cc1=O
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: COc1coc(CNC=C2C(=O)NC(=O)c3ccc(Br)cc32)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-aminomethyl-5-methoxy-pyran-4-one (116 mg, 0.75 mmole), 4 mL of N,N-dimethylformamide and 4-methoxymethylene-6-bromo-4H-isoquinoline-1,3-dione (212 mg, 0.75 mmole) is stirred for one hour at ambient temperature. The reaction mixture is evaporated to dryness, dissolved in 7.5% methanol in chloroform passed through Florisil eluting with 7.5% methanol in chloroform. The eluate is evaporated, treated with acetonitrile, the resulting solid filtered and dried to give a light pink solid, 152 mg, (50%), mp 259-61° C. dec; MS (ES−): m/z 403 (M−H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[N:15]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:14]=2)=[N:5][C:6](S(C)(=O)=O)=[N:7][CH:8]=1)#[N:2].[CH:43]([NH2:46])([CH3:45])[CH3:44].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([C:3]1[C:4]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)[N:15]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:14]=2)=[N:5][C:6]([NH:46][CH:43]([CH3:45])[CH3:44])=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(NC(=O)OCc4ccccc4)cnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(NC(=O)OCc4ccccc4)cnc32)cc1
Yield: 81.6 %

Procedure:
Benzyl 3-(5-cyano-2-(methylsulfonyl)pyrimidin-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (0.826 g, 1.372 mmol) in THF (30 mL) was treated with isopropylamine (0.234 mL, 2.744 mmol, 2.0 Eq) and DIPEA (0.478 mL, 2.744mmol, 2.0 Eq) and allowed to heat at reflux for I hour. The mixture was concentrated in vacuo and purified by column chromatography (ISCO Companion™, 40 g column, 0-100% EtOAc/Petroleum ether) to give 0.651 g (82%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([F:16])=[CH:8][CH:7]=1)=[O:5].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:18][CH:3]([CH:2]([CH3:17])[CH3:1])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([F:16])=[CH:8][CH:7]=1)=[O:5]
Reactant: [Br-]
Reactant: CC(C)CC(=O)c1ccc(F)c2ccccc12
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(Br)C(=O)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-1-(4′-fluoronaphth-1-yl)butan-1-one (7 g) in anhydrous tetrahydrofuran (80 ml) was added phenyltrimethylammonium tribromide (11.5 g). The resulting mixture was stirred overnight at ambient temperature then partitioned between petroleum ether and water. The organic layer was separated, washed with water, brine, dried with sodium sulphate, filtered and evaporated in vacuo to yield crude 2-bromo-1-(4′-fluoronaphth-1-yl)-3-methylbutan-1-one. Sodium acetate (2.75 g) and anhydrous dimethylformamide (30 ml) were added and the resulting mixture was stirred at 80° C. for 5 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was back-extracted once with ethyl acetate. The combined organic layers were washed with water, brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound (4.8 g) was obtained following silica gel column chromatography of the residue in 30-100% dichloromethane in petroleum ether.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[C:15]([CH3:19])([CH3:18])[C:16]#[N:17].Cl[CH2:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23].O>CN(C=O)C>[CH:24]1([C:22](=[O:23])[CH2:21][O:14][C:12]2[CH:11]=[CH:10][C:9]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])=[C:8]([F:7])[CH:13]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(CCl)C1CCCC1
Reactant: CC(C)(C#N)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(OCC(=O)C2CCCC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.1 %

Procedure:
Potassium carbonate (3.1 g, 22 mmol) was added to a solution of 2-(2-Fluoro-4-hydroxy-phenyl)-2-methyl-propionitrile (1.0 g, 6.0 mmol) and 2-Chloro-1-cyclopentyl-ethanone (3.3 g, 22 mmol) in DMF (20 mL). The mixture was stirred at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with EtOAc (2×50 mL). The organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0-15% EtOAc in hexanes) to give the product (1.2 g, 75% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ: 1.57-1.93 (m, 14H), 3.10 (m, 1H), 4.64 (s, 2H), 6.65 (d, J=9.6 Hz, 2H), 7.37 (t, J=8.9 Hz, 1H).