Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]3[NH:16][CH:17]=[C:18]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[C:10]=23)[CH2:4]1.Br[CH2:26][CH2:27][O:28][CH3:29].CCN(C(C)C)C(C)C.O>CN(C=O)C>[Br:15][C:14]1[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][CH2:26][CH2:27][O:28][CH3:29])[CH2:4]2)=[C:10]2[C:18]([NH:19][C:20]([CH:22]3[CH2:23][CH2:24]3)=[O:21])=[CH:17][NH:16][C:11]2=[N:12][CH:13]=1
Reactant: COCCBr
Reactant: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCCN[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Temperature: 80 °C
Yield: 31 %

Procedure:
(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (0.100 g, 0.222 mmol; Example 29, Step C), 1-bromo-2-methoxyethane (0.0246 mL, 0.266 mmol), and DIEA (0.154 mL, 0.887 mmol, d 0.742) were placed in DMF (2 mL) and heated to 80° C. for 18 hours. The reaction was then poured into water and extracted with EtOAc. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-50% CH3CN/water). The product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(5-bromo-4-(3-(2-methoxyethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide (0.03 g, 30%). 1H NMR (400 MHz, D2O) δ 8.23 (s, 1H), 7.26 (s, 1H), 3.77-3.74 (m, 1H), 3.54-3.50 (m, 3H), 3.28-3.11 (m, 5H), 3.18 (s, 3H), 2.19-2.12 (m, 1H), 1.82-1.61 (m, 4H), 0.90-0.82 (m, 4H). LCMS (APCI+) m/z 436, 438 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=O)[C:7]2=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1cc(F)c2c(c1)C(=O)C(=O)N2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)c2[nH]ccc2c1
Temperature: 25 °C
Yield: 34.1 %

Procedure:
A solution of 7-fluoro-5-methylisatin (1.68 g, 9.43 mmol) in dry THF (50 mL) was added slowly to an ice cold, stirred suspension of LiAlH4 (1.18 g, 31 mmol) in dry THF (50 mL), refluxed for 2 h, cooled to room temperature then treated sequentially with H2O (1.2 mL), 15% NaOH (1.2 mL) and H2O (3 mL). The solution was filtered through a pad of Celite, washing the filter cake thoroughly with THF, the deep blue filtrate was concentrated in vacuo and purified by chromatography [SiO2; iso-Hexane:EtOAc (9:1)] to give the title compound (480 mg, 41%) as a pale blue oil; NMR δH (CDCl3) 8.19 (1H, br s), 7.21-7.16 (2H, m), 6.74 (1H, d, J 12.0 Hz), 6.51-6.46 (1H, m) and 2.42 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:43]([NH2:46])([CH3:45])[CH3:44].[Na+].[I-]>>[CH:43]([NH:46][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[C:27]5[CH2:35][CH2:34][NH:33][CH2:32][C:28]=5[N:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1)([CH3:45])[CH3:44]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(CCl)cc(C(F)(F)F)c3)c2)C1
Agent: [I-]
Agent: [Na+]
Product: CC(C)NCc1cc(NC(=O)n2ccc3cc(Oc4ncnc5c4CCNC5)ccc32)cc(C(F)(F)F)c1
Temperature: 45 °C

Procedure:
To a solution of the above mixture (0.15 g, 0.227 mmol) in 3 mL of DCM, isopropyl amine (0.06 mL, 0.680 mmol) is added followed by sodium iodide (0.1 g, 0.68 mmol). After 45 min, LC-MS shows that tert-butyl 4-(1-(3-((methylsulfonyloxy)methyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7 (8H)-carboxylate is converted to desired product and the tert-butyl 4-(1-(3-(chloromethyl)-5-(trifluoromethyl)phenylcarbamoyl)-1H-indol-5-yloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7 (8H)-carboxylate left over. To the reaction 3 mL (0.227 mmol) of isopropyl amine is added followed by NaI (0.1 g, 0.68 mmol) and the mixture is heated to 45° C. for 2 h. The solvent is then removed and the residue diluted with EtOAc, washed with H2O, brine and the organic layer dried over Na2SO4. Following concentration the residue is separated by FCC (25-100% EtOAc/heptane). This product is then treated with 60 mL of 50% TFA/DCM at rt for 1.5 h. After concentration the residue is separated by semi-prep HPLC (C-18; 10-100% I/H2O with 0.1% NH4OH) to provide the title compound. MS (ESI) m/z 525.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.13 (d, J=3.8 Hz, 1H), 7.95 (d, J=15.2 Hz, 2H), 7.38-7.52 (m, 2H), 7.11 (dd, J=9.0, 2.4 Hz, 1H), 6.78 (d, J=3.8 Hz, 1H), 3.81 (d, J=7.6 Hz, 4H), 3.03 (t, J=5.8 Hz, 2H), 2.68-2.79 (m, 3H), 1.03 (d, J=6.1 Hz, 6H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12]>>[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:16]=[C:14]([CH2:13][C:11]#[N:12])[S:15][CH:2]=1
Reactant: N#CCC(N)=S
Reactant: O=C(CBr)c1ccccn1
Product: N#CCc1nc(-c2ccccn2)cs1
Yield: 73 %

Procedure:
This compound was synthesized from 2-bromo-1-(pyridin-2-yl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (0.37 g, yield 73%): 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=5.5 Hz, 1H), 8.15 (m, 2H), 7.84 (t, J=8.4 Hz, 1H), 7.30 (m, 1H), 4.21 (s, 2H). MS (ESI) m/z: Calculated for C10H7N3S: 201.04. found: 202.2 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][O:13][C:14]1[CH:18]=[C:17]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: FC(F)Oc1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)F

Procedure:
In a similar manner as described for example B18, 207.7 mg of 2-(difluoromethoxy)benzyl bromide, 200 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate, 110.9 mg of potassium carbonate in 6 ml anhydrous DMF yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1([NH2:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(Br)c1[N+](=O)[O-]
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2ccccc2)c1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
A mixture of 1-bromo-3-methyl-2-nitrobenzene (1 g, 4.63 mmol), phenylamine (422 μL, 4.63 mmol), Cs2CO3 (2.11 g, 6.48 mmol) and (R)-BINAP (5 mol %, 143 mg, 0.23 mmol) in toluene (20 mL) was degassed with a stream of nitrogen prior to addition of Pd(OAc)2 (25 mg, 0.11 mmol) and was stirred at 110° C. under a nitrogen atmosphere for 18 h. After cooling to RT, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-35% DCM in cyclohexane) affording (3-Methyl-2-nitrophenyl)phenylamine as a red oil (931 mg, 88%). LCMS: RT 3.97 min [M+H]+ 229.1.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[CH:27][S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:24]=2)[NH:19][CH:18]=1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:31]([S:28]([CH2:27][CH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1)(=[O:30])=[O:29])[CH3:32]
Reactant: CCS(=O)(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Agent: [Pd]
Solvent: CCO
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Reaction time: 18 h
Yield: 62.4 %

Procedure:
A solution of 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-(2-ethylsulphonylethenyl)-1H-indole (Preparation 3; 160 mg, 0.35 mmol) in ethanol (5 ml) was hydrogenated over 10% palladium on charcoal (150 mg) at 15 p.s.i. (1.04 bar) and room temperature for 18 hours, and then filtered. Evaporation of the filtrate under reduced pressure yielded a foam which was purified by column chromatography on silica gel, eluting with a gradient of 0.880 aqueous ammonia: methanol:dichloromethane (0:10:90 to 1:10:90), to provide the title compound as a foam (70 mg). Rf 0.30 (SS 4). [α]D25 -11° (c=0.1, CH3OH). Found: C,63.13; H,7.37; N,8.55. C17H24N2O2S; 0.05 CH2Cl2 requires C,63.07; H,7.48; N,8.63%. δ(CDCl3): 1.35(3H,t), 1.65-1.90(5H,m), 2.70-3.10(6H,m), 3.25(4H,m), 3.35(1H,m), 5.25(0.10H,s, CH2Cl2), 6.98-7.04(2H,m), 7.22(1H,d), 7.45(1H,s), 8.12(1H,br s).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-:16].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13](=[O:15])[N:12]([CH2:1][C:4]3[CH:9]=[CH:8][C:7]([C:10]([O:14][CH3:13])=[O:16])=[CH:6][CH:5]=3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(-c2n[nH]c(=O)o2)cc1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(C(C)C)cc3)oc2=O)cc1
Yield: 184.5 %

Procedure:
5-(4-Isopropylphenyl)-1,3,4-oxadiazol-2(3H)-one (0.41 g, 2.0 mmol) is dissolved in dichloromethane (5 mL) and stirred vigorously with methyl 4-bromomethylbenoate (0.50 g, 2.2 mmol) in the presence of sodium hydroxide (1.25 N, 1.76 mL, 2.2 mmol) and tetra-n-butylammonium bromide (0.07 g, 0.022 mmol) at room temperature overnight. The solvent is removed in vacuum, and the residue is treated with water. The precipitate is collected by filtration, washed with hexanes thoroughly and dried in the air to provide methyl 4-{[5-(4-isopropylphenyl)-2-oxo-1,3,4-oxadiazol-3(2H)-yl]methyl}benzoate (0.65 g, 93%). (ES+): m/e 353.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Cl.[NH2:9][C:10](OCC)=[CH:11][C:12](OCC)=[O:13].CC[O-].[Na+]>C(O)C>[NH2:9][C:10]1[NH:7][C:5](=[O:6])[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:12](=[O:13])[CH:11]=1
Reactant: NC(=O)NC1CC1
Reactant: CCOC(=O)C=C(N)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(=O)n(C2CC2)c(=O)[nH]1
Yield: 55.9 %

Procedure:
A solution of cyclopropyl urea (10 g, 100 mmol, 1 eq) and ethyl 3-amino-3-ethoxy-acrylate HCl (19.55 g, 100 mmol, 1 eq) in Ethanol (125 ml) was heated at 75° C. for 2 hours. To this solution was added 2 equivalents of NaOEt then heated for an additional one hour. Solvent was evaporated, water (50 ml) was added then acidified via concentrated HCl to pH of 4-5. The resulting precipitate was obtained by filtration and washed with cold water to give the desired product (9.35 g, 56%) after vacuum dried overnight at 40° C.: The desired isomer was determined via 2D-NMR; 1H NMR (400 MHz, DMSO-d6) δ 10.18 (1H), 6.10 (2H), 4.44 (1H), 2.38 (1H), 0.85 (2H), 0.62 (2H); m/z (ES+) 168.17
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[Cl:18])(C)(C)C.Cl>O1CCOCC1.CCOCC>[Cl:18][C:9]1[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=1[CH2:7][C:6]([OH:19])=[O:5]
Reactant: CC(C)(C)OC(=O)Cc1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(O)Cc1ccc(C(F)(F)F)cc1Cl
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A solution of (2-chloro-4-trifluoromethylphenyl)-acetic acid tert-butyl ester (40 g, 135.7 mmol) in dioxane (100 mL) containing conc. HCl (31.3 mL) was stirred at 50° C. for 5 h. After cooling the mixture to r.t., it was diluted with Et2O and the organic layer was washed with H2O (3×). The organic phase was dried (MgSO4) and the solvent was removed in vacuo. Recrystallization of the residue with AcOEt-hexane yielded the title compound as a solid showing: 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.55 (dd, 1H, J=1.0, 8.0 Hz), 7.47 (d, 1H, J=8.0 Hz), 3.92 (s, 2H). MS (ESI) m/z 237 (M−H)−.
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.[CH3:16][N:17]([CH3:30])[C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]>CO>[CH3:30][N:17]([CH3:16])[C:18]1[CH:26]=[CH:25][C:21]([C:22]2[O:15][N:14]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=3)[N:1]=2)=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]
Reactant: CN(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Solvent: CO
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N(C)C)c([N+](=O)[O-])c3)n2)cc1F

Procedure:
The title compound was obtained following procedure described for example 4, step 1, but starting from Intermediate 1 (300 mg; 1.41 mmol) and Intermediate 35 (326.90 mg; 1.56 mmol). Title compound was isolated after trituration with MeOH as a brown powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.50 (d, J=2.1 Hz, 1H), 8.16 (dd, J=9.1, 2.2 Hz, 1H), 8.09 (d, J=7.2 Hz, 1H), 8.03 (dd, J=8.2, 1.5 Hz, 1H), 7.98-7.94 (m, 1H), 7.38 (d, J=9 Hz, 1H), 3.90 (s, 3H), 2.99 (s, 6H). LC/MS (Method B): 387.2 (M+H)+. HPLC (Method A) Rt. 5.07 min (purity: 98%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.Cl.[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]([NH2:41])[CH3:40].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]([NH:41][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=1)=[O:22])[CH3:40]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC(N)c1ncco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ncco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (210 mg, 0.48 mmol) and 1-oxazol-2-yl-ethylamine dihydrochloride (198 mg, 0.86 mmol). DMF (2.2 ml) was added followed by N,N-diisopropylethylamine (0.55 ml, 3.15 mmol) and HATU (199 mg, 0.52 mmol). The light yellow solution was stirred at room temperature overnight. Water was added and the resulting suspension was filtered. The solid was washed with water and petroleum ether then dried under high vacuum to afford 248 mg (97%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-oxazol-2-yl-ethyl)-amide as a light yellow powder.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[CH3:36]>>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([O:25][C:19]2[CH:20]=[CH:21][C:22]([F:24])=[C:23]3[C:18]=2[CH2:17][CH2:16][C@H:15]3[O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:2])=[O:26])[CH2:6][O:7][C:8]=3[CH:13]=2)=[C:29]([CH3:36])[CH:30]=1)#[N:33]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cc1cc(C#N)ccc1F
Product: Cc1cc(C#N)ccc1Oc1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-fluoro-3-methyl-benzonitrile following a procedure analogous to that described for Intermediate 12. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 2): tR=1.14 min; Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[OH:7][C:8]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].[C:23](OC=C)(=O)[CH2:24]C.C1(C(C2C=CC(OC=C)=CC=2O)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:12]1([C:10]([C:9]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:8]=2[O:7][CH:23]=[CH2:24])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: C=COC(=O)CC
Agent: C=COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=COc1cc(O)ccc1C(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (1.27 g, 1.9 mmol) and sodium carbonate (24.9 g, 0.23 mol)) in toluene (280 ml) were added 2,4-dihydroxybenzophenone (40 g, 0.19 mol) and vinyl propionate (75.1 g, 0.75 mol), followed by stirring at 100° C. in an atmosphere of argon gas for 3 hours. The reaction mixture was analyzed by gas chromatography to find that 2-hydroxy-4-vinyloxyphenyl phenyl ketone [i.e., 2-hydroxy-4-vinyloxyphenyl(phenyl)methanone] and 4-hydroxy-2-vinyloxyphenyl phenyl ketone [i.e., 4-hydroxy-2-vinyloxyphenyl(phenyl) methanone] were formed in yields of 90% and 2%, respectively, with a conversion from 2,4-dihydroxybenzophenone of 99%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:34][C:33](=[O:35])[N:32]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]4[N:47]=[CH:46][N:45]=[C:44]([C:48]([OH:50])=O)[CH:43]=4)[CH2:38][CH2:37]3)[CH2:31][CH2:30][C:29]=2[CH:51]=1.Cl.Cl.[C:54]1([C:60]2[C:64]3[CH2:65][NH:66][CH2:67][CH2:68][C:63]=3[NH:62][N:61]=2)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C.CO>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:34][C:33](=[O:35])[N:32]([CH:36]3[CH2:37][CH2:38][N:39]([C:42]4[CH:43]=[C:44]([C:48]([N:66]5[CH2:67][CH2:68][C:63]6[NH:62][N:61]=[C:60]([C:54]7[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=7)[C:64]=6[CH2:65]5)=[O:50])[N:45]=[CH:46][N:47]=4)[CH2:40][CH2:41]3)[CH2:31][CH2:30][C:29]=2[CH:51]=1
Reactant: c1ccc(-c2n[nH]c3c2CNCC3)cc1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5[nH]nc(-c6ccccc6)c5C4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
90 mg (0.24 mmol) TBTU were added to 80 mg (0.20 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 75 mg (0.28 mmol) 3-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride, 120.0 μL (0.86 mmol) triethylamine in 0.9 mL DMF and stirred overnight at RT. The reaction mixture was combined with 1 mL methanol, 1 mL saturated sodium hydrogen carbonate solution and 8 mL ice water. The precipitate was suction filtered, washed with water and diethyl ether and dried.
Reaction SMILES: C[O-].[Na+].[C:4]([NH:7][CH2:8][CH:9]1[O:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]([C:28]4[CH:33]=[CH:32][C:31]([O:34]S(C)(=O)=O)=[CH:30][CH:29]=4)[C:24](=[O:27])[NH:25][N:26]=3)=[C:17]([F:39])[CH:16]=2)[CH2:10]1)(=[O:6])[CH3:5].C(O)(=O)C>CO>[F:39][C:17]1[CH:16]=[C:15]([N:11]2[CH2:10][C@H:9]([CH2:8][NH:7][C:4](=[O:6])[CH3:5])[O:13][C:12]2=[O:14])[CH:20]=[CH:19][C:18]=1[C:21]1[S:22][CH:23]([C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)[C:24](=[O:27])[NH:25][N:26]=1
Reactant: CC(=O)NCC1CN(c2ccc(C3=NNC(=O)C(c4ccc(OS(C)(=O)=O)cc4)S3)c(F)c2)C(=O)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)C(c4ccc(O)cc4)S3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
25% Sodium methoxide solution in methanol (0.027 ml, 0.117 mmol) is added to methanesulfonic acid 4-(2-{4-[5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluorophenyl}-5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-6-yl)-phenyl ester (0.050 g, 0.0932 mmol) in methanol (2 ml) and the mixture is stirred at room temperature overnight. The reaction mixture is neutralized with acetic acid (0.020 ml), evaporated to dryness and the residue is purified by PTLC (10% MeOH/DCM) to give product as a white solid (0.039 g, 92%); 1H NMR (300 MHz, DMSO-d6) δ 1.80 (s, 3H), 3.40-3.45 (bs, 2H), 3.74 (dd, J=6.9, 10.5 Hz, 1H), 4.12 (t, J=9.3 Hz, 1H), 4.70-4.79 (m, 1H), 4.98 (s, 3H), 6.73 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.7 Hz, 1H), 7.37 (dd, J=1.8, 8.7 Hz, 1H), 7.55-7.60 (m, 2H), 8.25 (t, J=5.7 Hz, 1H); mp >200 (decomp.); MS (m/z): [M+H]+=459.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[CH3:10][CH:11]([C:17](OCC)=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH:4][C:17](=[O:18])[CH:11]([CH3:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Nc1cc(F)ccc1F
Reactant: CCOC(=O)C(C)C(=O)OCC
Product: CCOC(=O)C(C)C(=O)Nc1cc(F)ccc1F

Procedure:
Prepared according to Procedure A using 2,5-difluoroaniline (5.00 g, 38.7 mmol) and diethyl 2-methylmalonate to give ethyl 3-(2,5-difluorophenylamino)-2-methyl-3-oxopropanoate. Mass Spectrum (ESI) m/e=258.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:24])=[C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)(=[O:13])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].C[Li].[CH3:27]COCC>C1COCC1>[Cl:24][C:7]1[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:27])[CH3:2])=[CH:9][C:8]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)(=[O:13])=[O:12]
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C(C)=O)ccc2Cl)cc1OC
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cc(C(C)(C)O)ccc2Cl)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of N-(5-acetyl-2-chloro-phenyl)-3,4-dimethoxy-benzenesulfonamide (1.4 g, 3.8 mmol) in THF (16 mL) at −78° C. was added dropwise a solution of methyl lithium in ether (1.6 M, 6.5 mL, 2.75 eq). The mixture was stirred at −78° C. for 30 min and then allowed to warm to RT. The mixture was partitioned between EA and NH4Cl solution, the aqueous phase was once more extracted with EA and the combined organic layers were dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (hex/EA 2:1, 1:1) to give the desired product (0.97 g, 67%) as a yellowish foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[C:10]2([CH2:18][CH2:17][CH2:16]C2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC(CO)C2(CCCCC2)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[C:10]2([CH2:16][CH2:17][CH2:18]2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C2(CCCC2)C1
Agent: CC(C)(C)OC(=O)N1CC(CO)C2(CCCCC2)C1
Product: CC(C)(C)OC(=O)N1CC(CO)C2(CCC2)C1

Procedure:
In the similar procedure, 2-tert-butoxycarbonyl-4-hydroxymethyl-2-azaspiro[4.4]nonane (compound 105) (1H-NMR (CDCl3) δppm: 1.46 (9H, s), 1.61 (8H, s), 3.0-3.9 (7H, m)) and 2-tert-butoxycarbonyl-4-hydroxymethyl-2-azaspiro[4.5]decane (compound 107)