Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:22]2[C:17](=[CH:18][C:19](Br)=[CH:20][CH:21]=2)[C:16]=1[O:27][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:35](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:24]([CH3:25])=[CH:23][C:22]2[C:17](=[CH:18][C:19]([CH3:35])=[CH:20][CH:21]=2)[C:16]=1[O:27][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:30])=[O:29])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2ccc(Br)cc2c(OS(=O)(=O)C(F)(F)F)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc2cc(C)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2c1
Temperature: 125 °C

Procedure:
To a solution of (S)-2-(7-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyethyl pivalate (825 mg, 1.45 mmol) in 1,4-dioxane (7 mL) was added potassium carbonate (601 mg, 4.35 mmol), trimethylboroxine (220 mg, 1.74 mmol), and PdXPhos catalyst (107 mg, 0.145 mmol). The mixture was heated in a sealed vial in the microwave at 125° C. for 1 h. The mixture was filtered and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the desired product. 1H-NMR: 400 MHz, (CDCl3) δ: 7.84 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.62 (s, 1H), 7.36 (d, J=8 Hz, 1H), 5.48 (dd, J=9, 3 Hz, 1H), 4.65 (dd, J=12, 9 Hz, 1H), 4.16 (dd, J=12, 3 Hz, 1H), 2.75 (s, 3H), 2.54 (s, 3H), 1.23 (s, 9H) 1.12 (s, 9H).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl.[OH-].[K+]>>[OH:13][CH2:12][CH:11]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2][CH2:9]1
Reactant: Oc1ccccc1O
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Product: OCC1COc2ccccc2O1

Procedure:
0.5 mole of pyrocatechol were stirred vigorously with 1.5 moles of epichlorohydrin and 1 mole of 10% strength aqueous potassium hydroxide solution at 100° C. After the mixture had been cooled, it was extracted with ether, the ether extract was washed with dilute potassium hydroxide solution and water, dried and evaporated and the product was recrystallized from ethanol. Melting point: 87°-90° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[NH:11][NH2:12].[CH3:13][CH2:14][C:15](=O)[CH2:16][C:17](=O)[CH2:18][CH3:19].C(N(CC)CC)C>C(O)C>[CH2:14]([C:15]1[CH:16]=[C:17]([CH2:18][CH3:19])[N:11]([C:4]2[C:3]([CH3:2])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=2[CH3:10])[N:12]=1)[CH3:13]
Reactant: CCC(=O)CC(=O)CC
Reactant: Cc1cc(C)c(NN)c(C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1cc(CC)n(-c2c(C)cc(C)cc2C)n1
Yield: 95 %

Procedure:
A solution of 7.46 g (0.04 mol) of 2,4,6-trimethylphenylhydrazine hydrochloride, 5.12 g (0.40 mol) of 3,5-heptanedione and 4.18 mL (0.60 mol) of triethylamine in 100 mL of absolute ethanol was refluxed overnight. The solvent was evaporated from the cooled reaction mixture and the residues were partitioned between water and ethyl acetate. The organic extracts were dried with brine and magnesium sulfate, and the solvent was evaporated to give the desired product in 95% yield. This compound was used in the subsequent reaction without further purification 1H-NMR (CDCl3): 11 (3H, t, J=7),1.24 (3H, t, J=7),1.90 (6H, s), 2.22 (2H, q, J-7), 2.28 (3H, 5.96 (1H, s), 6.86 (2H, s).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17][N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2cccnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
To a suspension of sodium hydride (934 mg, 0.0358 mol) in DMF (57 mL) was added dropwise under N2, a solution of 1H-pyrrolo[2,3-b]pyridine (3.00 g, 0.0254 mol) in DMF (20 mL). The mixture was stirred at r.t. for 45 min. then cooled to 0° C. and treated dropwise with [2-(trimethylsilyl)ethoxy]methyl chloride (6.32 mL, 0.0357 mol). The mixture was stirred at rt for 12 h. then poured into water (10 mL), stirred for 30 min. and extracted with Et2O (4×10 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product which was chromatographed over silica gel eluting with hexane→1:9 Et2O: hexane to afford 6 g desired product.
Reaction SMILES: [C@H:1]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>CN(C=O)C>[C:36]([NH:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C@H:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][O:2]3)[CH2:14][CH2:15]2)=[CH:20][CH:21]=1)(=[O:27])=[O:26])(=[O:38])[CH3:37]
Reactant: NS(=O)(=O)c1ccc(N2CCN(CC[C@@H]3OCCc4ccccc43)CC2)cc1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NS(=O)(=O)c1ccc(N2CCN(CC[C@@H]3OCCc4ccccc43)CC2)cc1
Reaction time: 1 h

Procedure:
(S)-(-)-4-[4-[2-(Isochroman-1-yl)ethyl]piperazin-1-yl]benzenesulfonamide (EXAMPLE 49, 0.203 g) is stirred in DMF (2 ml) and triethylamine (0.211 ml) and acetyl chloride (0.108 ml) is added. The mixture is stirred at 20°-25° for one hr and then at 50° for 4 days. After cooling, the mixture is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phases are dried over sodium sulfate, concentrated, and the residue is chromatographed (silica gel; ethyl acetate/dichloromethane (20/80)) to give the title compound after crystallization from methanol/dichloromethane/hexane, mp 160°-161°; MS (m/z) 443; IR (mineral oil) 1593, 1157, 1094, 1136 and 1109 cm-1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]>>[C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[N:29]=4)=[CH:24][CH:23]=3)[CH:16]=2)[NH:11][CH:10]=1)#[N:8]
Reactant: C1COCCN1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(N5CCOCC5)n4)cc3)cc12

Procedure:
Using morpholine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 2.98 (bt, 2H, J=7 Hz); 3.56 (m, 2H); 3.70 (bs, 4H); 3.79 (bs, 4H); 7.18 (d, 1H, J=9 Hz); 7.32 (d, 1H, J=5 Hz); 7.49 (m, 2H); 7.94 (d, 2H, J=8 Hz); 8.22 (m, 3H); 8.50 (d, 1H, J=5 Hz); 8.74 (bt, 1H); 12.20 (bs, 1H). MS (ion spray) m/z 453 (M+H)+.
Reaction SMILES: N1CCCCC1.[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[CH:16]([C:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20])([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:20])[CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Cc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(C)C(=O)C(=Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
0.9 ml of piperidine is added to 24.8 g (0.2 mol) of 4-fluorobenzaldehyde and 32.4 g (0.2 mol) of benzyl isopropyl ketone in 150 ml of toluene and the mixture is heated to reflux overnight. After cooling to room temperature, the mixture is extracted several times using water and the organic phase is dried over magnesium sulphate and concentrated in vacuo. The residue is subjected to incipient distillation up to a bath temperature of 150° C. at 0.1 mbar in a high vacuum and 43.8 g of crude product are obtained in the distillation residue.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.CC1C=CC2C=CC3C=C[C:32](C)=[N:33]C=3C=2N=1.CN>CN(C=O)C.C1COCC1.[Cu]I>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]2[C:5]3[CH:6]=[CH:7][C:2]([NH:33][CH3:32])=[CH:3][C:4]=3[O:21][CH:9]2[CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc2ccc3ccc(C)nc3c2n1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OC2C1
Agent: [Cu]I
Agent: CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNc1ccc2c(c1)OC1CN(C(=O)OC(C)(C)C)CCC21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Anhydrous DMF was sparged with argon gas for 1 h before being used. Tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate (1 g, 2.5 mmol) sodium tert-butoxide (723 mg, 7.5 mmol), neocuproine (52 mg, 0.25 mmol) and copper (I) iodide (290 mg, 1.5 mmol) were dissolved in anhydrous DMF (20 mL). To this mixture was added a 2M solution of methylamine in THF (6 mL) and the reaction shaken at 80° C. for 16 h. The solvent was evaporated and the residue dissolved in DCM and washed with H2O (3×). The solvent was evaporated and the crude residue used as such in the next reaction step.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][NH2:27])=[CH:16]1.C(OCC)(=O)C>CS(C)=O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][CH2:26][NH:27][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=2[NH2:14])=[CH:16]1
Reactant: NCCCc1c[nH]c2ccccc12
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1c(OCCNCCCc2c[nH]c3ccccc23)cccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 68.3 %

Procedure:
A solution containing 2-(2-chloro-ethoxy)-6-nitro-phenylamine (4.1 g, 19 mmol) and 3-(1H-indol-3-yl)-propylamine (7.1 g, 40.8 mmol) in anhydrous dimethylsulfoxide (50 ml) was heated at 60° C. for 12 hours. Ethyl acetate (200 ml) was added and the mixture was washed with saturated sodium bicarbonate (3×200 ml) and brine (200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product. Purification by chromatography (ethyl acetate:hexanes:2N ammonia methanol=25:25:1) afforded 4.6 g (68.9%) of the product as a yellowish red viscous oil; MS EI m/e 354 (M+).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].O.O.O.O.C([O-])(=[O:13])C.[Mn+2:15].C([O-])(=O)C>O>[OH2:3].[OH2:13].[C:1]([O-:6])(=[O:5])[C:2]([O-:4])=[O:3].[Mn+2:15]
Reactant: CC(=O)[O-]
Reactant: O=C(O)C(=O)O
Agent: [Mn+2]
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 10 l four-neck round-bottom flask with a stirrer, thermometer and reflux condenser was initially charged with 176.0 g (1.95 mol) of oxalic acid in 4200 ml of water, and the resulting solution was admixed dropwise at room temperature with a solution of 318.6 g (1.30 mol) of manganese(II) acetate tetrahydrate in 2100 ml of water, and stirred for a further 15 min after the addition had ended. Subsequently, the reaction mixture was heated to reflux and stirred for a further 30 min. After cooling to room temperature, the white precipitate was filtered off with suction, washed three times with 200 ml of water each time and dried in a vacuum drying cabinet at room temperature overnight.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[N:29][CH:28]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:31]3[CH:32]=[N:27][CH:28]=[N:29][CH:30]=3)[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1Br
Reactant: OB(O)c1cncnc1
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 169 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((2-hydroxyethyl)(methyl)amino)nicotinamide (Stage 179.1) and pyrimidin-5-ylboronic acid to afford a white crystalline solid. HPLC (Condition 4) tR=5.02 min, UPLC-MS (Condition 3) tR=0.96 min, m/z=450.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.69 (s, 3H) 3.38-3.65 (m, 4H) 4.67 (t, J=5.08 Hz, 1H) 7.34 (d, J=8.21 Hz, 2H) 7.85 (d, J=8.99 Hz, 2H) 8.13 (d, J=2.35 Hz, 1H) 8.75 (d, J=1.56 Hz, 1H) 8.95 (s, 2H) 9.17 (s, 1H) 10.22 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CCCC[C@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 90.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (98.0 mg, 0.159 mmol) prepared in Example 167c, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (67.0 mg, 90%) as a colorless solid.
Reaction SMILES: C(OCC1C(N2CCN3C4CCCCC=4C=C3C2=O)=CC=CC=1C1C=C(NC2C=CC(F)=CN=2)C(=O)N(C)C=1)(=O)C.[C:42]([O:45][CH2:46][C:47]1[C:52](B2OC(C)(C)C(C)(C)O2)=[CH:51][C:50]([F:62])=[CH:49][C:48]=1[N:63]1[CH2:74][CH2:73][C:72]2[C:71]3[CH2:70][C:69]([CH3:76])([CH3:75])[CH2:68][C:67]=3[S:66][C:65]=2[C:64]1=[O:77])(=[O:44])[CH3:43].Br[C:79]1[N:80]=[C:81]([NH:87][C:88]2[CH:89]=[C:90]3[C:95](=[CH:96][CH:97]=2)[CH2:94][N:93]([CH:98]2[CH2:101][O:100][CH2:99]2)[CH2:92][CH2:91]3)[C:82](=[O:86])[N:83]([CH3:85])[CH:84]=1>>[C:42]([O:45][CH2:46][C:47]1[C:52]([C:79]2[N:80]=[C:81]([NH:87][C:88]3[CH:89]=[C:90]4[C:95](=[CH:96][CH:97]=3)[CH2:94][N:93]([CH:98]3[CH2:99][O:100][CH2:101]3)[CH2:92][CH2:91]4)[C:82](=[O:86])[N:83]([CH3:85])[CH:84]=2)=[CH:51][C:50]([F:62])=[CH:49][C:48]=1[N:63]1[CH2:74][CH2:73][C:72]2[C:71]3[CH2:70][C:69]([CH3:75])([CH3:76])[CH2:68][C:67]=3[S:66][C:65]=2[C:64]1=[O:77])(=[O:44])[CH3:43]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C2COC2)C3)c1=O
Agent: CC(=O)OCc1c(-c2cc(Nc3ccc(F)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C3COC3)C4)n2)cc(F)cc1N1CCc2c(sc3c2CC(C)(C)C3)C1=O

Procedure:
Following the procedures as described for 148b and starting with 247b and 305 mg of 222a, 277 mg of 249a was obtained as a yellow solid (51%). MS: [M+H]+ 698.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH3:19])[CH:3]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Br:20]N1C(=O)CCC1=O>ClCCl>[Br:20][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH:3]([CH:2]([CH3:1])[CH2:18][CH3:19])[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])=[CH:12][CH:13]=1
Reactant: CCC(C)C(C(=O)OC(C)(C)C)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCC(C)C(C(=O)OC(C)(C)C)c1ccc(CBr)cc1

Procedure:
15 g (59.1 mmol) of tert-butyl 3-methyl-2-(4-methylphenyl)pentanoate, 11 g (62 mmol) of N-bromosuccinimide and 97 mg (0.59 mmol) of 2,2′-azobis-2-methylpropanenitrile in 150 ml of dichloromethane were stirred under reflux for 2 h. After the reaction had gone to completion, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 16.22 g (47.5 mmol, 80% of theory) of a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([N+:16]([O-])=O)[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[N:4]1)[CH3:2]>CO.O.[Pd]>[NH2:16][C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:11]2[C:6]=1[CH:5]=[N:4][N:3]2[CH2:1][CH3:2]
Reactant: CCn1ncc2c([N+](=O)[O-])cc(C(=O)OC)cc21
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCn1ncc2c(N)cc(C(=O)OC)cc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a solution of methyl 1-ethyl-4-nitro-1H-indazole-6-carboxylate (D198) (2.2 g, 8.8 mmol, 1 equiv) in MeOH (100 ml) and H2O (10 ml) was added 10% palladium on charcoal (50% wet, 700 mg, 16% w/w) and the resulting mixture was stirred at 60° C. for 30 min then cooled to room temperature. The catalyst was removed by filtration through a pad of celite and most of the solvent removed in vacuo. The residue was partitioned between AcOEt and a saturated aqueous NaHCO3 solution and the two layers were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was triturated with iso-hexane to give methyl 4-amino-1-ethyl-1H-indazole-6-carboxylate (D199) (1.55 g, 80%) which was used in the next step without further purification. [M+H]+=220.1, RT=3.31 min.
Reaction SMILES: [CH3:1][O-:2].[Na+].C([C@H]1COC(=O)N1[C:17](=[O:40])[C@@H:18]([O:37][CH2:38][CH3:39])[C@@H:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][C:22]=1[CH2:35][CH3:36])[OH:20])C1C=CC=CC=1>CO>[CH3:1][O:2][C:17](=[O:40])[C@@H:18]([O:37][CH2:38][CH3:39])[C@@H:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:23][C:22]=1[CH2:35][CH3:36])[OH:20]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1CC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1CC
Temperature: 0 °C
Yield: 64.5 %

Procedure:
A 5.4 M solution of sodium methoxide (640 μl, 3.5 mmol) was added to an ice-cooled and stirred suspension of (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-ethyl-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one (1.58 g, 3.1 mmol) in dry methanol (9 ml). The mixture was stirred at 0° C. for 15 min, quenched and neutralized by the addition of dilute aqueous hydrochloric acid (1.0 M). The solution was concentrated under reduced pressure and the residue dissolved in ice water/ethyl acetate 1/1. The layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with ice water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 730 mg (2.0 mmol, 65%) of the title compound as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[NH:19][CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[C:23](O)(=[O:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[N:19]([C:23](=[O:25])[CH3:24])[CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1c2cc[nH]c2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Reactant: CC(=O)O
Product: CC(=O)n1ccc2c1CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl)-methanone is reacted with acetic acid to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[C:13]1([O:19][CH2:20][CH:21]2[O:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CS(C)=O>[OH:23][CH:21]([CH2:20][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:22][NH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: NCCCc1ccc(C(N)=O)s1
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(CCCNCC(O)COc2ccccc2)s1

Procedure:
921 mg of 5-(3-aminopropyl)-2-thiophenecarboxamide and 0.68 ml of 2,3-epoxypropyl phenyl ether were heated to 90° in 15 ml of dimethylsulfoxide for 14 hours. The reaction mixture was poured into water and extracted with methylene chloride. The dried methylene chloride solutions were evaporated in vacuo and the residue was chromatographed on silica gel, whereby there were obtained 800 mg of 5-[3-[[(RS)-2-hydroxy-3-phenoxypropyl]amino]propyl]-2-thiophenecarboxamide, m.p. 129°-130°, ε276 =12130.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][S:19]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:21])=[O:20]
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCCC3)cs2)C1
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a solution of 3-hydroxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (290 mg, 1.14 mmol) (obtained as described in Reference Example 26(2)) in methylene chloride (9 ml) were added methanesulfonyl chloride (0.30 ml, 5.12 mmol) and triethylamine (0.70 ml, 5.12 mmol) in an ice bath, and the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (1:1)→ethyl acetate as the eluant to afford 3-methanesulfonyloxy-1-(4-pyrrolidinocarbonyl-1,3-thiazol-2-yl)azetidine (335 mg, yield 89%) as a pale yellow solid.
Reaction SMILES: [OH-].[Na+].[CH:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[CH3:14]>CCO.O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[O:12])[CH:14]=[CH:13][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
Step A Add 10% aqueous NaOH (38 mL) to a solution of p-anisaldehyde (25 mL, 0.206 mol) and acetophenone (23.97 mL, 0.206 mol) in EtOH (500 mL). Stir the mixture at room temperature over night. Dilute the mixture with water and extract with ether. Combine the ethereal extracts, wash with water and brine, dry over Na2SO4 and concentrate to a solid. Recrystallize the solid from ether/hexanes to provide 27.51 g (56%) of 4'-methoxychalcone, mp 72°-74° C.