Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>C=Cl.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:15][S:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])(=[O:34])=[O:33])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Oc1cccc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Oc1cccc(OCc2ccccc2)c1)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 3-benzyloxyphenol (2.97 g, 15 mmol), as prepared in the preceding step, in methylene chlorine (50 mL) at 0° C., was added N,N-diisopropylethylamine (2 mL) and 2-chlorobenzenesulfonyl chloride (3.27 g, 15.5 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (200 mL), washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a colorless liquid (5.35 g, 95%). 1H-NMR (300 MHz, CDCl3) δ 4.97 (s, 2H), 6.71 (dd, 1H), 6.78 (t, 1H), 6.85 (dd, 1H), 7.17 (t, 1H), 7.37 (m, 5H) 7.58 (m, 2H), 7.91 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:14][CH:15]3[CH2:20][CH2:19][N:18](C(OCC)=O)[CH2:17][CH2:16]3)OCC[O:10]2)[CH:6]=[CH:7][CH:8]=1.[BrH:26].CC(O)C>O>[BrH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:10])[CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1CCC(CC2(c3cccc(OC)c3)OCCO2)CC1
Agent: Br
Solvent: CC(C)O
Solvent: O
Product: COc1cccc(C(=O)CC2CCNCC2)c1
Yield: 30 %

Procedure:
A mixture of 30 parts of ethyl 4-[2-(3-methoxyphenyl)-1,3-dioxolan-2-ylmethyl]-1-piperidinecarboxylate, 225 parts of a hydrobromic acid solution 48% in water and a small amount of 2-propanol is stirred and refluxed for 2 hours. The reaction mixture is cooled. The precipitated product is filtered off and dried, yielding 9.5 parts (30%) of 1-(3-methoxyphenyl)-2-(4-piperidinyl)ethanone hydrobromide.
Reaction SMILES: [CH:1]12[CH2:7][C:4]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][N:13]=[CH:12]4)([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[CH:18]([C:20]1[CH:21]=[CH:22][C:23]([CH3:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)=O>>[NH:14]1[C:15]2[C:11](=[CH:10][C:9]([NH:8][C:4]34[CH2:7][CH:1]([CH2:6][CH2:5]3)[N:2]([CH2:18][C:20]3[CH:21]=[CH:22][C:23]([CH3:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=3)[CH2:3]4)=[CH:17][CH:16]=2)[CH:12]=[N:13]1
Reactant: c1cc2[nH]ncc2cc1NC12CCC(C1)NC2
Reactant: Cc1ccc(C=O)cc1NS(C)(=O)=O
Product: Cc1ccc(CN2CC3(Nc4ccc5[nH]ncc5c4)CCC2C3)cc1NS(C)(=O)=O

Procedure:
Reaction of Intermediate 25 with N-(5-formyl-2-methylphenyl)methanesulfonamide affords the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([N:18]3[CH:22]=[C:21]([C:23]4[C:24]5[CH:31]=[CH:30][NH:29][C:25]=5[N:26]=[CH:27][N:28]=4)[CH:20]=[N:19]3)[CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)[C:3]=1[CH3:32].[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH:33]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([N:18]3[CH:22]=[C:21]([C:23]4[C:24]5[CH:31]=[CH:30][NH:29][C:25]=5[N:26]=[CH:27][N:28]=4)[CH:20]=[N:19]3)[CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)[C:3]=1[CH3:32])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1c(Cl)ncnc1N1CCC(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Reactant: Nc1ccccc1
Product: Cc1c(Nc2ccccc2)ncnc1N1CCC(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Yield: 35.2 %

Procedure:
A solution of 3-[1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.0081 g, 0.018 mmol) in Aniline (95 uL, 1.0 mmol) was heated at 180° C. for 2.5 hours. The reaction was purified by preparative-LCMS (pH 10) to give 3.2 mg white solid (35% yield). 1H NMR (400 MHz, DMSO): δ 12.05 (1H, br); 8.77 (1H, s); 8.61 (1H, s); 8.58 (1H, s); 8.15 (1H, s); 8.1 (1H, s); 7.55 (1H, d); 7.53 (2H, m); 7.2 (2H, t); 6.92 (1H, d); 6.9 (1H, m); 4.57 (1H, m); 3.6 (1H, m); 3.45 (1H, m); 3.27 (2H, m); 2.7 (1H, m); 2.58 (1H, m); 2.02 (1H, m); 1.98 (3H, s); 1.85 (1H, m); 1.3 (2H, m); 1.01 (1H, m). LCMS (M+1): 505.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@H:15]1[CH2:19][N:18](C(OC(C)(C)C)=O)[C@H:17]([C:27]([O:29][CH3:30])=[O:28])[CH2:16]1)=[O:13])[CH2:7]2)=[CH2:2].[ClH:31]>CCOC(C)=O>[ClH:31].[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@@H:15]1[CH2:16][C@@H:17]([C:27]([O:29][CH3:30])=[O:28])[NH:18][CH2:19]1)=[O:13])[CH2:7]2)=[CH2:2]
Reactant: C=Cc1cccc2c1CN(C(=O)O[C@@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: C=Cc1cccc2c1CN(C(=O)O[C@H]1CN[C@H](C(=O)OC)C1)C2
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 1-tert-butyl 2-methyl (2S,4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (13.9 g, 33.4 mmol) in EtOAc (700 mL) was cooled in an ice bath then saturated with hydrogen chloride gas. The reaction flask was sealed and allowed to warm to RT. After 3.5 h the solvent was removed by evaporation to give the title compound as a gray solid, 11.2 g, 95% yield). 1H NMR (500 MHz, ppm, CD3OD) δ 7.47-7.45 (m, 1H), 7.32-7.31 (m, 1H), 7.26-7.21 (m, 1H), 6.79-6.73 (m, 1H), 5.79-5.73 (m, 1H), 5.46 (s, 1H), 5.41-5.38 (m, 1H), 4.80-4.72 (m, 4H), 3.91 (s, 3H), 3.74-3.63 (m, 2H), 2.77-2.71 (m, 1H), 2.51-2.46 (m, 1H). LRMS (ESI) m/z 317 [(M+H)+; calcd for C17H21N2O4: 317].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>[Cu]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CS(=O)(=O)c1ccc(I)cc1
Agent: [Cu]
Product: CS(=O)(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 120 °C

Procedure:
A mixture of 4-methanesulphonyliodobenzene (18 g), 2-bromonitrobenzene (12.7 g) and copper powder (12 g) was heated at 120° C. for 30 hours to yield a residue which was purified by chromatography on a silica column eluted successively with 5:95 mixture, a 10:90 mixture, a 25:75 mixture and then a 40:60 mixture of ethylacetate and hexane to give 4'-methanesulphonyl-2-nitrobiphenyl (m.p. 178° C.). 4'-methanesulphonyl-2-nitrobiphenyl (5 g) was heated at 90°-95° C. for 6 hours with hydrated sodium sulphide (17.3 g) and ethanol (100 ml) to give 2-amino-4'-methanesulphonylbiphenyl (m.p. 164°-165° C.).
Reaction SMILES: S(C)C.[CH:4]([Li])([CH3:6])[CH3:5].[C:8]([NH:27][C@H:28]([CH2:31][CH3:32])[CH:29]=[O:30])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH4+].[Cl-]>CCOCC>[CH3:5][CH:4]([CH:29]([OH:30])[C@H:28]([NH:27][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:31][CH3:32])[CH3:6]
Reactant: [Li]C(C)C
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CSC
Solvent: CCOCC
Product: CC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(O)C(C)C
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (1.37 g, 2.2 eq, 6.66 mmol) in Et2O (100 mL) under an argon atmosphere at −78° C., was added isopropyllithium (0.7 M in pentane, 17.29 mL, 4 eq, 12.1 mmol) dropwise, and the solution allowed to warm to room temperature. The mixture was recooled to −70° C., to which was added a solution of (R)-2-(trityl-amino)-butyraldehyde (1 g, 1 eq, 3.03 mmol) in Et2O (25 mL) dropwise with stirring. The reaction mixture was stirred at this temperature for 1 h, then allowed to warm to −55° C. and stirred at this temperature for 3 h. To the reaction mixture was added a saturated aqueous solution of NH4Cl (100 mL) and allowed to warm to room temperature over 16 h. The reaction mixture was extracted with Et2O (2×200 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel gradient column chromatography, eluted with hexane:ether (100:0→90:10) to afford the title compound as a colourless oil. Yield: 0.53 g (47%). (50% de 3S,4R: 50% de 3R,4R) 1H-NMR (d6-DMSO, 250 MHz): δ 0.44 (t, 3H, J=7.03 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 0.52 & 0.77 (2×d, 6H, J=6.48 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 0.79-1.13 (m, 2H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 1.72 (m, 1H, —NHCH(CH2CH3)CH(CH (CH3)2)OH), 2.11 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 2.77 (m, 1H, —NH CH(CH2CH3)CH(CH(CH3)2)OH), 2.99 (m, 1H, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 4.55 (d, 1H, J=5.21 Hz, —NHCH(CH2CH3)CH(CH(CH3)2)OH), 7.15-7.46 (m, 15H, 3×Ph).
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15].C(=O)(O)[O-].[Na+]>O>[F:10][C:11]([F:21])([F:20])[C:12]1[C:5]2[C:3](=[C:2]([CH3:1])[C:8]([OH:9])=[CH:7][CH:6]=2)[O:4][C:14](=[O:15])[CH:13]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Cc1c(O)cccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
A slurry of 2-methylresorcinol (12.4 g, 0.100 mole) and ethyl 4,4,4-trifluoroacetoacetate (18.4 g, 0.100 mole) was added slowly to 100 ml of ice cold sulfuric acid with vigorous stirring. After completion of addition, the solution was allowed to warm to room temperature and was subsequently stirred for 24 hours. The reaction mixture was then slowly added to 500 ml of ice water (300 g ice and 200 ml water) with vigorous stirring. The desired product precipitated from the solution as a light pink solid. The solid was then isolated by vacuum filtration, transferred to a 500 ml beaker, 200 ml of water was added to achieve a slurry and the pH was adjusted to 6 with sodium bicarbonate. The solid was then filtered and recrystallized from ethanol-water to yield 19.5 g (80%) of the desired product. The melting point of the product was 197°-198 ° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a stirred solution of 3-phenyl-1H-indole-2-carboxylic acid ethyl ester (3.99 g, 15.0 mmol) in DMF (25 mL) cooled to 0° C. and under a nitrogen atmosphere was added NaH (60% in mineral oil, 720 mg, 18.0 mmol). After stirring for 10 min at RT, the reaction mixture was cooled to 0° C. and 4-methylbenzenesulfonyl chloride (3.44 g, 18.0 mmol) in DMF (15 mL) was added. Stirring was continued for 16 h at RT then the mixture was poured into 1.0M HCl and extracted with EtOAc (×2). The combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording 3-Phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester as a colourless oil (3.25 g, 52%). 1H NMR (CDCl3, 400 MHz): δ 8.08 (1H, d, J=8.43 Hz), 7.92 (2H, d, J=8.37 Hz), 7.53-7.36 (7H, m), 7.28-7.21 (3H, m), 4.35 (2H, q, J=7.15 Hz), 2.36 (3H, s), 1.25 (3H, t, J=7.14 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]2=[CH:7][C:8]3[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][C:13]=3[N:5]2[CH2:4][CH2:3]1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28](O)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:14][C:10]4[CH:11]=[CH:12][C:13]5[N:5]6[CH2:4][CH2:3][C:2]([CH3:15])([CH3:1])[C:6]6=[CH:7][C:8]=5[CH:9]=4)=[O:29])[CH2:26][CH2:27]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC1(C)CCn2c1cc1cc(N)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCn2c1cc1cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1,1-Dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-amine (40.0 mg, 0.200 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (41.2 mg, 0.200 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.2 μL, 0.600 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added to the mixture and the resulting solution was allowed to stir for 5 minutes at room temperature. The crude product was then purified by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 388.2, found 389.2 (M+1)+. Retention time of 2.02 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.06-7.02 (m, 2H), 6.96-6.90 (m, 2H), 6.03 (s, 2H), 5.98 (d, J=0.7 Hz, 1H), 4.06 (t, J=6.8 Hz, 2H), 2.35 (t, J=6.8 Hz, 2H), 1.42-1.38 (m, 2H), 1.34 (s, 6H), 1.05-1.01 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:9]([OH:11])=[O:10])=[CH:6][S:7][CH:8]=1)[CH3:2].S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)Cl>[Cl:15][C:8]1[S:7][CH:6]=[C:5]([C:9]([OH:11])=[O:10])[C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cscc1C(=O)O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOc1c(C(=O)O)csc1Cl
Reaction time: 0.5 h

Procedure:
A 15.45 g. portion of 4-ethoxy-3-thiophenecarboxylic acid is suspended in 30 ml. of chloroform. To this is added dropwise 8.1 ml. of sulfuryl chloride with stirring. The mixture is stirred for 30 minutes and the precipitate is collected, giving 5-chloro-4-ethoxy-3-thiophenecarboxylic acid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:16])([CH3:15])[CH2:5][O:6][C:7]1[C:8]([NH2:14])=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1.[H-].[Na+]>CS(C)=O.O>[Br:13][C:11]1[CH:10]=[N:9][C:8]2[NH:14][C:3](=[O:2])[C:4]([CH3:16])([CH3:15])[CH2:5][O:6][C:7]=2[CH:12]=1
Reactant: COC(=O)C(C)(C)COc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)COc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 3-(2-amino-5-bromo-pyridin-3-yloxy)-2,2-dimethylpropionic acid methyl ester (880 mg, 2.90 mmol) in DMSO (40 mL) was added NaH (60% in oil, 139 mg, 3.48 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with water (100 mL), and further stirred for 15 min. The resulting precipitate was collected by filtration to give the title compound (600 mg, 76%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.34 (br s, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 4.01 (s, 2H), 1.32 (s, 6H); ESI MS m/e 271 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1[F:40])[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:5]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][C:31]=1[F:40])[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(C(F)(F)F)cc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(Cc1ccc(C(F)(F)F)cc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)O)cc1
Yield: 94.4 %

Procedure:
Methyl 2-{2-[4-(2-{butyl[2-fluoro-4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethoxy}benzoate (0.230 g, 0.410 mmol) was dissolved in a mixture of THF/water (1/1, 4 ml). Lithium hydroxide (0.015 g, 0.617 mmol) was added. The reaction was performed in an single node microwave oven (14 min, 150 deg). Work-up by removing the solvent by evaporation and addition of HCl (2 ml, 1 M). The water-phase was extracted with two portions of EtOAc (20 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.212 g of 2-{2-[4-(2-{butyl[2-fluoro-4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]ethoxy}benzoic acid (yield 94.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[N:9]=1.[OH-].[Na+].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH:22]=1>CN(C=O)C>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:22]=[C:21]([CH2:20][N:13]3[CH:14]=[CH:15][C:10]4=[N:9][C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[N:16][C:11]4=[CH:12]3)[O:25][N:24]=2)=[CH:31][CH:30]=1
Reactant: ClCc1cc(-c2ccc(Cl)cc2)no1
Reactant: Fc1ccccc1-c1nc2ccncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc2ccn(Cc3cc(-c4ccc(Cl)cc4)no3)cc-2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a suspension of 2-(2-fluorophenyl)-3H-imidazo[4,5-c]pyridine (11.0 g, 50.0 mmoles) in DMF was added a 10% (w/v) solution of aqueous NaOH. To this solution, 5-(chloromethyl)-3-(4-chlorophenyl)isoxazole (13.68 g, 60.0 mmoles) dissolved in DMF was added. The reaction mixture was stirred at room temperature and monitored every half hour by LCMS. The reaction was stopped at 4 hours, after LCMS showed no progress between at 2 hour and 4 hour monitor points. The reaction product was triturated with first with water and then with EtoAc (3×). The material was crystallized by dissolving the material in MeOH with heat, followed by precipitation with water. This crystallization process was then repeated yielding 5-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (15.385 g, 38 mmole) as white crystal at a yield of 74%. 1H 300 Mhz (d6-DMSO) sigma 6.02 (s, 2p); 7.13 (s, 1p); 7.26-7.35 (m, 2p); 7.43-7.52 (m, 1p); 7.56 (d, 2p); 7.84 (d, 1); 7.89 (d, 2p); 8.24 (d, 1); 8.28-8.36 (m, 1p); and 9.19 (s, 1p). LCMS data M/Z=405.31
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:12][C:11]4[N:17]=[CH:18][N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[CH2:26][C:27]#[N:28])[C:10]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:30][OH:31].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[OH:31][NH:30][C:27](=[NH:28])[CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:10]2[C:9]3[CH:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:17]=[CH:18]1
Reactant: NO
Reactant: N#CCc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N=C(Cc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21)NO

Procedure:
The title compound is prepared in analogy to Example 67 starting from 300 mg (0.832 mmol) of [2-(8-phenyl-imidazo[4,5-c]quinolin-1-yl)phenyl]-acetonitrile (Example 64), 346 mg (0.499 mmol) hydroxylamine hydrochloride in 7 ml DMF, and 465 mg sodium carbonate in 2.5 ml water. The compound is isolated as colorless powder. mp: 253-254° C.; MS: 394 (M+1); HPLC: tret=6.57 min (Grad 1).
Reaction SMILES: Cl.[Br:2][C:3]1[N:4]=[C:5]([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=12.C(N(CC)C(C)C)(C)C.[C:27]([O:30][CH2:31][C:32](Cl)=[O:33])(=[O:29])[CH3:28]>ClCCl>[C:27]([O:30][CH2:31][C:32]([N:15]1[CH2:16][CH2:17][C@@H:13]([C:5]2[N:6]3[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]3=[C:3]([Br:2])[N:4]=2)[CH2:14]1)=[O:33])(=[O:29])[CH3:28]
Reactant: Cc1nccn2c([C@@H]3CCNC3)nc(Br)c12
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)N1CC[C@@H](c2nc(Br)c3c(C)nccn23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To (R)-1-bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride (0.15 mmol, 50 mg) in dichloromethane (4 ml) and N,N-diisopropylethylamine (0.889 mmol, 0.155 ml) at 0° C. was added dropwise a solution of acetoxyacetyl chloride (0.187 mmol, 0.020 ml) in dichloromethane (0.5 ml). After stirring at room temperature for one hour the reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate solution, water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) to give (R)-2-(3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-1-yl)-2-oxoethyl acetate (45 mg).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[Sn:19](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:28]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:29][CH2:30][CH3:31]
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccccc2)cc1

Procedure:
2.5 M of n-BuLi (2.1 mL/hexane, 5.32 mmol) was added to 4-bromobiphenyl (1.24 g, 5.32 mmol/THF (20 mL)) and reacted at −78° C. for 40 minutes under a dry and anaerobic operation condition to form a solution. SnBu3Cl (1.65 mL, 5.85 mmol) was then added to the solution and reacted at −78° C. for 1 hour. After returning to room temperature, the solution was continuously reacted for 8 hours. After the reaction was completed, the solution was extracted by ether (30 mL) and deionized water (50 mL). An organic phase was collected. After removal of ether by a rotary concentrator, the organic phase was purified by reduced-pressure distillation to form a transparent colorless oily product (21, 1.83 g, 78%).
Reaction SMILES: BrBr.[OH-:3].[Na+].[C:5]([C:8]1[CH:9]=[CH:10][C:11]2[O:20][C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[C:13]([CH3:22])([CH3:21])[C:12]=2[CH:23]=1)(=[O:7])C>O.O1CCOCC1>[CH3:21][C:13]1([CH3:22])[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[O:20][C:11]2[CH:10]=[CH:9][C:8]([C:5]([OH:7])=[O:3])=[CH:23][C:12]1=2
Reactant: [OH-]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)c1cccnc1O2
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)c2cc(C(=O)O)ccc2Oc2ncccc21
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
4.8 g of bromine is added dropwise to a solution of 3.3 g of sodium hydroxide in 28 ml of water at below 0°C, and the mixture is allowed to stand at 0°C for 15 minutes. To the mixture is added dropwise and slowly a solution of 2.4 g of 7-acetyl-5,5-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine in 10 ml of dioxane. The whole mixture is allowed to stand at room temperature for 2 hours, and then the solvent is removed by distillation under reduced pressure. To the residue are added water and benzene, and the mixture is warmed to 30°-40°C. The aqueous layer is neutralized with hydrochloric acid. The crystalline precipitate is recrystallized from aqueous acetic acid to give 1.9 g of 5,5-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylic acid melting at 241°-242°C.