Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH2:11]Br)[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1.[OH:21][CH2:22][C:23]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][O:21][CH2:22][C:23]2([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:8]2[C:4](=[CH:5][N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:7]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: C[Si](C)(C)CCOCn1cc2cc(Br)cc(CBr)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A flask was charged with 5-bromo-7-(bromomethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (0.61 g, 1.45 mmol), tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.444 g, 1.52 mmol), and dimethylformamide (5 mL). The reaction was cooled to 0° C. and treated with sodium hydride (0.073 g, 3.05 mmol) in several portions. After stirring for 15 min, the ice bath was removed and stirring continued for 15 min. The reaction was cooled to 0° C. and quenched by the cautious addition of saturated ammonium chloride. The reaction was poured into diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% EtOAc/Hex) gave 720 mg (79%) as a gum. 1H-NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.38 (m, 4H), 7.24 (m, 1H), 7.13 (d, J=1.5 Hz, 1H), 5.65 (s, 2H), 4.81 (s, 2H), 3.76 (bs, 2H), 3.58 (t, J=8.2 Hz, 2H), 3.53 (s, 2H), 3.06 (m, 2H), 2.22 (m, 2H), 1.95 (m, 2H), 1.44 (s, 9H), 0.91 (t, J=8.2 Hz, 2H), 0.00 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.1, 145.5, 142.9, 130.5, 128.6, 127.4, 126.6, 126.5, 123.3, 122.2, 121.3, 116.0, 81.9, 80.0, 79.4, 68.5, 67.6, 41.9, 40.3 (br), 32.0, 28.6, 17.9, −1.3. Mass spec.: 630.14 (MH)+.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([NH:11][CH2:12][C@H:13]([NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2)(=[O:18])=[O:17])[CH3:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(OC([NH:36][CH2:37][C:38](O)=[O:39])=O)(C)(C)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[ClH:1].[NH2:36][CH2:37][C:38]([N:11]([CH2:12][C@H:13]([NH:15][S:16]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[N:24][CH:23]=[CH:22]2)(=[O:18])=[O:17])[CH3:14])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C[C@H](CNCCc1ccccc1)NS(=O)(=O)c1ccc2cnccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@H](CN(CCc1ccccc1)C(=O)CN)NS(=O)(=O)c1ccc2cnccc2c1
Yield: 151.3 %

Procedure:
A free form (220 mg) of the compound of Example 23 and N-(tert-butoxycarbonyl)glycine (25 mg) were condensed (230 mg, 73%) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (137 mg) in dichloromethane. Subsequently, 100 mg of the title compound was obtained as a white solid (61%) from 150 mg of a free form according to the methods described in Steps 2 and 3 of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:29])[C:25]=1[O:26][CH2:27][CH3:28])[C:5]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[C:10]([O:21]C)[CH:9]=1)=[O:6].B(Cl)(Cl)Cl.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:29])[C:25]=1[O:26][CH2:27][CH3:28])[C:5]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[C:10]([OH:21])[CH:9]=1)=[O:6]
Reactant: CCOc1c(Cl)cc(C(=O)Nc2ccc(C(=O)OC(C)(C)C)c(OC)c2)cc1Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOc1c(Cl)cc(C(=O)Nc2ccc(C(=O)O)c(O)c2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.9 %

Procedure:
A solution of tert-butyl 4-(3,5-dichloro-4-ethoxybenzamido)-2-methoxybenzoate (5) (55 mg, 0.13 mmol) in DCM (5 mL) was cooled to 0° C. and treated dropwise with a solution of 1 M boron trichloride in DCM (349 μL, 349 μmol). The reaction mixture was stirred at 0° C. for 1 h and then at RT for 2 h. The reaction mixture was cooled to 0° C. and water (0.5 mL) and sat. aq. NaHCO3 (2 mL) were added. The resulting white precipitate was collected by filtration and washed with water (2 mL). The solid was dried, then purified by capture and release on SAX, eluting with 5% AcOH in THF to afford 4-(3,5-dichloro-4-ethoxybenzamido)-2-hydroxybenzoic acid (AAA-057) (11 mg, 24%) as a white solid: m/z 370 [M+H]+ (ES+), 368 [M−H]− (ES−); 1H-NMR (400 MHz, DMSO-d6) δ: 10.51 (1H, s), 8.06 (2H, s), 7.76 (1H, d), 7.48 (1H, d), 7.28 (1H, dd), 4.14 (2H, q), 1.91 (1H, s), 1.40 (3H, t), 1.35 (1H, s).
Reaction SMILES: [OH:1][C@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1.[N:15]([O-])=[O:16].[Na+].O>C(O)(=O)C>[OH:1][C@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[C:11]=2[N:15]=[O:16])[CH:6]=[N:5]1
Reactant: C[C@@H](O)Cn1ncc2ccc(O)cc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H](O)Cn1ncc2ccc(O)c(N=O)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 465.1 %

Procedure:
To a solution of 1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol (2.0 g, 1.04 mmol) in acetic acid (20 mL) was added sodium nitrite (0.72 g, 10.4 mol) and the mixture was stirred at room temperature for 1 hour. Water (200 mL) was added and the mixture was extracted with ethyl acetate (2×200 mL). The combined extracts were washed with water (200 mL), and a saturated aqueous solution of sodium bicarbonate (200 mL), dried over magnesium sulfate, filtered and evaporated to a residue which was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a red solid (1.07 g, 47%): LC/MS m/z 222.
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH3:37])[C@H:3]([NH:7][C:8]([C@H:10]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[CH:24][CH:23]=1)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:9])[C:4]([OH:6])=O.[CH3:39][O:40][CH2:41][C@@H:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:1][C:2]([CH3:38])([CH3:37])[C@H:3]([NH:7][C:8]([C@H:10]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[CH:24][CH:23]=1)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:9])[C:4]([NH:49][C@@H:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:41][O:40][CH3:39])=[O:6]
Reactant: COC[C@@H](N)c1ccccc1
Reactant: COc1cccc(-c2ccc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)(C)C)cc2C)c1
Product: COC[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(-c2cccc(OC)c2)c(C)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Yield: 80.9 %

Procedure:
According to the procedure of Preparation 19 d), tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-(carboxy)propyl]amino}carbonyl)-6-(3′-methoxy-2-methylbiphen-4-yl)hexanoate (660 mg, 1.26 mmol) was reacted with (1S)-2-methoxy-1-phenylethylamine (190 mg, 1.260 mmol). Work-up as above, followed by flash chromatography (eluting with hexane:ethyl acetate=3:1) to give tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1s)-2-methoxy-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-(3′-methoxy-2-methylbiphen-4-yl)hexanoate (672 mg, 81%) as a colourless foam.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12](=[O:46])[C@H:13]([CH2:35][CH2:36][CH2:37][NH:38]C(OC(C)(C)C)=O)[N:14]([C:16](=[O:34])[C@H:17]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)[NH:18]C(OC(C)(C)C)=O)[CH3:15].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12](=[O:46])[C@H:13]([CH2:35][CH2:36][CH2:37][NH2:38])[N:14]([C:16](=[O:34])[C@H:17]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)[NH2:18])[CH3:15]
Reactant: CN(C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)[C@@H](N)Cc1ccc(O)cc1)[C@@H](CCCN)C(=O)Oc1ccc2ccccc2c1

Procedure:
Boc-Tyrosyl-Nδ-Boc-Nα-methylornithinyl 2-naphthyl ether (125 mg) was treated with trifluoroacetic acid (Procedure E) to afford titled product (100 mg) as a white solid: 1H NMR (400 MHz, D2O) δ1.77 (m, 4H), 2.78 (m, 3H), 3.08 (m, 4H), 4.06 (dd, J=11.4; 3.6 Hz, 1H), 4.17 (dd, J=1 1.5; 8.4 Hz, 1H), 4.72 (t, J=7.8 Hz, 1H), 4.89 (m, 1H), 6.65 (d, J=10.8 Hz, 2H), 7.17 (d, J=10.8 Hz, 2H), 7.22 (dd, J=9.6; 1.1 Hz, 1H), 7.34 (s, 1H), 7.51 (t, J=8.4 Hz, 1H), 7.61 (t, J=8.4 Hz, 1H), 7.94 (m, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][N:6]([CH2:25][C:26](=[O:29])[NH:27][CH3:28])[C:7]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[CH:11][CH:10]=1)=[O:8])=[O:4]>CO.[Pd]>[CH3:28][NH:27][C:26]([CH2:25][N:6]([CH2:5][C:3](=[O:4])[NH:2][CH3:1])[C:7]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)=[O:8])=[O:29]
Reactant: CNC(=O)CN(CC(=O)NC)C(=O)c1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)CN(CC(=O)NC)C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
To a solution of Example I (0.73 g, 1.84 mmol) in MeOH (30 mL) was added 10% Pd/C (200 mg). The reaction mixture was then stirred at ambient temperature under 1 atmosphere of H2 for 45 min. The reaction mixture was filtered, the solid washed with EtOH, and the combined organics concentrated in vacuo to yield 4-(bis((methylcarbamoyl)methyl)carbamoyl)benzoic acid (0.52 g, 92% yield). 1H NMR (CDCl3) δ9.16 (s, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 4.04 (d, J=6 Hz, 4H), 2.94 (m, 6H); MS (ESI) m/e: 308 (M++1).
Reaction SMILES: [CH2:1]([O:13][CH:14]([CH3:17])[CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>O>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:16][CH2:15][CH:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:17])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCOC(C)CO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 9 h

Procedure:
6.6 g of 2-dodecyloxypropanol and 20 ml of dry pyridine were mixed and cooled with NaCl-ice. 8.0 g of p-toluenesulfonic acid chloride was added little by little, and the reaction was continued for 9 hours. The reaction mixture returned to room temperature was mixed with a mixture of 30 ml of conc. hydrochloric acid added to 110 g of water, and the mixture was extracted with benzene and dried over anhydrous Na2SO4. Evaporation of benzene gave (2-dodecyloxypropyl) p-toluenesulfonate as an oily product. Yield: 10.7 g.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O.O.O.Cl[Sn]Cl>Cl.O>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1ccc2c(c1)C(=O)OC2
Yield: 83.8 %

Procedure:
To a solution of 6-nitroisobenzofuran-1(3H)-one (15.0 g, 0.0800 mol) in HCl/H2O (375 mL/125 mL) was added SnCl2.2H2O (75.0 g, 0.330 mol). The reaction mixture was heated at reflux for 4 h, quenched with water, and extracted with ethyl acetate (300 mL×3). The organic layer was dried over Na2SO4 was evaporated in vacuo to give 6-aminoisobenzofuran-1(3H)-one (10.0 g, 78%). 1H NMR (300 MHz, CDCl3) 7.23 (d, J=8.1, 1H), 7.13 (d, J=2.1, 1H), 6.98 (dd, J=8.1, 2.1, 1H), 5.21 (s, 2H), 3.99 (br s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1.C(N(CC)CC)C.[H][H]>O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1
Reactant: [H][H]
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ncn(-c2ccc(N)cc2F)n1
Yield: 73.2 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-3-methyl-1H-[1,2,4]triazole (250 mg, 1.13 mmol) was dissolved in tetrahydrofurane (6 mL) and triethylamine (5 mL) and stirred for 2 hours with 10% palladium on carbon (55 mg) under 1.5 bar of hydrogen. The reaction mixture was filtered and the solvent was removed under reduced pressure to yield the title compound (159 mg, 73%) as a yellow solid MS ISP (m/e): 193.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.31 (d, 1H), 7.45 (dd, 1H), 6.51 (m, 2H), 3.94 (s broad, 2H), 2.48 (s, 3H). Mp 122-125° C.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[C:12]2[C:11](=[O:20])[NH:10][CH:9]=[CH:8][C:7]=2[N:6]=1)[CH3:4].C(#N)C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:5]([CH:3]([CH3:4])[CH2:2][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:6][C:7]3[CH:8]=[CH:9][NH:10][C:11](=[O:20])[C:12]=3[C:13]=2[CH:18]=1
Reactant: CC(CBr)c1nc2cc[nH]c(=O)c2c2cc(F)ccc12
Reactant: C1COCCN1
Solvent: CC#N
Product: CC(CN1CCOCC1)c1nc2cc[nH]c(=O)c2c2cc(F)ccc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A suspension of 6-(2-bromo-1-methylethyl)-9-fluorobenzo[c]-1,6-naphthyridin-1(2H)-one (HBr salt) (25 mg, 0.060 mmol) in morpholine (1.0 mL) was stirred at 100° C. for 1 h. After cooling to room temperature, acetonitrile was added, and the resulting solution was concentrated to a crude residue. The resulting crude residue was purified by preparative reverse phase HPLC eluting with an acetonitrile/water (with 0.05% TFA as a modifier) gradient to afford 9-fluoro-6-(1-methyl-2-morpholin-4-ylethyl)benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (500 MHz, DMSO-D6). δ 11.86 (br d, 1H), 9.76 (dd, 1H), 8.63 (dd, 1H), 7.62 (br t, 1H), 7.57 (br t, 1H), 6.76 (d, 1H), 4.20 (br m, 1H), 3.47 (br s, 4H), 2.80 (br dd, 1H), 2.65 (br m, 1H), 2.43 (br s, 4H), 1.33 (d, 3H). LRMS (ESI) calc'd for (C19H20FN3O2) [M+H]+, 342.2; found 342.1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>ClCCl>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1cccc2cccnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2cccnc12)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of compound quinolin-8-yl-amine (3.0 g, 20.8 mmol) in dichloromethane (40 ml) and triethylamine (3.1 ml, 21.9 mmol), 4-bromo-benzoyl chloride (4.8 g, 21.9 mmol) in dichloromethane (20 ml) is added drop wise at room temperature and the resulting mixture is stirred for 16 h. After completion of the reaction (monitored by TLC) the mixture is diluted with dichloromethane (100 ml) and washed with water and saturated sodium hydrogen carbonate solution. The organic layer is dried over sodium sulfate and concentrated in vacuo. The resulting crude product is purified by column chromatography (silica gel, 10% ethyl acetate/hexane) to obtain 4-bromo-N-quinolin-8-yl-benzamide (5.2 g, 15.9 mmol, 76%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:10](=[O:11])[N:9]([CH:12]3[C:18](=[O:19])[NH:17][C:15](=O)[CH2:14][CH2:13]3)[C:7](=[O:8])[C:5]=2[CH:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[O:19]=[C:18]1[CH:12]([N:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH2:13][CH2:14][C:15](=[S:29])[NH:17]1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C1NC(=S)CCC1N1C(=O)c2ccccc2C1=O
Yield: 132.6 %

Procedure:
Compound 203 (1.14 g, 5 mmol) was suspended in CH2Cl2 (100 mL). To the mixture was added CF3COOH (10 mL) and this then was stirred at room temperature for 4 h. The solvent was evaporated to give crude 204 (1.25 g): 1H NMR (DMSO-d6) δ 11.42 (s, 1H), 8.70 (br, 2H), 4.31 (dd, J=5.4 Hz, J=13 Hz), 2.88-2.72 (m, 2H), 2.25-2.09 (m, 2H). A mixture of crude 204 (1.25 g) and phthalic anhydride (0.89 g, 6 mmol) and Et3N (1.39 ml, 10 mmol) in THF (150 mL) was refluxed for two days. The reaction mixture was concentrated and the residue was crystallized from ethyl acetate to give thalidomide (201) (0.89 g, 69%) as white crystals; mp 276° C. (lit. 276-279° C.). A mixture of thalidomide 201 (258 mg, 1 mmol) and Lawesson's reagent (222 mg, 0.55 mmol) in toluene (50 ml) was stirred at reflux for 12 h; thereafter, solvent was removed under vacuum. The resulting residue was purified by column chromatography using CH2Cl2 as the eluent to afford compound 205 (200 mg, 73%) as a yellow solid: mp 225-226° C.; 1H NMR (DMSO-d6) δ 12.83 (s, 1H, NH), 8.00-7.92 (m, 4H, Ph), 5.32 (dd, J=5.6 Hz, J=12.9 Hz, 1H, H-3′), 3.28-3.25 (m, 2H, H-5′), 2.60-2.54 (m, 1H, H-4′), 2.17-2.10 (m, 1H, H-4′); 13C NMR (DMSO-d6) δ 208.7(C-6′), 165.3(C-2′), 165.2(C-1 & C-3), 133.1(C-5 & C-6), 129.3 (C-3a, C-7a), 121.7 (C -4 & C-7), 46.9 (C-3′), 38.9 (C-5′), 21.79 (C-4′); MS (CI/CH4) m/z 274 (M+); Anal. (C13H10N2O3S) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[CH:18]\I)[CH3:14]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH:18]=[CH:17][C:16]([O:15][CH2:13][CH3:14])=[O:20])=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C=C\I
Reactant: C#Cc1ccc(C(=O)OC)cc1
Product: CCOC(=O)C=CC#Cc1ccc(C(=O)OC)cc1

Procedure:
The general procedure was used to convert 4-Ethynyl-benzoic acid methyl ester and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (30% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow solid (450 mg, 88% yield). 1H NMR (400 MHz, CDCl3) δ 8.01-7.99 (d, J=8.5, 2H), 7.59-7.57 (d, J=8.5, 2H), 6.37-6.34 (d, J=11.4, 1H), 6.20-6.17 (d, J=11.4, 1H), 4.29-4.23 (q, J=7.1, 2H), 3.91 (s, 3H), 1.34-1.30 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 166.36, 164.60, 131.91, 130.31, 129.52, 129.37, 127.29, 122.25, 99.73, 88.79, 60.55, 52.24, 14.30. Anal. Calcd. for C15H14O4: C, 69.76; H, 5.46; Found C, 69.90; H, 5.55. m.p.: 49.0°-51.0° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[Li+].[CH3:20][CH:21]([N-]C(C)C)[CH3:22].C(Br)C=C.[NH4+].[Cl-]>C1COCC1>[CH3:1][C:2]1[N:3]([CH:13]([CH2:22][CH:21]=[CH2:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=1
Reactant: C=Cc1c(C(F)(F)F)nc(C)n1CC(=O)OCC
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(C(=O)OCC)n1c(C)nc(C(F)(F)F)c1C=C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
To a cooled (−78° C.) solution of ethyl 2-[2-methyl-4-(trifluoromethyl)-5-vinyl-imidazol-1-yl]acetate (790 mg, 3.01 mmol) in THF (6 mL) under nitrogen atmosphere was added LDA (2 M, 3 mL, 6.03 mmol) drop wise. After stirring the reaction mixture at −78° C. for 15 min, allyl bromide (521 μL, 6.03 mmol) was added slowly and the reaction mixture was allowed to warm to room temperature and stirred for 2 h. A saturated NH4Cl solution (20 mL) was added to the reaction mixture at 0° C. and the mixture was then extracted with EtOAc (2×100 mL). The combined EtOAc layers were then washed with brine (50 mL), dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (SiO2, 80% EtOAc/hexanes) to obtain ethyl 2-[2-methyl-4-(trifluoromethyl)-5-vinyl-imidazol-1-yl]pent-4-enoate (127 mg, 0.42 mmol, 14% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:24]4[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)cc4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (168 mg, 0.5 mmol) and commercially available 4-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (110 mg, 46%). MS (ISN) 471.0 [(M−H)−]; mp 237° C.
Reaction SMILES: [S:1]([N:11]1[CH2:13][CH:12]1[CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:22][NH2:23]>CO>[CH3:22][NH:23][CH2:13][CH:12]([NH:11][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)N2CC2CC2(O)CCCCC2)cc1
Solvent: CO
Product: CNCC(CC1(O)CCCCC1)NS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 1-((1-tosylaziridin-2-yl)methyl)cyclohexanol (270 mg, 0.87 mmol) and methylamine in MeOH was stirred at rt for 4 h and concentrated to give 1-(3-(methylamino)-2-(tosylamino)propyl)cyclohexanol. The crude product was used in the next step without purification. MS m/z 341 (M+H+).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:22][CH2:21][CH:20]=[CH:19][C:16]=3[CH:17]=2)[CH2:12][C:11]1=[O:23])[CH3:9].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>ClCCl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([CH:12]2[C:13]3[C:18](=[CH:17][C:16]4[CH:19]=[CH:20][CH2:21][O:22][C:15]=4[CH:14]=3)[N:10]([CH2:8][CH3:9])[C:11]2=[O:23])=[O:33])=[CH:27][CH:26]=1
Reactant: CCN1C(=O)Cc2cc3c(cc21)C=CCO3
Reactant: O=C=Nc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2)c2cc3c(cc21)C=CCO3
Temperature: 0 °C
Yield: 60 %

Procedure:
To a slurry of 128 mg. (3.2 mmoles) of sodium hydride (washed with petroleum ether) in 4 ml. of dimethylformamide was added 500 mg. (2.3 mmoles) of 1-ethyl-2-oxo-2,3-dihydro-pyrano[2,3-f]indole followed after 15 minutes of stirring by 0.36 ml. (3.2 mmoles) of 4-fluorophenylisocyanate. The reaction mixture was allowed to stir at room temperature for 30 minutes, and was then added to a mixture of dichloromethane (50 ml.) and ice water (50 ml.). The aqueous layer was extracted with 35 ml. of dichloromethane and was then acidified with 4N hydrochloric acid. The acidified layer was extracted with fresh dichloromethane, and the organic phase separated, dried over magnesium sulfate and concentrated under vacuum to dryness, 1.6 g. The residue was taken up in ethyl acetate, washed with a brine solution and dried over magnesium sulfate. Removal of the solvent gave 709 mg. of crude product. Recrystallization from dichloromethane-diisopropyl ether gave 490 mg. (60% yield) of product, m.p. 212°-214° C.