Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([N:5]([CH2:13][C@@H:14]1[CH2:18][C@@H:17]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C@@H:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH3:37])[N:23]=[CH:22][N:21]=2)[CH2:16][C@@H:15]1[O:38][Si](C(C)(C)C)(C)C)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])=[O:3].C1COCC1.F.N1C=CC=CC=1>N1C=CC=CC=1>[NH2:1][S:2]([N:5]([CH2:13][C@@H:14]1[CH2:18][C@@H:17]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C@@H:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH3:37])[N:23]=[CH:22][N:21]=2)[CH2:16][C@@H:15]1[OH:38])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9])(=[O:3])=[O:4]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(O[C@@H]2C[C@@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)[C@@H](O)C2)ncn1
Temperature: 23 °C
Reaction time: 19 h

Procedure:
To a solution of tert-butyl (aminosulfonyl)({(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}-pyrimidin-4-yl)oxy]cyclopentyl}methyl)carbamate (331.5 mg, 0.0004094 mol) in THF (1.84 mL, 0.0228 mol) and pyridine (1.84 mL) at 0° C. was added pyridine hydrofluoride (0.25 mL, 0.0028 mol) dropwise. The mixture was allowed to slowly warm to 23° C. and stirred for 19 hours. To the reaction was added pyridine hydrofluoride (0.25 mL, 0.0028 mol) and the mixture was stirred an additional 6 hours. The reaction was quenched by the dropwise addition of saturated aqueous NaHCO3. The mixture was partitioned with additional saturated aqueous NaHCO3 and EtOAc, separated, and the aqueous was extracted with EtOAc (2×) and CH2Cl2 (2×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (30 to 70% EtOAc/hexanes) to collect 34.5 mg (15%) of the title compound. LC/MS: Rt=1.64 min, ES+ 550 (FA standard).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=4[O:31][CH3:32])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH3:33]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:24]([O:31][CH3:32])=[CH:25][CH:26]=[CH:27][C:28]=4[O:29][CH3:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH2:33])=[O:14])=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)O)c3cc(Cl)ccc23)CC1
Reactant: N
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(N)=O)c3cc(Cl)ccc23)CC1

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2,6-dimethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) ammonia in THF gave the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br-:10].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1cnccn1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(CBr)c1cnccn1
Reaction time: 8 h
Yield: 38.3 %

Procedure:
Acetylpyrazine (244 mg, 2.0 mmol) was suspended in glacial acetic acid (10 mL) and treated with pyridinium tribromide (640 mg, 2.0 mmol). The reaction mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with 1:1 hexane/ethyl acetate, to provide 2-(2-bromoacetyl)pyrazine as a brown solid (154 mg, 38%). 1H NMR (200 MHz, DMSO-d6) δ 9.16 (d, J=1.5 Hz, 1H), 8.94 (d, J=2.4 Hz, 1H), 8.82 (dd, J=1.5, 2.4 Hz, 1H), 4.99 (s, 2H).
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:39]2[N:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Nc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2ccccn2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.19 mL, 1.09 mmol) and 2-aminopyridine (170 mg, 1.31 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (88 mg, 47% yield).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]=[N:13][C:12]=2[S:16]CCC(OCC)=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[O-]CC.[K+]>C(O)C>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:15][N:14]=[N:13][C:12]=2[SH:16])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)CCSc1nnsc1-c1ccc(C(C)(C)C)cc1
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2snnc2S)cc1
Yield: 114.5 %

Procedure:
A solution of 15.9 g of 3-[[5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazol-4-yl]thio]propanoic acid, ethyl ester in 75 ml of anhydrous ethanol was treated with 105 ml of 0.5M potassium ethoxide in ethanol. After 3 hours the solvent was partially removed in vacuo and 200 ml of anhydrous ether was added. The resulting solid was collected, washed with ether, redissolved in methanol, filtered and the filtrate concentrated to 10-15 ml. A 250 ml portion of anhydrous ether was added and the solid was collected and dried in vacuo, giving 13 g of 5-[4-(1,1-dimethylethyl)phenyl]-1,2,3-thiadiazol-4-thiol, potassium salt as a yellow solid, mp>150° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:21]([C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(O)(=O)C.CCOC(C)=O>[C:15]([O:14][C:13]([NH:12][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@H:3]([OH:20])[CH2:2][NH:1][CH2:21][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:19])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A solution of tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (200 mg, 0.713 mmol) in THF was added methyl 3-formylbenzoate (117.1 mg, 0.713 mmol) and stirred for 30 min at room temperature. NaB(OAc)3H (302.5 mg, 1.43 mmol) was then added portionwise in 30 min, finally 5 drops of acetic acid was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was separated and dried (MgSO4). Concentration in vacuo was followed by purification with flash chromatography to give the desired product as a white solid (300 mg, % yield). 1H NMR (CDCl3): d: 7.999 (m, 2H), 7.589 (m, 1H), 7.451 (m, 1H), 7.254 (m, 5H), 3.956 (s, 3H), 3.892 (m, 3H), 3.549 (m, 1H), 3.040-2.850 (m, 2H), 2.793 (m, 2H), 1.374 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4]/[CH:5]=[CH:6]/[C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C1C=CC=CC=1>CCOCC>[CH3:22][C:21]1[CH2:20][CH2:19][C@H:18]([OH:28])[CH2:17][C:16]=1/[CH:15]=[CH:14]\[C:13]1[C@@H:12]2[CH2:11][CH2:10][C@H:9]([C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:8])[C@@:26]2([CH3:27])[CH2:25][CH2:24][CH:23]=1
Reactant: CC(C)C/C=C/[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC1=C(/C=C\C2=CCC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]23)C[C@@H](O)CC1
Yield: 40.4 %

Procedure:
(5Z,7E,22E)-9,10-Secocholesta-5,7,10(19),22-tetraen-3α-ol (5) A solution of compound (4) (100 mg, 0.26 mmol) in ether (120 ml)-benzene (30 ml) mixture was degassed with argon for 40 min. The solution was irradiated at 0° C. for 13 min in a quartz immersion well equipped with UV lamp and filter. The solvent was removed under reduced pressure and the residue separated by HPLC, using 1% 2-propanol in hexane as eluent to obtain the pure previtamin D derivative (40.4 mg, 40%) which was collected at 24 ml; NMR δ 0.72 (3H, s, 18-H3), 0.87 (6H, d, J=6.7 Hz, 26-H3 and 27-H3), 1.04 (3H, d, J=6.8 Hz, 21-H3), 1.65 (3H, s, 19-H3), 3.91 (1H, m, 3-H), 5.28 (2H, br m, 22-H and 23-H, 5.50 (1H, m, 11-H), 5.69 and 5.96 (2H, AB q, J=12.5 Hz, 7-H and 6-H); UV λmax 260.5 nm; λmin 234 nm. The previtamin (40 mg, 0.1 mmol) in ethanol (100 ml) was heated under reflux for 3 h. After removal of solvent, the product mixture was separated by HPLC (elution with 1% 2-propanol in hexane). The yield of the vitamin (5) (collected at 34 ml) was 30.8 mg (77%) mp (hexane) 99°-101° C.; NMR δ 0.56 (3H, s, 18-H3), 0.88 (6H, d, J=6.7 Hz, 26-H3 and 27-H3), 1.02 (3H, d, J=6.6 Hz, 21-H3), 3.96 (1H, m, 3-H), 4.82 and 5.05 (2H, each narr. m, 19-H2), 5.27 (2H, br m, 22-H and 23-H), 6.03 and 6.24 (2H, ABq, J=11.4 Hz, 7-H and 6-H; UV λmax 265 nm, λmin 228 nm; IR: 3420,1458,1441,1378,1366,1050,970,943,891,862 cm-1 ; mass spectrum, m/e (M+, 22), 349 (M+ -H2O-Me, 4), 271 (M+ -side chain, 8), 253 (M+ -side chain-H2O, 13), 136 (100), 118 (80).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:20]([CH3:22])([CH3:21])[S:19](=[O:24])(=[O:23])[C@H:18]2[CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=3[C@@:17]2([CH3:37])[N:16]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:20]([CH3:22])([CH3:21])[S:19](=[O:23])(=[O:24])[C@@H:18]2[CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=3[C@@:17]2([CH3:37])[N:16]=1)[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3CCC[C@@H]2S(=O)(=O)C1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3CCC[C@H]2S(=O)(=O)C1(C)C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
A solution of tert-butyl-N-((4aS,11bR)-10-nitro-3,3,11b-trimethyl-4,4-dioxido-3,4a,5,6,7,11b-hexahydrobenzo[3,4]cyclohepta[1,2-b][1,4]thiazin-2-yl)-N-tert-butoxycarbonyl-carbamate (806 mg, 1.461 mmol) in THF (10 ml) was treated with potassium tert-butoxide (1M in THF) (0.584 ml, 0.584 mmol) dropwise at rt. The mixture became dark after first few drops added. After 5 min stirring the reaction was quenched by 3 ml sat NH4Cl solution, stirred for 5 min, then diluted with water (2 ml) and EtOAc (3 ml). Organic layer was washed with brine and concentrated. The residue was purified by FC using 40 g RediSep Gold column (10-70% EtOAc in heptane) to afford tert-butyl-N-((4aR,11bR)-10-nitro-3,3,11b-trimethyl-4,4-dioxido-3,4a,5,6,7,11b-hexahydrobenzo[3,4]cyclohepta[1,2-b][1,4]thiazin-2-yl)-N-tertbutoxycarbonyl-carbamate (615 mg, 1.115 mmol, 76% yield). LC/MS (ESI+) m/z=574 (M+Na).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18](OB(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=3)[CH:3]=2)[CH:8]=1
Reactant: COc1cccc(OB(O)O)c1
Reactant: COc1ccc2cc(Br)ccc2c1
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2)c1
Reaction time: 22 h
Yield: 81 %

Procedure:
The compound is prepared by the reaction of 2-bromo-6-methoxynaphthalene (500 mg, 2.11 mmol, 1 eq) with 3-methoxyphenylboric acid (321 mg, 2.11 mmol, 1 eq) according to method A within 22 h. Purification by column chromatography with a mixture of hexane/ethyl acetate 9/1 yields the desired product in a yield of 81% (451 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:9]=3[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[K+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1C(=O)CCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:9]=3[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.4 %

Procedure:
To a stirred solution of 3,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (201 mg, 1.0 mmol) in NMP (3 mL) was added powdered KOH (392 mg, 7.0 mmol). After stirring for 10 min at RT, 2-(trifluoromethyl)-5-vinylpyridine (346 mg, 2.0 mmol) was added to the reaction mixture and stirring continued for another 3 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 3,6-dimethyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (80 mg). 1H NMR (CDCl3, TFA salt) δ (ppm): 8.38 (s, 1H), 8.0 (s, 1H), 7.5 (d, 2H), 7.4 (d, 1H), 4.4 (t, 2H), 3.58 (s, 2H), 3.2 (t, 2H), 2.68 (t, 2H), 2.5 (t, 2H), 2.47 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:12]([NH2:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:11][C:2]1[O:19][C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:20][C:3]=1[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(C)Br
Reactant: NC(=O)c1ccccc1
Product: CCOC(=O)Cc1nc(-c2ccccc2)oc1C

Procedure:
reacting methyl 4-bromo-3-oxovalerate with benzamide to give methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate, or reacting ethyl 4-bromo-3-oxovalerate with benzamide to give ethyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate,
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].O[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[O:5][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13](=[O:14])[CH:12]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: O=C(CO)c1ccccc1
Product: Cc1ccccc1-c1cc(=O)c2ccccc2o1

Procedure:
7 is prepared from 2-methylbenzoyl chloride (8) and 2-hydroxyacetophenone by the procedure of Example 1. The material is purified by vacuum column (eluting with 10% ethyl acetate in hexane), yielding 7 with a melting point of 45.5°-47.5° C.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH3:16])=[CH:7][C:6]=1/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH3:4].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:20][C:19](=[O:21])/[CH:18]=[CH:17]/[C:6]2[CH:7]=[C:8]([O:15][CH3:16])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CCCCc1c(/C=C/C(=O)O)cc(OC)c2ccccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)cc(OC)c2ccccc12
Yield: 87.8 %

Procedure:
As in Example 113, (E)-3-(1-butyl-4-methoxy-2-naphthalenyl)-2-propenoic acid (3.7 g) was reacted with 4-nitrophenol (1.99 g) in dichloromethane (40 mL) in the presence of 1,3-dicyclohexylcarbodiimide (2.7 g). The crude reaction product was crystallized from 2-propanol to give 4.63 g of (E)-3-(1-butyl-4-methoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester, mp 121.5°-122.5° C. Anal. Calcd for C24H23NO5 : C, 71.10; H, 5.72; N, 3.45 Found: C, 70.93; H, 5.77; N, 3.52
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.Cl.[C:25]1([CH2:41][NH:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH:26]=1.O>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([N:32]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)[CH2:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH2:41][NH:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[CH:26]=1)=[O:7]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Reactant: Fc1ccc(CNCc2cccc(CNCc3ccc(F)cc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cc(Cl)cc(Cl)c1O)N(Cc1ccc(F)cc1)Cc1cccc(CNCc2ccc(F)cc2)c1
Yield: 21.4 %

Procedure:
To a solution of 3,5-dichloro-2-hydroxybenzoic acid (300 mg, 1.449 mmol) in DMF (5 mL) at rt was added EDCI.HCl (300 mg, 1.565 mmol) followed by N,N′-(1,3-phenylenebis(methylene))bis(1-(4-fluorophenyl)methanamine) (365 mg, 1.036 mmol) in 2 mL of DMF and hydrated HOBt.H2O (200 mg), and the reaction mixture was stirred at rt overnight. The mixture was directly purified by prep HPLC to provide a monoacylated product 3,5-dichloro-N-(4-fluorobenzyl)-N-(3-((4-fluorobenzylamino)methyl)benzyl)-2-hydroxybenzamide (0.12 g, 21.4%) and a diacylated product, N,N′-(1,3-phenylenebis(methylene))bis(3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxybenzamide) (0.245 g, 32.4%). 1H NMR (CD3OD): δ 7.34˜6.80 (m, 16H), 4.59 (s, 4H), 4.24 (s, 4H); MS (ESI): (M+H)+=731.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].Cl[CH2:15][C:16]1[C:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:15][C:16]2[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])[N:3]=1
Reactant: Cc1cccc2cc(CCl)c(-c3ccccc3C(F)(F)F)nc12
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure I using 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.41 g, 1.6 mmol, 1 eq) in DMF (5 mL), NaH (60%, 0.138 g, 3.5 mmol, 2.2 eq), and 3-(chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline (0.58 g, 1.7 mmol, 1 eq) in DMF (3 mL). After purification, 3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained as white solid. 1H NMR (DMSO-d6) δ ppm 8.27 (1 H, s), 7.99 (1 H, s), 7.88 (1 H, d, J=7.8 Hz), 7.73-7.79 (1 H, m), 7.65 (1 H, d, J=6.7 Hz), 7.51-7.61 (3 H, m), 7.28-7.35 (1 H, m), 5.41-5.54 (2 H, m), 2.60 (3 H, s). Mass Spectrum (ESI) m/e=561.0 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC#N>[CH2:20]([N:27]1[CH2:28][CH2:29][N:30]([C:33]2[CH:34]=[CH:35][C:36]([NH:39][C:8]3[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:37][CH:38]=2)[CH2:31][CH2:32]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 180 °C
Yield: 101.8 %

Procedure:
A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.400 g, 1.334 mmol), [4-(4-benzylpiperazin-1-yl)phenyl]amine (0.357 g, 1.334 mmol) and TEA (0.190 ml, 1.334 mmol) in MeCN (5 ml) was heated in a microwave reactor at 120° C. for 35 mins, 160° C. for 20 mins and 180° C. for 20 mins. The reaction mixture was evaporated and the residue was purified by flash chromatography (Horizons Biotage) using 35-65% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.721 g, 78%). 1H NMR (500 MHz CDCl3); δ 7.40-7.32 (m, 3H), 7.30-7.24 (m, 2H), 7.22-7.18 (m, 1H), 7.16-7.08 (m, 4H), 6.60 (d, 2H), 6.52 (d, 2H), 3.78 (t, 2H), 3.57 (d, 2H), 3.05 (t, 4H), 2.57 (t, 4H), 1.92-1.84 (m, 2), 1.54-1.46 (m, 2H), 1.01 (t, 3H); 13C NMR (125 MHz CDCl3).: 159.7, 149.4, 138.1, 131.5, 129.5, 129.4, 128.9, 128.5, 128.1, 127.9, 127.4, 125.1, 123.6, 118.8, 109.4, 63.3, 53.1, 49.5, 40.4, 30.5, 20.3, 13.8; Mass Spectrum: M+H+ 531.
Reaction SMILES: C(OC([N:8]1[C:11]2([CH2:15][CH2:14][N:13]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH2:12]2)[CH:10]([CH3:25])[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(Cl)(Cl)Cl>CO>[CH3:25][CH:10]1[C:11]2([CH2:15][CH2:14][N:13]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH2:12]2)[NH:8][CH2:9]1
Reactant: CC1CN(C(=O)OC(C)(C)C)C12CCN(c1ncnc3[nH]ccc13)C2
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC1CNC12CCN(c1ncnc3[nH]ccc13)C2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 138.2 %

Procedure:
An optically-active compound of 3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylic acid tert-butyl ester (9.5 g) was mixed with 4M hydrochloric acid-1,4-dioxane (50 ml), chloroform (50 ml) and methanol (100 ml), and the mixture was stirred at 60° C. for 30 minutes. The mixture was concentrated under reduced pressure, and azeotroped with toluene to give the titled compound (9.3 g).
Reaction SMILES: [CH:1]([S:3]([CH:6]=[CH2:7])(=[O:5])=[O:4])=[CH2:2].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[CH2:8]([N:15]1[CH2:7][CH2:6][S:3](=[O:5])(=[O:4])[CH2:1][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CS(=O)(=O)C=C
Reactant: NCc1ccccc1
Solvent: CCO
Product: O=S1(=O)CCN(Cc2ccccc2)CC1
Yield: 39.9 %

Procedure:
Divinyl sulphone (0.8 ml, 10 mmol) was added to a solution of benzylamine (1.09 ml, 10 mmol) in ethanol (4 ml) and heated under reflux for 2 hours. The solvent was removed under reduced pressure, the residue dissolved in dichloromethane (30 ml) and washed with saturated aqueous sodium hydrogencarbonate solution (15 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (100:0 to 99:1) to afford the title compound as a yellow oil (0.9 g).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:25][NH:26][CH3:27]>>[CH3:25][N:26](/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1)[CH3:27]
Reactant: CNC
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CN(C)/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 7 %

Procedure:
Prepared as in Example 1 from 2-benzoyl-benzo[b]thiophen-3-ol, phosphorus(V) chloride and 40% aqueous dimethylamine solution with a yield of 7% of theory.