Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([N:32]=[C:2]=[O:4])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(N=C=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8.74 g of triphosgene in 125 ml of methylene chloride cooled to 0° C. is added dropwise a solution of p-(tetradecyloxy)aniline, 7.95 g of triethylamine and 239.93 mg of dimethylaminopyridine in 125 ml of methylene chloride over 30 minutes. Stirring at ambient temperature is continued for 4 hours. The solvent is evaporated and the residue stirred with ether and filtered. The cake is washed with additional ether and the combined filtrates evaporated to give the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[OH:31].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(O)c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.8g, 0.013 mol) NaHCO3 (1.1 g), several crystal of KI, 1-[4-(3-chloropropoxy)-3-hydroxyphenyl]ethanone, and acetonitrile (100 ml) was refluxed for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed (water), dried (MgSO4), and the solvent was concentrated to afford 5.7 g of a thick yellow oil. The oil was chromatographed on a Waters Prep 500 LC on silica gel, eluting with 7% methanol/methylene chloride. Concentration of the appropriate fraction afforded a yellow oil, which upon standing yielded 3.5 g of the compound as a pale, yellow solid. The solid was recrystallized from ethyl alcohol to afford 2.7 g (50%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl[propoxy]-3-hydroxyphenyl]ethanone as a pale Yellow solid, m.p.=122°-124° C.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([NH2:44])[C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[O:26]1[CH2:27][CH2:28][N:23]([C:5]2[C:6]3[N:7]([CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]=4)[N:10]=3)[C:2]([C:37]3[CH:38]=[C:39]([NH2:44])[C:40]([NH2:43])=[N:41][CH:42]=3)=[CH:3][N:4]=2)[CH2:24][CH2:25]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Reactant: CC1(C)OB(c2cnc(N)c(N)c2)OC1(C)C
Product: Nc1cc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cnc1N
Yield: 54.3 %

Procedure:
Compound 2b (1.00 g, 2.30 mmol, as prepared in Example 2, Step B) was subjected to Suzuki coupling conditions with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2,3-diamine (1.62 g, 6.91 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 6b (580 mg, 51% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C26H24N8O: 465.2 (M+H). Found 465.3.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22](C(F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C([C:38](C2C=CC(NC3C=CC=CC=3OC)=CC=2Cl)=[O:39])C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:39][CH3:38])=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: COc1ccccc1Nc1ccc(C(=O)c2cc(N)ccc2C)c(Cl)c1
Product: COc1ccccc1Nc1ccc(C(=O)c2cc(N=[N+]=[N-])ccc2C)c(Cl)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 441 (0.27 mmol). The crude product was used without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:23][C:24](=[O:26])[CH3:25])[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[CH:14]=2)=[C:4]([N+:27]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C1COCC1.O.[Zn]>[NH2:27][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[CH:10]=[C:11]([NH:23][C:24](=[O:26])[CH3:25])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:14]=1
Reactant: CC(=O)Nc1cc(Nc2ccc(Br)cc2[N+](=O)[O-])cc(-c2ccc(F)cc2F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(Nc2ccc(Br)cc2N)cc(-c2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of N-(5-(4-bromo-2-nitrophenylamino)-2′,4′-difluorobiphenyl-3-yl)acetamide (3.2 g, 6.92 mmol) in THF (30 ml) were added a solution of ammonium chloride (3.7 g, 69.22 mmol, 10 eq.) in water (15 ml) and zinc (4.53 g, 69.22 mmol, 10 eq.). The mixture was stirred at RT for 6 h and filtered. The filtrate was diluted with water and extracted as in Example 1(d). The solvent was distilled off under reduced pressure to afford the product in 87% yield (2.6 g).
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[C:27](O)=[O:28])[CH:20]=[CH:19][CH:18]=1>>[S:1]1[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[C:27]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:26]=2[N:17]=[CH:18][CH:19]=[CH:20]3)=[O:28])=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: O=C(O)c1cccc2cccnc12
Reactant: c1ccc2sc(CC3CCCCN3)cc2c1
Product: O=C(c1cccc2cccnc12)N1CCCCC1Cc1cc2ccccc2s1
Yield: 1.8 %

Procedure:
The title compound (4 mg) was prepared from 2-benzo[b]thiophen-2-ylmethyl-piperidine D83 (133 mg) and 8-quinoline carboxylic acid (109 mg) according to a procedure similar to that described for Example 4.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:20][NH2:21])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29].Cl>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[C:5]([NH:20][NH:21][C:28](=[O:30])[CH3:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1
Reactant: NNc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NNc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1
Reaction time: 3 h

Procedure:
To [3-fluoro-4-[3-(trifluoromethyl)phenoxy]phenyl]hydrazine hydrochloride (0.35 g) prepared using the method described in Example 1, in ethyl acetate (5 mL), was added pyridine (0.24 mL) at −10° C. After dropwise addition of acetyl chloride (0.1 mL), the mixture was stirred for 3 h and then acidified with 6 M HCl. Water was added, and the product was extracted with ether. The organic layer was separated, dried, and concentrated. The residue was purified by column chromatography on silica (using dichloromethane, followed by 5:1 dichloromethane:ether as eluants) to give a solid (0.2 g).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[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].C(OC([N:35]1[C:39]([C:40]#[N:41])=[CH:38][CH:37]=[C:36]1B(O)O)=O)(C)(C)C>>[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:36]3[NH:35][C:39]([C:40]#[N:41])=[CH:38][CH:37]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1B(O)O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 29 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 22.1) and (1-(tert-butoxycarbonyl)-5-cyano-1H-pyrrol-2-yl)boronic acid (Stage 29.1) to afford a beige solid. UPLC-MS (Condition 3) tR=1.06 min, m/z=474.1 [M+H]+, m/z=472.2 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.81 (m, 1H) 1.81-1.91 (m, 1H) 2.94 (d, J=11.74 Hz, 1H) 3.22-3.28 (m, 1H) 3.32 (d, J=3.42 Hz, 1H) 3.40-3.49 (m, 1H) 4.23 (br. s, 1H) 4.88 (br. s, 1H) 6.30 (d, J=3.67 Hz, 1H) 7.00 (d, J=3.67 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.82-7.89 (m, 2H) 8.07 (d, J=2.20 Hz, 1H) 8.76 (d, J=2.20 Hz, 1H) 10.17 (s, 1H) 12.60 (br. s, 1H).
Reaction SMILES: [Cl:1][CH:2]([CH2:27][O:28][CH3:29])[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:16](=[O:26])[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[O:19])=O.O1CCCC1.Cl>CN(C)C1C=CN=CC=1.O>[Cl:1][CH:2]([C:3]1[C:17]([C:18]([NH:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[O:19])=[C:16]([OH:26])[C:7]2[C:6](=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:9][CH:8]=2)[N:5]=1)[CH2:27][O:28][CH3:29]
Reactant: COCC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COCC(Cl)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A mixture of 33.35g of the product of Step A, 10g of 4-dimethylamino-pyridine and 300ml of tetrahydrofuran was refluxed for 30 minutes and was then cooled to room temperature and poured into a mixture of water and 2N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was washed, dried and evaporated to dryness. The residue was empasted with ether, vacuum filtered, washed and dried under reduced presssure at 60° C. to obtain 28.2g of 2-(1-chloro-2-methoxyethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide melting at 186° C.
Reaction SMILES: [Na:1].CC1(C)O[C@H](C[O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)=[O:18])[C:11]=2[CH3:28])CO1.[CH3:30][C:31]1([CH3:43])[CH2:36][O:35][C:34]2([CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]2)[O:33][CH2:32]1>>[Na:1].[CH3:30][C:31]1([CH3:43])[CH2:32][O:33][C:34]2([CH2:37][CH2:38][CH:39]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:19]4[NH:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[N:20]=4)=[O:18])[C:11]=3[CH3:28])[CH2:40][CH2:41]2)[O:35][CH2:36]1
Reactant: Cc1c(OC[C@@H]2COC(C)(C)O2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: CC1(C)COC2(CCC(O)CC2)OC1
Agent: [Na]
Product: Cc1c(OC2CCC3(CC2)OCC(C)(C)CO3)ccnc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
The same procedure as in the steps (14a) to (14e) of Example 14 was repeated using the 3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-ol obtained in the step (81a) above to obtain the title compound (275 mg, the total yield of 5 steps: 3.3%) as a white solid. Note that in the same process as in the step (14b), after acetic anhydride was added, 10 equivalents of triethylamine relative to pyridine 1-oxide derivative was added to perform the reaction. In the same process as in the step (14c), tetrahydrofuran was used as a solvent instead of ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20]([OH:22])=O)[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:22])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: Nc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)O)C2=O)cn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)Nc3ccccc3)C2=O)cn1
Temperature: 65 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
3-(1-(1-methylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)acetic acid (example 10-44) (100 mg, 0.3 mmol), aniline (33 mg, 0.36 mmol), Pybop (187 mg, 0.36 mmol) and triethyl amine (0.05 mL, 0.36 mmol) were mixed in DMF (1 mL). The reaction stirred at 65° C. for 4 hours. The reaction was allowed to cool to room temperature and then diluted with ethyl acetate (2 mL). The organic phase was washed with saturated sodium bicarbonate solution (2×, 2 mL) and then with saturated NaCl solution (1 ml). The organic phase was extracted, dried over anhydrous Na2SO4, and filtered. The crude product was re-suspended in MeOH (1 mL) and purified by reversed phase HPLC (5-95% acetonitrile in H2O; 16 minute gradient). The pure fractions were combined and solvent was removed on the rotovap to afford 2-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)-N-phenylacetamide as a white solid (50%). 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H), 2.40 (s, 3H), 2.72 (m, 1H), 3.14-3.13 (d, 1H, J=4 Hz), 4.54-4.51 (d, J=8 Hz 1H), 5.04 (s, 2H), 6.53 (bs, 1H), 7.15-7.13 (m, 1H), 7.33-7.22 (m, 2H), 7.47-7.45 (d, J=8 Hz, 2H), 7.78 (bs, 1H), 7.09 (s, 1H), 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.75 μM.
Reaction SMILES: O=P(Cl)(Cl)Cl.[NH:6]1[C:10]2[CH:11]=[C:12]([C:15]([NH2:17])=O)[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[OH-].[Na+]>CN(C=O)C>[NH:6]1[C:10]2[CH:11]=[C:12]([C:15]#[N:17])[CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: NC(=O)c1ccc2nc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
Under ice-cooling, to DMF (30 ml) was slowly added dropwise POCl3 (6.68 g, 4.06 ml), followed by reaction at room temperature for 2 hours, and then a solution of 1H-benzimidazole-6-carboxamide (2.38 g) in DMF (47.6 ml) was added thereto, followed by stirring at room temperature for 2 hours. To the solution was added a 1M aqueous NaOH solution (pH 6 to 7), followed by stirring at room temperature for 0.5 hour. The solution was extracted with EtOAc, and the organic layer was combined, washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography, and powdered/washed with IPE to obtain 1H-benzimidazole-6-carbonitrile (0.58 g) as a pale red crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20]O)[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][Cl:24])[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCC(CO)CC2)ccc1Cl
Product: O=C(O)c1cc(S(=O)(=O)N2CCC(CCl)CC2)ccc1Cl

Procedure:
2-Chloro-5-(4-hydroxymethylpiperidinosulfonyl)benzoic acid (5.0 g.) is refluxed overnight with 50 ml. of thionyl chloride. After evaporation to dryness, the residue is dissolved in 70 ml. of acetone, 30 ml. of water added and the mixture is allowed to stand at room temperature for a half hour. The solution is then filtered and concentrated to half volume. On the addition of 20 ml. of water a precipitated oil is obtained which crystallizes on stirring. Recrystallization from acetone-benzene yields the product, m.p. 175°-177° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH:20]=[O:21])[CH:7]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][OH:21])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1cccc(Oc2ccc(Br)cc2CO)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.9 %

Procedure:
To [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.70 g, 1.9 mmol) in MeOH (20 mL) was added sodium borohydride (0.07 g, 1.9 mmol), and the reaction was stirred for 5 minutes at room temperature. Once no starting material was seen by analytical tlc, the mixture was worked-up to give the desired product (0.7 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].CCN(CC)CC>C1COCC1>[CH3:18][C:15]1[CH:14]=[C:13]([C:6]2[C:7](=[O:12])[NH:8][C:9]3[C:4]([C:5]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:3][C:2]([NH:1][C:25](=[O:27])[CH3:26])=[CH:11][CH:10]=3)[O:17][N:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(N)ccc3[nH]c2=O)on1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2[nH]c(=O)c(-c3cc(C)no3)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A flask charged with 6-amino-3-(3-methyl-isoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (0.027 mg, 0.085 mmol)(Example 52), acetic anhydride (0.01 mL, 0.100 mmol), NEt3 (0.018 mL, 0.13 mmol) and 1 mL of THF was stirred for 6 hrs at 25° C. The title compound was eluted from a 5 g SPE with 100% EtAc to give 0.015 g (50%) of a white solid. 1H NMR (400 MHz, CDCl3) 12.30 (s, 1H), 8.06 (s, 1H), 7.72 (m, 1H), 7.36 (m, 5H), 7.14 (m, 2H), 6.36 (s, 1H), 2.22 (s, 3H), 2.02 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C21H17N3O3 359.1, found 360.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[CH:3]=1.[I:22]N1C(=O)CCC1=O>C(#N)C.ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([S:14][C:15]([F:16])([F:17])[F:18])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[I:22]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)n1
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(SC(F)(F)F)cc2Cl)c(N)c1I

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylsulphenylphenyl)pyrazole (10 g) in acetonitrile (50 ml) at room temperature was added N-iodosuccinimide (6.4 g) in acetonitrile (25 ml). After 15 minutes the mixture was evaporated to dryness leaving and the residual buff solid taken up in dichloromethane (300 ml). The solution was washed with water (75 ml, ×3), then brine (50 ml), then dried (MgSO4) and evaporated. Trituration with hexane (100 ml, ×2) to provide the title compound as buff solid m.p. 172-174° C.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH3:20])=[N:18][CH:19]=[C:14]2[C@H:13]([NH:21]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>ClCCl>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH3:20])=[N:18][CH:19]=[C:14]2[C@H:13]([NH2:21])[CH2:12][CH2:11]1
Reactant: Cc1ncc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ncc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2N
Reaction time: 2 h

Procedure:
Hydrochloric acid (4.0 M in dioxane; 3.0 mL, 12.0 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-9-yl]carbamate (33 mg, 0.087 mmol) in dichloromethane (3 mL). After 2 h, the reaction mixture was concentrated to give the hydrochloride salt of the title compound. MS 278.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:23]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccccc1C(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 80.1 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) 2-methoxybenzoyl chloride, 13.4 mg (80%) of the title compound were recovered as a beige solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:8]C(=O)C)[CH3:7])(=[O:3])[CH3:2].[C:12](OC)(=[O:14])C>CO>[C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[CH3:12][OH:14].[CH2:5]([OH:4])[CH:6]([OH:8])[CH3:7]
Reactant: CC(=O)OCC(C)OC(C)=O
Solvent: CO
Solvent: COC(C)=O
Product: CC(O)CO
Temperature: 62 °C

Procedure:
A suspension is prepared from 800 parts of 1,2-diacetoxypropane, 960 parts of methanol and 176 parts of cation exchanger (®Lewatit SPC 108) in a stirred reactor, provided with a distillation unit, by stirring at 300 rpm, and the mixture is heated at 62° C. (The exchange resin is a sulfonated styrene/divinylbenzene copolymer resin; it has a macro-porous structure and a particle size of from 0.3 to 15 mm). 910 parts of the azeotropic mixture of methanol and methyl acetate, of boiling point 54° C., are distilled off in the course of 4 hours. The ion exchanger is then filtered off. Distillation gives 470 parts of a methyl acetate/methanol mixture and 376 parts of 1,2-propanediol.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[F:21][C:22]([F:38])([F:37])[C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][C:35]#[N:36])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1>>[F:21][C:22]([F:37])([F:38])[C:23]1[CH:24]=[C:25]([C:33]2[CH:34]=[C:35]([NH2:36])[N:12]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:11]3[CH:10]=2)[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccco2)n1)c1ccccc1
Reactant: N#CC=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Nc1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc2nc(-c3ccco3)nn12

Procedure:
The title compound, MS m/e (%): 412 (M+, 100), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-furan-2-yl-1H-[1,2,4]triazole and 3-[3,5-bis(trifluoromethyl)phenyl]acrylonitrile.