Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:28][C:27](=O)[CH:26]=[C:25]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N:36]3[CH:40]=[CH:39][N:38]=[N:37]3)[CH:31]=2)[O:24]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:28])[CH2:26][C:25](=[O:24])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnn3)c2)O1
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J9) (306 mg. 1.0 mmol) and 2,2-dimethyl-6-(3-[1,2,3]triazol-1-yl-phenyl)-[1,3]dioxin-4-one (Example L9) (271 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow solid (394 mg).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([OH:12])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:18][C:19]1[N:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1>>[Si:1]([O:8][C@@H:9]([CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:10]([NH:25][C:22]1[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][N:23]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)OC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: Cc1cnc(N)cn1
Product: Cc1cnc(NC(=O)[C@H](COC(C)C)O[Si](C)(C)C(C)(C)C)cn1

Procedure:
C8a was prepared in an analogous fashion to C4d from (S)-2-(tert-butyldimethylsilyloxy)-3-isopropoxypropanoic acid C7c and 5-methylpyrazin-2-amine. 1H NMR (400 MHz, CDCl3) δ 0.20 (3H, s), 0.21 (3H, s), 1.0 (9H, s), 1.14 (3H, d), 1.17 (3H, d), 2.54 (3H, s), 3.61-3.65 (2H, m), 3.77-3.80 (1H, m), 4.40 (1H, dd), 8.14 (1H, d), 9.01 (1H, s), 9.43 (1H, d)
Reaction SMILES: [CH3:1][C@@:2]([OH:31])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:30])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:3]OS(C1C=CC(C)=CC=1)(=O)=O.C(O)C.[OH-].[Na+]>O>[O:31]1[C@:2]([CH3:1])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:30])[CH2:19][CH2:20][CH2:21][CH:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@](C)(O)CCCC(C)CCCC(C)CCCC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CCCC(C)CCCC(C)CCC[C@]1(C)CO1
Reaction time: 16 h

Procedure:
1.52 g (3.3 mmol) of (2R,6RS,10RS)-2,6,10,14-tetramethyl-1-tosyloxy-2-pentadecanol were dissolved ind 20 ml of ethanol. 2 ml of sodium hydroxide solution (50%) were then added and the mixture was stirred for 16 hours. Subsequently, 50 ml of water were added and the mixture was stirred up with HYFLO. The suspension was then filtered and washed with water. The residue was triturated with diethyl ether, dried over sodium sulphate, filtered and concentrated. There was obtained (2R,6RS,10RS)-1,2-epoxy-2,6,10,14-tetramethylpentadecane with [α]D20 =-0.21° (c=2% in CHCl3).
Reaction SMILES: [CH:1](=[N:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:20]1.C[Si](C=[N+]=[N-])(C)C>CO>[CH:1](=[N:8][NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:20])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1ccccc1NN=Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccccc1NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
2-(N′-Benzylidene-hydrazino)-benzoic acid (5.0 g, 20.81 mmol) in 1:1 tetrahydrofuran and methanol (50 mL) was reacted with a solution of trimethylsilyl diazomethane in hexanes (2.0M, 12 mL, 25.0 mmol) at 0° C. for 1 hour then stirred at 25° C. for 48 hours. The solvent was removed under vacuum to give the title compound as a solid (6.00 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ ppm 3.87 (s, 3 H) 6.84 (td, J=7.54, 1.10 Hz, 1 H) 7.41 (m, 3 H) 7.54 (m, 1 H) 7.74 (m, 3 H) 7.86 (dd, J=8.09, 1.47 Hz, 1 H) 8.21 (s, 1 H) 11.02 (s, 1 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:22])([F:21])[C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][OH:20])[CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[F:11][C:12]([F:21])([F:22])[C@H:13]1[CH2:14][CH2:15][C@H:16]([CH:19]=[O:20])[CH2:17][CH2:18]1
Reactant: OC[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (6.2 mL, 87.4 mmol) in anhydrous CH2Cl2 (300 mL) was added dropwise DMSO (12.5 mL, 0.17 mol) at −78° C. under N2. After the mixture was stirred at −78° C. for 30 min., a solution of (trans-4-(trifluoromethyl)cyclohexyl)methanol (5.3 g, 29.1 mmol) in CH2Cl2 (40 mL) was added dropwise while keeping the internal temperature below −65° C. After being stirred for 30 min., a solution of Et3N (40.5 mL, 0.29 mol) in CH2Cl2 (60 mL) was added dropwise slowly, keeping the internal temperature below −65° C. The reaction mixture was stirred at −78° C. for 1 h, and warmed to rt overnight. The mixture was washed with water (3×300 mL) and brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (eluting with 15% EtOAc in petroleum ether) to give trans-4-(trifluoromethyl)cyclohexane-1-carbaldehyde (4.6 g, 87%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](N(C2C=CC=C(O)C=2)CC2NCCN=2)=[CH:6][CH:7]=1.CC([N:32]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH2:33][CH2:34][Cl:35])COC1C=CC=CC=1.COC1C=C2C(N)=NC(N3CCN(C(C4OC=CC=4)=O)CC3)=NC2=CC=1OC.C1C=CC(CC2NCCN=2)=CC=1>>[CH:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:32]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:33][CH2:34][Cl:35])=[CH:42][CH:41]=1
Reactant: CC(COc1ccccc1)N(CCCl)Cc1ccccc1
Reactant: Cc1ccc(N(CC2=NCCN2)c2cccc(O)c2)cc1
Agent: COc1cc2nc(N3CCN(C(=O)c4ccco4)CC3)nc(N)c2cc1OC
Agent: c1ccc(CC2=NCCN2)cc1
Product: ClCCN(Cc1ccccc1)Cc1ccccc1

Procedure:
phentolamine; phenoxybenzamine; prazosin; tolazoline;
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]([CH2:17][CH3:18])[N:5]=1.C(O)(C(F)(F)F)=O.O>C1COCC1>[CH2:17]([N:6]1[C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:8][C:4]([CH:3]=[O:2])=[N:5]1)[CH3:18]
Reactant: CCn1nc(C(OC)OC)cc1-c1cccc(C#N)c1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCn1nc(C=O)cc1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A mixture of 3-(3-dimethoxymethyl-1-ethyl-1H-pyrazol-5-yl)-benzonitrile (5.0 g, 18.4 mmol), TFA (5.0 mL), H2O (20 mL) and THF (50 mL) was stirred at RT for 1 hour and then concentrated under reduced pressure to remove the organic solvents. The residue was neutralised with 1N NaOH solution (100 mL), extracted with EtOAc (2×150 mL), dried (MgSO4) and concentrated under reduced pressure while dry loading onto MgSO4. The mixture was then purified by column chromatography on silica eluting with 35-60% EtOAc/iso-hexanes to yield the desired aldehyde (2.91 g, 70%). 1H NMR (CDCl3, 500 MHz) δ 10.00 (1H, s), 7.80-7.72 (1H, m), 7.70 (1H, s), 7.67-7.60 (2H, m), 6.84 (1H, s), 4.23 (2H, q, J=7.3 Hz), 1.49 (3H, t, J=7.3 Hz). MS (ES+) C13H11N3O requires: 225, found: 226 (M+H+, 100%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=1)[CH3:3].C(N(CCCC)CCCC)CCC.[NH:33]1[C:37]2[CH:38]=[CH:39][C:40]([C:42](O)=[O:43])=[CH:41][C:36]=2[N:35]=[CH:34]1.[I-].ClC1C=CC=C[N+]=1C>CN(C)C=O>[CH2:2]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:42]([C:40]3[CH:39]=[CH:38][C:37]4[NH:33][CH:34]=[N:35][C:36]=4[CH:41]=3)=[O:43])=[CH:10][CH:11]=2)[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=1)[CH3:3]
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CCc1nn(-c2ccccc2)c2cc(N)ccc12
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCc1nn(-c2ccccc2)c2cc(NC(=O)c3ccc4[nH]cnc4c3)ccc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 3-ethyl-1-phenyl-1H-indazol-6-amine hydrochloride (300 mg, 1.10 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL), tributylamine (492 mg, 2.66 mmol, 2.50 equiv), 1H-benzo[d]imidazole-5-carboxylic acid (180 mg, 1.11 mmol, 1.00 equiv), 2-chloro-1-methylpyridinium iodide (330 mg, 1.29 mmol, 1.20 equiv). The resulting solution was stirred for 2 days at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (50:1). The resulting mixture was diluted with methanol (10 mL) and the solids were washed with diethyl ether (1×50 mL) to yield N-(3-ethyl-1-phenyl-1H-indazol-6-yl)-1H-benzo[d]imidazole-5-carboxamide as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[CH3:32][N:33]1[CH:37]=[C:36]([CH:38]=O)[CH:35]=[N:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:54]CCl>C(O)(=O)C>[ClH:54].[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:38][C:36]2[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: Cn1cc(C=O)cn1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C[C@@H]2CN(Cc3cnn(C)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.2 g), 1-methyl-4-formyl-1H-pyrazole (50 mg), and sodium triacetoxyborohydride (151 mg) in dichloromethane (2 ml) was added one drop of acetic acid. After being stirred at room temperature overnight, the solution was evaporated under reduced pressure. The resulting residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate-methanol as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(1-methyl-1H-pyrazol-4-yl)methyl]piperazine hydrochloride (97 mg).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:23])[CH2:21]Cl)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[OH-].[Na+]>CCOCC>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH:20]([CH3:23])[CH2:21][NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH2:8])=[CH:17][CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(CCl)Cc1ccc(C(C)(C)C)cc1
Reactant: N[C@@H]1CCCC[C@H]1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(CN[C@@H]1CCCC[C@H]1N)Cc1ccc(C(C)(C)C)cc1
Temperature: 140 °C
Reaction time: 10 h
Yield: 83.5 %

Procedure:
274 g of trans-1,2-diaminocyclohexane and 134.4 g of 3-(4-tert.-butylphenyl)-2-methylpropyl chloride (German Laid-Open Application DOS No. 2,752,096) were stirred for 10 hours at 140° C. and then cooled to +10° C. in an ice bath, and 200 ml of a 50% strength by weight sodium hydroxide solution were added slowly, followed by the addition of 200 ml of ether. The organic phase was separated off, dried over potassium hydroxide and distilled to give 151 g of N-(3-(4-tert.-butylphenyl)-2-methylpropyl)-trans-1,2-diaminocyclohexane of boiling point 175°-180° C./0.3 mbar. Yield: 83.3% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][C:27]1([CH3:33])[CH3:32]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[C:27]([CH3:33])([CH3:32])[CH2:28]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: CN1CCNCC1(C)C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C)C(C)(C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1,2,2-trimethylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (br. s., 6 H) 2.20 (s, 3 H) 2.35 (s, 3 H) 2.60 (t, J=5.05 Hz, 2 H) 2.97-3.72 (m, 4 H) 7.53 (dd, J=8.08, 1.52 Hz, 1 H) 7.59 (d, J=1.01 Hz, 1 H) 7.85 (d, J=8.08 Hz, 1 H) 7.93 (d, J=7.33 Hz, 1 H) 7.98 (s, 1 H) 8.36 (d, J=8.59 Hz, 1 H) 8.43 (br. s., 1 H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>O1CCOCC1>[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN(SSc1ccc(Cl)cc1)C(=O)F
Reactant: CN1C(=O)C(C)(C)SC1=NO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(SSc1ccc(Cl)cc1)C(=O)ON=C1SC(C)(C)C(=O)N1C

Procedure:
2-[[O-[N-Methyl-N-(4-chlorophenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was prepared according to the procedure described in Example I, by reacting 5.0 g (0.0287 m) of 3,5,5-trimethyl-2-oximinothiazolidin-4-one, 7.22 g (0.0287 m) of N-methyl-N-(4-chlorophenylthiosulfenyl)carbamoyl fluoride and 2.9 g (0.0287 m) of triethylamine in 50 ml of dioxane. 2-[[O-[N-Methyl-N-(4-chlorophenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was crystallized from isopropyl ether to yield 5.9 g of a white solid, m.p. 74°-76° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.N1C=CC=CC=1.[Br:22]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:22])=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: BrBr
Reactant: COc1ccc(-c2cnc(N)cn2)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(N)c(Br)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.3 %

Procedure:
To a solution of 2-amino-5-(4-mcthoxyphenyl)pyrazinc 16a (0.35 g, 1.7 mmol) and pyridine (0.20 mL, 2.6 mmol) in chloroform (20 mL), bromine (Br2) (0.13 mL, 2.6 mmol) was added dropwise in chloroform (3 mL) at −10° C. After 6 h stirring at room temperature, the reaction mixture was washed with water, the organic layer dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography using dichloromethane-EtOAc (90:10 v/v) as eluent, to obtain 0.33 g of 17a as an brown solid (mp 166-170° C., 70% yield). 1H-NMR (CDCl3): 3.83 (s, 3H), 5.04 (br s, 2H), 6.92-6.96 (m, 2H), 7.76-7.80 (m, 2H), 8.31 (s, 1H). GC-MS (EI): m/z 279,281 (M1, 100).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[CH2:22][C:21]3[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([O:31]C(C)(C)C)=[O:30])[CH:25]=[N:26][C:20]=3[NH:19][C:18]2=[O:36])[CH2:11][CH2:10]1.[Cl:37]CCl>>[ClH:37].[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[CH2:22][C:21]3[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])[CH:25]=[N:26][C:20]=3[NH:19][C:18]2=[O:36])[CH2:11][CH2:10]1
Reactant: CN1CCN(CCN2Cc3cc(/C=C/C(=O)OC(C)(C)C)cnc3NC2=O)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CCN2Cc3cc(/C=C/C(=O)O)cnc3NC2=O)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a suspension (E)-tert-butyl 3-(3-(2-(4-methylpiperazin-1-yl)ethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylate (1.1 g, 3.76 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was solubilized in a solution of hydrochloric acid in dioxane (4N, 10 mL). After 10 minutes stirring at room temperature, the precipitate was filtered and washed with diethyl ether to afford the title product as a pale yellow solid (90 mg, quantitative).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[C:4]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(CC)cc3cc(OC)ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Temperature: 60 °C
Yield: 98 %

Procedure:
To a solution of ethyl (2E)-3-(4-{[3-ethyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)-2-propenoate (59) (0.67 g, 1.49 mmol) in THF (10 mL) and EtOH (10 mL) was added 1 N NaOH (12 mL). The resulting mixture was heated at 60° C. for 2 h. Cooled in an ice bath, the mixture was acidified with 2 N HCl and extracted with EtOAc (3×50 mL). The extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product, which was triturated with hot hexanes (containing a small amount of CHCl3 and MeOH) to give 0.62 g (98%) of the title compound (60) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.13 (t, J=7.5 Hz, 3H), 2.56 (q, J=7.5 Hz, 2H), 3.94 (s, 3H), 6.23 (d, J=15.9 Hz, 1H), 6.59 (d, J=8.8 Hz, 2H), 7.04 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.10-7.16 (m, 2H), 7.19 (d, J=2.5 Hz, 1H), 7.20-7.30 (m, 5H), 7.60 (s, 1H), 7.63 (d, J=15.8 Hz, 1H), 7.70 (d, J=9.2 Hz, 1H). LCMS (ESI): m/z 423 (M−H)−.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].[CH2:13](N)[CH3:14].[F:16][C:17]([F:40])([F:39])[C:18]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][N:34]=[CH:33]2)([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH3:29])[CH:21]=1)[OH:19]>N1C=CC=CC=1>[CH2:7]([NH:3][C:1]([N:35]1[C:36]2[C:32](=[CH:31][C:30]([C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH2:29][CH:13]=[CH2:14])[CH:21]=3)([OH:19])[C:17]([F:16])([F:39])[F:40])=[CH:38][CH:37]=2)[CH:33]=[N:34]1)=[O:2])[CH3:6]
Reactant: Cn1cc(C(O)(c2ccc3[nH]ncc3c2)C(F)(F)F)c2ccccc21
Reactant: CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3C(=O)NCC)c2)C(F)(F)F)c2ccccc21
Temperature: 100 °C
Reaction time: 5 h
Yield: 23.8 %

Procedure:
To a solution of carbonyldiimidazole (0.282 mmol) in 1 mL pyridine was added ethylamine (0.282 mmol; 2.0 M in THF) dropwise. The mixture was stirred 5 hours and then 2,2,2-trifluoro-1-(1H-indazol-5-yl)-1-(1-methyl-1H-indol-3-yl)ethanol (0.189 mmol) was added. The mixture was heated at 100° C. for 16 hours in a sealed tube. Removal of the volatiles provided a residue which was purified by flash silica gel chromatography using 33% ethyl acetate in hexanes. The product-rich fractions were concentrated in vacuo to afford the title compound (0.045 mmol), m.p. 162° C.-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[SH:11][CH2:12][CH:13]([OH:15])[CH3:14]>>[Cl:1][C:2]1[CH:9]=[C:8]([S:11][CH2:12][CH:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(O)CS
Product: CC(O)CSc1ccc(C#N)c(Cl)c1

Procedure:
2 g of 2-chloro-4-fluorobenzonitrile was reacted with 1-mercapto-2-propanol via Procedure Q to afford 2-chloro-4-(2-hydroxypropylthio)benzonitrile. 2.5 g of 2-chloro-4-(2-hydroxypropylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-hydroxypropylthio)benzoic acid. 2.1 g of 2-chloro-4-(2-hydroxypropylthio)benzoic acid was reacted via Procedure R to give 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 465.2 (M)+.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]=1)=O.Cl.[NH2:14]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]=1)#[N:14]
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
A mixture of 3-formyl-5-methylindole (0.50 g), hydroxylamine hydrochloride (0.44 g) and sodium acetate (0.52 g) in acetic acid (5 ml) was stirred for 2 hours, then acetic anhydride (2.5 ml) was added to the mixture and allowed to react under reflux for 0.5 hour. After cooling, the reaction mixture was poured into ice-water and extracted with ethyl acetate. After filtration of insoluble materials, the filtrate was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and chloroform. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give 3-cyano-5-methylindole (109 mg).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH3:4].C(O)C>O>[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:20][C:21]([CH3:27])([CH3:28])[C:22]([OH:24])=[O:23])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH3:4]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aqueous sodium hydroxide (1.5 mL of 50%, 19 mmol) was added to a mixture of ethyl 3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropanoate (5.0 g, 14 mmol), ethanol (50 mL), and water (5 mL). The reaction was stirred for two hours at ambient temperature; an analysis by TLC indicated that starting material was present. Additional aqueous sodium hydroxide (0.5 mL of 50%) was added, and the reaction was heated at reflux for two hours and concentrated under reduced pressure. Ethanol (100 mL) was added to the residue and then removed under reduced pressure to provide 3-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2,2-dimethylpropanoic acid, which was dried overnight under vacuum.