Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH2:32]([N:34](C(C)C)[CH:35](C)C)C.CNC>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([N:34]([CH3:35])[CH3:32])=[O:30])=[CH:26][CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)s5)nn34)ccnc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)N(C)C)s5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiophene-2-carbonyl chloride (0.260 g, 0.58 mmol) in dichloromethane was added N-ethyl-N-isopropylpropan-2-amine (0.20 ml, 1.2 mmol) and dimethylamine (1.4 ml, 2.9 mmol). The solution was stirred at room temperature for one hour then was concentrated in vacuo. The residue was triturated with water and filtered; the resulting precipitate was triturated with acetonitrile and filtered to yield the product as an off-white solid. MS m/z=461.0 [M+1]+. Calc'd for C23H20N6O3S: 460.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:28]=1[CH2:29][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C)c1CO
Reactant: N#CCCc1cccc(O)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(CCC#N)c1
Temperature: 25 °C

Procedure:
A solution of 3-(3-hydroxyphenyl)propanenitrile (Step B, 1.25 g, 8.5 mmol) and diisopropyl azodicarboxylate (DIAD, 1.87 g, 9.26 mmol) in dry THF (10 ml) was added drop wise to a solution of 2,6-Dimethylbenzyl alcohol (1.27 g, 9.3 mmol) and triphenylphosphine (TPP, 2.43 g, 9.26 mmol) in dry THF (30 ml) at 0° C. under argon. The reaction mixture was warmed to room temperature for 4 hours or until all the starting material is consumed, diluted with ether and washed with water (2×). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16](O)=[S:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH3:23][O:22][N:21]([CH3:20])[C:16]([C:8]1[NH:9][C:10]2[C:15]([C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[S:17]
Reactant: CNOC
Reactant: OC(=S)c1[nH]c2ccccc2c1-c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CON(C)C(=S)c1[nH]c2ccccc2c1-c1ccccc1

Procedure:
The title compound was prepared from 3-phenylthioindole-2-carboxylic acid (1.0 g, 3.7 mmol), N,O-dimethylhydroxylamine hydrochloride (0.54 g, 5.5 mmol), triethylamine (1.5 mL, 11 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (1.64 g, 3.7 mmol) according to the procedure described in Example 1 for N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O-:19])=[O:18])=[C:15]([OH:20])[C:14]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:27][C:28]([NH2:30])=[O:29]>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][C:11]([CH3:16])([CH3:12])[CH3:10])=[O:18])=[C:15]([O:20][CH2:27][C:28](=[O:29])[NH2:30])[C:14]([C:21]3[CH:25]=[CH:24][O:23][CH:22]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)CBr
Reactant: O=C([O-])c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: CC(C)(C)OC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OCC(N)=O

Procedure:
6-(benzenesulphonylmethyl)-3-(furan-3-yl)-2-hydroxybenzoate (Intermediate 120) and 2-bromoacetamide.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[I:27]I>ClCCl.C(Cl)(Cl)Cl>[Cl:26][C:21]1[CH:20]=[C:19]([N:18]2[CH:2]([CH2:3][I:27])[CH2:1][C:4]3[C:5]4[C:6]2=[N:7][CH:8]=[N:9][C:10]=4[CH:11]=[C:12]([O:16][CH3:17])[C:13]=3[O:14][CH3:15])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reactant: II
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(3-chloro-4-fluoro-phenyl)-amine (0.102 g, 0.27 mmol) (from Example 18, Step E, supra) in dichloromethane (20 mL) was added I2 (0.69 g, 2.7 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with chloroform (100 mL) and washed with a saturated aqueous Na2SO3 solution. The organic layer was separated, dried over Na2SO4, and concentrated to give the desired 4-(3-chloro-4-fluoro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenalene as a yellow foam. (Yield 0.134 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N+](C1C=CC([C:16]2[C:24]([CH2:25][C@H:26]3[C@@H:31]([OH:32])[C:30]4[CH:33]=[C:34]([O:37][CH2:38][C:39]5[S:40][C:41]6[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:42]=6[N:43]=5)[CH:35]=[CH:36][C:29]=4[O:28][CH2:27]3)=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([O-])=[O:19])=CC=1)([O-])=O>>[F:48][C:45]1[CH:46]=[CH:47][C:41]2[S:40][C:39]([CH2:38][O:37][C:34]3[CH:35]=[CH:36][C:29]4[O:28][CH2:27][C@@H:26]([CH2:25][C:24]5[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=5)[C:18]([NH:1][C:2]5[S:3][CH:4]=[CH:5][N:6]=5)=[O:19])[C@@H:31]([OH:32])[C:30]=4[CH:33]=3)=[N:43][C:42]=2[CH:44]=1
Reactant: Nc1nccs1
Reactant: O=C([O-])c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1-c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1nccs1)c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1
Yield: 13.3 %

Procedure:
Synthesis was carried out as in example 1, but using 1.43 grams 2-aminothiazole instead of methane sulfonamide, and using 1.17 grams cis-4-nitrophenyl-3-[[6-[(5-fluoro-2-benzothiazolyl)methoxy]-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-yl]methyl]benzoate. There was obtained 145 milligrams of product, m.p. 120° C.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([OH:16])=O)[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[F:32])[N:28]([CH2:33][C@@H:34]1[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35]1)[C:27]([C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])=[CH:26]2.C(N(CC)CC)C>CN(C=O)C.ClCCl>[F:17][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][C:31]=4[F:32])[N:28]([CH2:33][C@@H:34]4[CH2:38][O:37][C:36]([CH3:39])([CH3:40])[O:35]4)[C:27]([C:41]([CH3:45])([CH3:44])[CH2:42][OH:43])=[CH:26]5)=[O:16])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: CC1(C)OC[C@@H](Cn2c(C(C)(C)CO)cc3cc(N)c(F)cc32)O1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC1(C)OC[C@@H](Cn2c(C(C)(C)CO)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)c(F)cc32)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
DMF (3 drops) was added to a stirring mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7 mmol) and thionyl chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The solution was concentrated under vacuum and then toluene (3 mL) was added and the mixture was concentrated again. The toluene step was repeated once more and the residue was placed on high vacuum for 10 minutes. The acid chloride was then dissolved in dichloromethane (10 mL) and added to a mixture of (R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-1H-indol-2-yl)-2-methylpropan-1-ol (1.8 g, 5.4 mmol) and triethylamine (2.24 mL, 16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room temperature for 1 hour. The reaction was washed with 1N HCl solution, saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated to yield the product as a black foamy solid (3 g, 100%). ESI-MS m/z calc. 560.6, found 561.7 (M+1)+. Retention time 2.05 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (s, 1H), 7.42-7.40 (m, 2H), 7.34-7.30 (m, 3H), 6.24 (s, 1H), 4.51-4.48 (m, 1H), 4.39-4.34 (m,2H), 4.08 (dd, J=6.0, 8.3 Hz, 1H), 3.69 (t, J=7.6 Hz, 1H), 3.58-3.51 (m, 2H), 1.48-1.45 (m, 2H), 1.39 (s, 3H), 1.34-1.33 (m, 6H), 1.18 (s, 3H) and 1.14-1.12 (m, 2H) ppm
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH2:9][CH2:8][C:7]3[S:10][C:11]([NH:13][C:14]([CH:16]4[C:18]([CH3:20])([CH3:19])[C:17]4([CH3:22])[CH3:21])=[O:15])=[N:12][C:6]=3[C:5]=12.CC(C)([O-])C.[K+].[CH3:29][O:30][CH2:31][CH2:32]Br>COCCOC.CCOC(C)=O>[CH3:29][O:30][CH2:31][CH2:32][N:12]1[C:6]2[C:5]3=[N:1][O:2][N:3]=[C:4]3[CH2:9][CH2:8][C:7]=2[S:10]/[C:11]/1=[N:13]\[C:14]([CH:16]1[C:18]([CH3:20])([CH3:19])[C:17]1([CH3:22])[CH3:21])=[O:15]
Reactant: CC1(C)C(C(=O)Nc2nc3c(s2)CCc2nonc2-3)C1(C)C
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COCCn1c2c(s/c1=N\C(=O)C1C(C)(C)C1(C)C)CCc1nonc1-2
Temperature: 250 °C

Procedure:
The product of Example 123B (1 equiv), potassium tert-butoxide (1.1 equiv) and 2-bromoethyl methyl ether (1 equiv) were combined in DME (0.1 M) and heated in a SmithSynthesizer™ microwave at 250° C. for 15 minutes. The mixture was diluted with EtOAc and washed with 1 M aqueous NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography afforded the title compound and the product of Example 124. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 6H), 1.26 (s, 6H), 1.57 (s, 1H), 3.10 (t, J=7.5 Hz, 2H), 3.23 (s, 3H), 3.26 (t, J=7.4 Hz, 2H), 3.71 (t, J=5.8 Hz, 2H), 4.67 (t, J=5.8 Hz, 2H); MS (ESI+) m/z 377 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13][C:14]=2[N:15]=1)#[N:2].[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[N:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:18][C:10]1=2
Reactant: C1CNCCN1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21
Product: CC1(C)c2cc(N3CCNCC3)ccc2C(=O)c2c1[nH]c1nc(C#N)ccc21

Procedure:
According to the method used for synthesizing Compound B2-1, trifluoromethanesulfonic acid 2-cyano-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluoren-8-yl ester was introduced with piperazine to obtain the title compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19](O)=[O:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>ClCCl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[O:20])=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: CN1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Reaction time: 4 h

Procedure:
1-Benzenesulfonylindole-3-carboxylic acid (3.01 g, 0.01 moles) was stirred with oxalyl chloride (1.309 g, 0.011 moles) in 20 mL dichloromethane at 0 to 25° C. for 3-4 hours. After completion of the reaction (T.L.C.), volatile substances were distilled off under the reduced pressure. The residue was taken in 20 mL dichloroethane and to this stirred solution, was added N-methylpiperazine (1.1 g, 0.011 moles). The reaction mixture was further stirred for next 3-5 hours till the reaction completes (TLC). Reaction mixture was diluted with dichloromethane 20 mL), washed with water, brine and saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and the organic solvents were evaporated under vacuo. The product was purified using column chromatography on silica gel G stationary phase and suitable combinations of ethyl acetate and methanol in increasing gradient as the mobile phase. IR spectra (cm−1) 3140, 1621, 1552, 1451; Mass (m/z): 484 (M+H)+
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].F[C:22]1[N:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:22]3[N:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=3)[CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Reactant: COC(=O)c1ccc(F)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(C(=O)OC)cn3)C[C@H]2OC)nc1Cl
Yield: 96.3 %

Procedure:
The same operation as in Example (158a) was performed using cis(±)-4-chloro-5-ethyl-N-(3-methoxypiperidin-4-yl)-1H-imidazole-2-carboxamide hydrochloride obtained in Example (159a) (104 mg, 0.32 mmol), methyl 6-fluoropyridine-3-carboxylate (50 mg, 0.32 mmol) and diisopropylethylamine (125 mg, 0.97 mmol), to obtain 130 mg of the title compound as a yellow brown oily substance (96%).
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[Cl:8][CH:9]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10]1>CO.ClCCl>[Cl:8][CH:9]1[CH2:12][CH:11]([C:13]([O:15][CH3:2])=[O:14])[CH2:10]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C1CC(Cl)C1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CC(Cl)C1

Procedure:
TMS-diazomethane (2.0 M in diethyl ether, 2.2 ml, 4.4 mmol) was added dropwise to a solution of 3-chlorocyclobutanecarboxylic acid (540 mg, 4.0 mmol) in methanol (5.0 mL) and dichloromethane (5.0 mL) at 0° C. The reaction mixture was concentrated under reduced pressure to afford methyl 3-chlorocyclobutanecarboxylate. The material was used in the subsequent reaction without purification.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[N:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][NH:37][C:38](=[O:39])[C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].C(Cl)Cl>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[N:20][C:19]([N:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][NH:37][C:38](=[O:39])[C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4c5cc[nH]c(=O)c5n(C5CCCC5)c4n3)nn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]ccc2c3cnc(Nc4ccc(N5CCNCC5)nn4)nc3n(C3CCCC3)c12

Procedure:
Compound 162 was treated with 1:1 TFA/DCM (2 mL) at room temperature for an hour. The solvent was evaporated. The residue was re-dissolved in 4 mLl methanol and purified on a C-18 reverse phase column (150×30 mm, 4 micro) using Mass directed preparative HPLC and gradient elution of acetonitrile in water containing 0.1% TFA to provide the title compound 161 as a TFA salt. LCMS retention time (minutes): 0.793. LCMS-ESI (POS), M/Z, M+1: 432.2
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:14])[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)=[O:4].S(Cl)([Cl:17])=O>ClCCl>[Cl:17][C:11]([CH:8]1[CH2:9][CH2:10][C:5]([CH3:14])([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)=[O:12]
Reactant: COC(=O)C1(C)CCC(C(=O)O)CC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1(C)CCC(C(=O)Cl)CC1
Temperature: 38 °C

Procedure:
A solution of 4-(methoxycarbonyl)-4-methylcyclohexanecarboxylic acid (6.67 g, 33.3 mmol) in dichloromethane (30 mL) was charged with thionyl chloride (40 mL, 80 mmol) and then heated to 38° C. for 17 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to yield methyl 4-(chlorocarbonyl)-1-methylcyclohexanecarboxylate, which was used without further purification.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@:9]([OH:31])([C@H:16]([S:18][C@H:19]2[CH2:24][O:23][C@@H](C3C=CC=CC=3)[O:21][CH2:20]2)[CH3:17])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>CO>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@:9]([OH:31])([C@H:16]([S:18][CH:19]([CH2:20][OH:21])[CH2:24][OH:23])[CH3:17])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:5][CH:4]=1
Reactant: C[C@@H](S[C@H]1CO[C@@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
1 ml (12 mmol) of 12 N hydrochloric acid were added to a solution of 3.1 g (7.2 mmol) of (2R,3R)-2-(4-fluorophenyl)-3-[(cis-2-phenyl-1,3-dioxan-5-yl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Step 6(ii) above] in 39 ml of methanol. The resulting mixture was stirred at ambient temperature for 16 hours. At the end of this time, an aqueous sodium hydrogen carbonate solution was carefully added to the reaction mixture until the solution became weakly alkaline. Most of the methanol was evaporated from the mixture under reduced pressure. The resulting residue was then partitioned between ethyl acetate and aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel (30 g) column using a 1:9 mixture of methanol and ethyl acetate as the eluant to afford 2.15 g (yield 87%) of the title compound as a hygroscopic pale brown foamy solid.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1.Br>C(O)(=O)C>[Br:1][CH:11]([CH3:12])[C:10]([C:7]1[CH:8]=[N:9][C:4]([Cl:3])=[CH:5][CH:6]=1)=[O:13]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(Cl)nc1
Agent: Br
Solvent: CC(=O)O
Product: CC(Br)C(=O)c1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Bromine (45.4 g) is slowly added to the mixture of 1-(6-chloro-pyridin-3-yl)-propan-1-one (48.2 g), 0.4 ml of hydrobromic acid (33% solution in acetic acid) and 250 ml of acetic acid at room temperature under a nitrogen atmosphere. Subsequently, the mixture is slowly heated to 80° C. The reaction mixture is stirred at 80° C. for 30 min, during which a yellow suspension is formed, then cooled down to 10° C. and filtered. The solid remainder is washed with tert-butyl methyl ether to deliver 2-bromo-1-(6-chloro-pyridin-3-yl)-propan-1-one hydrobromide as a yellowish solid. To a suspension of this intermediate in 800 ml of tert-butyl methyl ether is added 400 ml of a saturated aqueous sodium bicarbonate solution and the reaction mixture is stirred for 15 min. The phases are separated, the organic layer is washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain 2-bromo-1-(6-chloro-pyridin-3-yl)-propan-1-one as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:3][C:4]([C:6]1[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][CH:11]=[C:10]([OH:21])[CH:9]=2)=[O:5]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C1=C(c2ccccc2)c2ccc(O)cc2C1=O
Yield: 98.6 %

Procedure:
6-Hydroxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (500 mg, 1.70 mmol) prepared in Preparation Example 2 was dissolved in methanol (30 mL), p-toluenesulfonic acid (65 mg, 0.34 mmol) was added thereto, refluxed for 24 hrs, and the solvent was removed therefrom by evaporation. The resulting residue was purified by flash chromatography to obtain 470 mg of the titled compound (yield: 98.6%) as a red solid.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:12][OH:13])C1C=CC=CC=1>CO.[Pd]>[NH2:10][C@H:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:12][OH:13]
Reactant: COc1ccc([C@H](CO)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc([C@@H](N)CO)cc1
Reaction time: 1.5 h
Yield: 102.1 %

Procedure:
A mixture of [(R)-2-Hydroxy-1-(4-methoxy-phenyl)-ethyl]-carbamic acid benzyl ester (761 mg, 2.53 mmol) and Pd/C (76 mg) in MeOH (8 mL) was stirred under H2 (1 atm) for 1.5 h. The mixture was filtered and the filtrate was concentrated to give the titled compound (432 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([O:22]CC)=O)[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[N:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:33][N:26]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:22])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NN1CCCCCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Product: O=C(NN1CCCCCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and hexahydro-1-H-azepin-1-amine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.90 (1H, br), 11.80 (1H, br), 10.13 (1H, br), 8.15 (1H, br s), 7.23 (3H, m), 7.11 (2H, t, J=8.8 Hz), 3.97 (2H, s), 2.94 (4H, m), 1.59 (8H, m); ES+ MS: 411 (M+H+, 100).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:20]=[C:21](CCN)[CH:22]=[CH:23][CH:24]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[C:23]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])[CH:22]=[CH:21][CH:20]=1
Reactant: NCCc1cccc(Cl)c1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCc1cccc(Cl)c1)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 14.5 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (1.22 g, 5.0 mmol) and 2-(3-chlorophenyl)ethylamine (0.79 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 0.24 g (14%) of the titled product as a white solid: