Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([O:37][CH3:38])([C:33]([F:36])([F:35])[F:34])[C:30](O)=[O:31]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30](=[O:31])[C:29]([F:28])([O:37][CH3:38])[C:33]([F:36])([F:35])[F:34])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: COC(F)(C(=O)O)C(F)(F)F
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: COC(F)(C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1)C(F)(F)F

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and rac-2,3,3,3-tetrafluoro-2-methoxy-propionic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=437.1 [M+H]+.
Reaction SMILES: N#N.Cl[C:4]1[N:5]=[N+:6]([O-:19])[C:7]2[C:16]([N:17]=1)=[CH:15][C:14]1[CH2:13][N:12]([CH3:18])[CH2:11][CH2:10][C:9]=1[CH:8]=2.[Sn](CC)(CC)(CC)[CH2:21][CH3:22]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([C:4]1[N:5]=[N+:6]([O-:19])[C:7]2[C:16]([N:17]=1)=[CH:15][C:14]1[CH2:13][N:12]([CH3:18])[CH2:11][CH2:10][C:9]=1[CH:8]=2)[CH3:22]
Reactant: CN1CCc2cc3c(cc2C1)nc(Cl)n[n+]3[O-]
Reactant: CC[Sn](CC)(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: COCCOC
Product: CCc1nc2cc3c(cc2[n+]([O-])n1)CCN(C)C3
Temperature: 85 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
Pd(PPh3)4 (350 mg, 0.3 mmol) was added to a N2-purged, stirred solution of chloride 257 (750 mg, 3.0 mmol) and Et4Sn (1.2 mL, 6.0 mmol) in DME (35 mL), and the mixture was stirred at 85° C. for 18 h under N2. The solution was cooled to 20° C. and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give 1-oxide 260 (590 mg, 81%) as a brown solid: mp 129-131° C.; 1H NMR δ 8.21 (s, 1H, H-10), 7.63 (s, 1H, H-5), 3.79 (s, 2H, H-6), 3.16 (t, J=6.0 Hz, 2H, H-8), 3.02 (q, J=7.6 Hz, 2H, CH2), 2.77 (t, J=6.0 Hz, 2H, H-9), 2.51 (s, 3H, NCH3), 1.43 (t, J=7.6 Hz, 3H, CH3); 13C NMR δ 167.3, 145.8144.6, 138.2, 131.7, 125.0, 118.8, 58.1, 52.3, 45.9, 30.7, 29.6, 12.2; MS (APCI) m/z 245 (MH+, 100%). Anal. calcd for C13H16N4O.¼H2O: C, 62.5; H, 6.7; N, 22.4. Found: C, 62.6; H, 6.6; N, 22.4%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[CH3:22].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([Br:12])=[C:14]([CH3:22])[CH:15]=1
Reactant: COC(=O)c1ccccc1N
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To 2-amino-benzoic acid methyl ester (3.1 g) in dichloromethane (31 mL) was slowly added 4-bromo-3-methyl-benzoyl chloride [21900-25-4] (4.8 g) and triethylamine (3.1 mL). The reaction mixture was then stirred at room temperature for 1 hour. After such time, the reaction mixture was further diluted with dichloromethane (50 mL) and washed with water. The combined aqueous phase was further extracted with dichloromethane. All combined organic phases were then dried over sodium sulfate and concentrated in vacuo. The residue was then recrystallised from ethanol to give 2-(4-bromo-3-methyl-benzoylamino)-benzoic acid methyl ester (6.14 g) as white crystals, m.p.=123° C. MS (m/e): 348.3 (M+H+, 100%).
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:7]([O:9]N1C(=O)CCC1=O)=O)[CH2:3][CH:4]([CH3:6])[CH3:5].C([O-])([O-])=O.[Na+].[Na+].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34]>O1CCCC1>[C:20]([O:19][C:17]([NH:1][C@H:2]([C:7]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: NCCC(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Boc-L-Leu-OSu (5 g, 15.24 mmol) was dissolved in a solution (200 ml) containing equal volumes of tetrahydrofuran and 5% Na2CO3. β-Alanine (2.71 g, 30.48 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. The organic solvent was removed in vacuo and the resulting aqueous solution was washed with diethyl ether (2×50 ml). On acidification with 5% NaHSO4, the product precipitated and was extracted into ethyl acetate (150 ml). The organic layer was washed with brine and dried over magnesium sulphate. On reduction to dryness, Boc-Leu-β-Ala was initially obtained as a clear oil but on standing at -20° C., formed an amorphous solid. The product was judged homogeneous by tlc in chloroform/methanol (4:1) (Rf 0.514) or chloroform/methanol (1:1) (Rf 0.554). Yield 2.89 g (63%), m.p. 91°-92° C. (Found: C, 55.61; H, 8.61; N, 9.29. C14H26O5N2 requires C, 55.63; H, 8.61; N, 9.27%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@H:64]([NH:67][C:68]([C@@H:70]3[CH2:73][CH2:72][N:71]3[C:74]([O:76][CH2:77][C:78]3[CH:83]=[CH:82][C:81]([N+:84]([O-:86])=[O:85])=[CH:80][CH:79]=3)=[O:75])=[O:69])[CH2:63]2)=[O:61])[CH2:43]1>>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=4)=[O:48])[C@H:44]([C:60]([N:62]4[CH2:66][CH2:65][C@H:64]([NH:67][C:68]([C@@H:70]5[CH2:73][CH2:72][N:71]5[C:74]([O:76][CH2:77][C:78]5[CH:83]=[CH:82][C:81]([N+:84]([O-:86])=[O:85])=[CH:80][CH:79]=5)=[O:75])=[O:69])[CH2:63]4)=[O:61])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(N[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)[C@@H]1CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](NC(=O)[C@@H]5CCN5C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 70.6 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (960 mg) and (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-[(2S)-1-(4-nitrobenzyloxycarbonyl)azetidin-2-ylcarbonylamino]pyrrolidin-1-ylcarbonyl]pyrrolidine (1.06 g), reaction and purification were carried out in a similar manner to that described in Example 1-(1), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-[(2S)-1-(4-nitrobenzyloxycarbonyl)azetidin-2-ylcarbonylamino]pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (1.14 g) was obtained as a powder.
Reaction SMILES: [Mg].[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1Br.[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].[Cl-].[NH4+]>C1COCC1>[F:9][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([C:29]2[CH2:30][CH2:31][CH:26]([CH2:25][CH2:24][CH2:23][CH2:22][C@H:19]3[CH2:18][CH2:17][C@H:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:21][CH2:20]3)[CH2:27][CH:28]=2)[C:3]=1[F:2]
Reactant: Fc1cccc(Br)c1F
Reactant: CCCCC[C@H]1CC[C@H](CCCCC2CCC(=O)CC2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCCCC2CC=C(c3cccc(F)c3F)CC2)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
Under nitrogen gas stream, 52.3 g (2150 mmol) of magnesium was added in 100 ml of THF, and a solution of 378 g (1960 mmol) of 2,3-difluoro-1-bromobenzene in 4.0 l of THF was added by drops thereto so that the reaction temperature was maintained at about 50° C. Further, after stirred at room temperature for 1 hour, a solution of 500 g (1630 mmol) of 4-(4-(trans-4-pentylcyclohexyl)butyl)cyclohexanone in 5.0 l of THF was added by drops to the solution and stirred at 50 to 60° C. for 2 hours, and then 1.0 l of saturated aqueous ammonium chloride solution was added to the solution to terminate the reaction. The reaction mixture was filtered with Celite, the solvent was distilled off under a reduced pressure, and then it was extracted with 2.0 l of toluene. The organic layer was washed with 1.0 l of water thrice and dried over anhydrous magnesium sulfate. After the anhydrous magnesium sulfate was removed by filtration, 23.7 g of p-toluenesulfonic acid monohydrate was added to the filtrate and heated to reflux for 4 hours. The organic layer was washed with 1.0 l of water thrice and dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: heptane) to obtain 436 g of a crude 1,2-difluoro-3-(4-(4-(trans-4-pentylcyclohexyl)-butyl)cyclohexene-1-yl)benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7]C(=O)O[C:10](=[O:11])[C:5]=2[CH:4]=1.CC#N.[NH2:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH2:30][CH2:29]2)=[O:27])[CH2:22][CH2:21]1>>[NH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([NH:18][CH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH2:30][CH2:29]2)=[O:27])[CH2:22][CH2:21]1)=[O:11]
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CC(C)C(=O)N1CCN(C(=O)[C@H]2CC[C@H](CN)CC2)CC1
Solvent: CC#N
Product: COc1ccc(N)c(C(=O)NC[C@H]2CC[C@H](C(=O)N3CCN(C(=O)C(C)C)CC3)CC2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 6-Methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (96 mg, 0.5 mmol) in CH3CN (5 mL) K2CO3 (140 mg, 1 mmol) and 1-[trans-4-(4-Aminomethyl-cyclohexanecarbonyl)-piperazin-1-yl]-2-methyl-propan-1-one (148 mg, 0.5 mmol) were added and the reaction was heated at 50° C. for 16 h. The solvent was removed under reduced pressure, 5 mL of 0.4M Na2CO3 solution were added and the mixture was stirred for 1 h. Then 5 mL of DCM were added, the organic phase collected, dried over Na2SO4 and the solvent removed under reduced pressure. 156 mg of the titled product were obtained (yield=68%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[N:5][S:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[C:22]([CH3:33])[C:21]=1[CH3:34]>>[CH:8]1([C:7]2[S:6][N:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=3)[C:3]=2[CH2:2][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([CH3:33])[C:21]=2[CH3:34])[CH2:10][CH2:9]1
Reactant: CCc1ccc(-c2nsc(C3CC3)c2CCl)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: CCc1ccc(-c2nsc(C3CC3)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 122 following Steps 5 and 7 by coupling of 4-(chloromethyl)-5-cyclopropyl-3-(4-ethylphenyl)-1,2-thiazole with ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as a yellow oil. 1H NMR (400 MHz, CD3OD) δ 7.59 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 5.06 (s, 2H), 2.92 (t, J=8.0 Hz, 2H), 2.70 (q, J=7.6, 15.6 Hz, 2H), 2.52 (t, J=7.2 Hz, 2H), 2.25-2.27 (m, 4H), 2.11 (s, 3H), 1.20-1.28 (m, 5H), 0.88-0.87 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C26H29NO3S, 436.2 (M+H). found 436.2.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([OH:15])=O.[CH3:16][NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C1(C)C=CC=CC=1>[CH3:16][N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:13]([C:3]1[C:4](=[O:12])[NH:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:15]
Reactant: CNc1ccccc1
Reactant: O=C(O)c1c(O)c2ccccc2[nH]c1=O
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C(=O)c1c(O)c2ccccc2[nH]c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,N-dicyklohexylcarbodiimide (2.2 parts) is added to a mixture consisting of 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxylic acid (2.0 parts), N-metylaniline (1.1 parts) and dry toluene (25 parts) while stirring. The stirring is continued at 110° C. for 4 hrs. The reaction mixture is cooled to room temperature and the precipitate formed is filtered off. The precipitate is dissolved at pH 8.2 in 2M sodium hydroxide solution and clarified by filtration to remove the N,N-dicyklohexylurea formed. The solution is acidified with hydrochloric acid solution and the precipitate formed is filtered off. The precipitate is washed with water and methanol and dried to give N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxamide, m p>300° C. (1:1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([N:21]=[N+:22]=[N-:23])=[O:12])=[CH:7][C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1Cl
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(C=CC(=O)N=[N+]=[N-])cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
24.0 g (0.1 mol) of 4-acetoxy-3-chloro-cinnamic acid are suspended in 90 ml of benzene and 14.6 ml (0.2 mol) of thionyl chloride are added. The reaction mixture is heated to the boil for half an hour under a reflux condenser and thereafter the solvent and excess thionyl chloride are removed by distillation under reduced pressure. The residual crude 4-acetoxy-3-chloro-cinnamic acid chloride is dissolved in 100 ml of absolute 1,2-dimethoxyethane, 19.5 g (0.3 mol) of sodium azide are added and thereafter the mixture is stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30° C. Hereupon, colourless crystals separate out. The crystallisation is completed by adding ether. 4-Acetoxy-3-chloro-cinnamic acid azide of melting point 102°-103° C. (decomposition) is thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:17][N:18]=[C:19]=[O:20]>C(Cl)Cl>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[NH:1][C:19](=[O:20])[N:18]([CH3:17])[C:4]2([OH:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CN=C=O
Solvent: ClCCl
Product: CN1C(=O)Nc2ccc(Cl)cc2C1(O)c1ccccc1
Yield: 96.5 %

Procedure:
A solution of 100 g (0.43 mole) of 2-amino-5-chlorobenzophenone and 40 g (0.7 mole) of methyl isocyanate in 300 ml of methylene chloride was refluxed for two days and then cooled. The solid portion of the reaction mixture was collected on a filter and washed with methylene chloride to give 119.8 g (96% yield) of 6-chloro-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2(1H)-quinazolinone as a white crystalline powder: mp 296°-298° (dec); 1H nmr (DMSO-d6), δ 2.66 ppm (s, 3H), 6.8-7.6 ppm (m, 8H) and 10.0 ppm (s, NH); 13C nmr (DMSO-d6) δ 86.6 ppm (for COH) and 151.4 ppm (for NHCO).
Reaction SMILES: [C:1](=[N:9][NH2:10])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[C:11]1([N:17]=[C:18]=[Se:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC#N>[C:11]1([NH:17][C:18]([NH:10][N:9]=[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH3:2])=[Se:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=NN)c1ccccn1
Reactant: [Se]=C=Nc1ccccc1
Solvent: CC#N
Product: CC(=NNC(=[Se])Nc1ccccc1)c1ccccn1
Temperature: 45 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
To a solution of 2.6 g (20 mmol) of 2-acetylpyridine hydrazone in 25 ml of CH3CN was added 3.6 g (20 mmol) of phenylisoselenocyanate. The clear red solution was heated with stirring to 45° C. for 3 hours, the solution was cooled to room temperature, and the crystals which separated were collected. Recrystallization of the product from EtOH gave 2.83 g (45%) of N-phenyl-2-[1-(2-pyridinyl)ethylidene]hydrazinecarboselenoamide as fine yellow needles, mp 153°-156° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:26])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:8]C(OCC1C=CC=CC=1)=O.[H][H]>C(O)C.[Pd].C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:26])[C@H:7]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH2:8]
Reactant: [H][H]
Reactant: COCCOC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCOC(=O)[C@@H](N)Cc1ccccc1
Yield: 91 %

Procedure:
A solution of N-(carbobenzyloxy)-L-phenylalanine 2-methoxy-ethyl ester (4.4 g, 12.3 mmol) in ethanol (75 mL) was treated with palladium on charcoal catalyst (440 mg, 10% Pd on charcoal) as a slurry in ethyl acetate (10 mL). Hydrogen gas was passed through the suspension for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide L-phenylalanine 2-methoxy-ethyl ester as a colorless oil (2.5 g, 92%). 1H-NMR; d (methanol-d4), 7.35-7.20 (5H, m), 4.27 (2H, m), 3.79 (1H, m), 3.57 (2H, m), 3.38 (3H, s), 3.10 (1H, dd), 2.90 (1H, dd) and 1.64 (2H, s).
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]([NH:15][NH2:16])=O)=[C:10]([F:17])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>C(O)CCC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]2[N:15]([C:13]([CH2:12][C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:17])[N:7]=[CH:6][CH:5]=[CH:4]4)=[N:20][N:21]=2)[N:16]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NNC(=O)Cc1c(F)cc2ncccc2c1F
Solvent: CCCCO
Product: Fc1cc2ncccc2c(F)c1Cc1nnc2ccc(Cl)nn12
Yield: 58.8 %

Procedure:
A solution of (5,7-difluoro-quinolin-6-yl)-acetic acid hydrazide (1.024 g, 4.32 mmol) and 3,6-dichloropyridazine (0.772 g, 5.18 mmol) in 60 mL of butan-1-ol was heated at 135° C. in a sealed tube for 16 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography to afford 842 mg of the title compound as a gray solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.96 (dd, 1H), 8.26 (d, 1H), 7.60-7.66 (m, 2H), 7.45 (d, 1H), 4.81 (s, 2H). LCMS (method A): [MH]+=332, tR=4.88 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14](OC)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH:14]=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: O=C[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of methyl trans-4-(4-chlorophenyl)cyclohexanecarboxylate (compound of formula (VIIa)) (25.3 g, 100 mmol) in dichloromethane (250 mL) at −78° C. under argon was added a 1M solution of diisobutylaluminium hydride (DIBAL) in dichloromethane (110 mL, 110 mmol) and the mixture was stirred for 90 minutes. A further 5 mLs of DIBAL was then added. Methanol (125 mL) was added with stirring and the mixture allowed to warm to −10° C. 1M aqueous hydrochloric acid (250 mL, 250 mmol) was then added with stirring. The aqueous layer was extracted with dichloromethane (250 mL) and the combined organics washed twice with water (2×125 mL). The organics were concentrated under vacuum to a volume of 75 mL, the residue was diluted by the addition ethyl acetate (125 mL) and the mixture was then concentrated under vacuum to a volume of 75 mL. The resulting mixture containing the title compound was used in the next step without analysis or purification.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]>C(O)(C)C>[N+:20]([C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)([O-:22])=[O:21]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Nc1ccc(O)cc1
Yield: 94.5 %

Procedure:
6.0 g of p-aminophenol was dissolved in 60 ml of isopropyl alcohol. To the solution was added 6.0 g of 4-chloro-3-nitro-benzotrifluoride and the resulting solution was heated under reflux for 12 hours. After the reaction, the solvent was removed by distillation and the residue was dissolved in benzene. The resulting solution was filtered and the solvent was removed from the filtrate by distillation. Thus, 7.5 g of the desired product was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2[NH:30][C:14]3[C:15]([Cl:29])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:32]>CO>[C:1]([C:5]1[C:6]([Cl:32])=[C:7]([C:11]2[NH:30][C:14]3[C:15]([Cl:29])=[N:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:27])([F:28])[F:26])=[CH:18][C:13]=3[N:12]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: Cn1nc(C(C)(C)C)cc1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(Cl)c2[nH]1
Solvent: CO
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2cc(-c3ccccc3C(F)(F)F)nc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-4-chloro-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine (101 mg, 0.232 mmol, Compound #74 freebase prepared according to Example 16, STEPS A, B and C) in DCM (2 mL) was treated with SO2Cl2 (28.3 μL, 0.348 mmol) and the resulting mixture was stirred at room temperature for 14 h. The resulting mixture was then diluted with MeOH (3 mL) and the solvent was removed under reduced pressure. The residue was chromatographed on a 25-g SiO2 pre-packed column eluting with 0:1-3:7 EtOAc/hexanes to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-4-chloro-6-(2-trifluoromethyl-phenyl)-3H-imidazo[4,5-c]pyridine. 1H-NMR (400 MHz, CD3OD) δ: 7.84 (d, J=7.8 Hz, 1H), 7.69-7.76 (m, 1H), 7.68 (s, 1H), 7.62-7.67 (m, 1H), 7.59 (d, J=7.6 Hz, 1H), 4.14 (s, 3H), 1.45 (s, 9H). Mass Spectrum (LCMS, ESI pos.): Calculated for C21H18Cl2F3N5: 468.1 (M+H). Measured: 468.1.