Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:64])[NH:28][CH:29]([C:33]([N:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[C:40]1[NH:41][C:42]([C:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[C:50](B4OC(C)(C)C(C)(C)O4)[CH:51]=3)[CH:46]=2)=[CH:43][N:44]=1)=[O:34])[CH:30]([CH3:32])[CH3:31].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>COCCOC.CCOC(C)=O.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:50]3[CH:49]=[CH:48][C:47]4[C:52](=[CH:53][CH:54]=[C:45]([C:42]5[NH:41][C:40]([CH:36]6[CH2:37][CH2:38][CH2:39][N:35]6[C:33](=[O:34])[CH:29]([NH:28][C:27]([O:26][CH3:25])=[O:64])[CH:30]([CH3:32])[CH3:31])=[N:44][CH:43]=5)[CH:46]=4)[CH:51]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 50.8 %

Procedure:
To a solution of 2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 2.5 mmol) and [2-Methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (1.97 g, 3.6 mmol, 1.5 equiv.) in DME (12.5 mL) was added K3PO4 (aqueous, 2 M, 3.9 mL, 7.8 mmol, 3 equiv.), Pd2dba3 (0.12 g, 0.13 mmol, 0.05 equiv.), and Xantphos (0.15 g, 0.26 mmol, 0.1 equiv.). The slurry was degassed with argon for 5 minutes and heated to 80° C. for 18 hours. The resulting reaction mixture was diluted with EtOAc/MeOH (10:1) and filtered through CELITE. The solution was washed with water and brine. The aqueous layer was back-extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 50→100% EtOAc in Hexanes) to provide 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.93 g, 49%) as a yellow powder. LCMS-ESI+: calc'd for C42H49N7O5: 731.4 (M+); Found: 732.9 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][OH:15])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1>C1COCC1.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1)[CH:14]=[O:15]
Reactant: OCc1cc(Cl)cc(-c2ccccn2)c1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: O=Cc1cc(Cl)cc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A solution of (3-chloro-5-(pyridin-2-yl)phenyl)methanol (116 mg; 0.64 mmol) in anh. THF (6 ml) was treated with MnO2 (877 mg; 10.09 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 6.5 h. The resulting reaction mixture was then filtered over celite, and the separated solids were washed with THF. The filtrate was concentrated to dryness under reduced pressure giving 3-chloro-5-(pyridin-2-yl)benzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.43 min.; no ionisation.
Reaction SMILES: C[C@@H]1NCCN(CC2C=CC(NS(C3C=NC(N4CCCCC4)=CC=3)(=O)=O)=CC=2)C1.[CH3:31][C@H:32]1[CH2:37][N:36]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][S:46]([C:49]3[CH:50]=[N:51][C:52]([N:55]4[CH2:60][CH2:59][O:58][CH2:57][CH2:56]4)=[CH:53][CH:54]=3)(=[O:48])=[O:47])=[CH:41][CH:40]=2)[CH2:35][CH2:34][N:33]1C(OC(C)(C)C)=O>>[CH3:31][C@@H:32]1[NH:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][S:46]([C:49]3[CH:50]=[N:51][C:52]([N:55]4[CH2:56][CH2:57][O:58][CH2:59][CH2:60]4)=[CH:53][CH:54]=3)(=[O:48])=[O:47])=[CH:41][CH:40]=2)[CH2:37]1
Reactant: C[C@H]1CN(Cc2ccc(NS(=O)(=O)c3ccc(N4CCOCC4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Agent: C[C@H]1CN(Cc2ccc(NS(=O)(=O)c3ccc(N4CCCCC4)nc3)cc2)CCN1
Product: C[C@H]1CN(Cc2ccc(NS(=O)(=O)c3ccc(N4CCOCC4)nc3)cc2)CCN1

Procedure:
The title compound was prepared in a similar manner to E3 using 1,1-dimethylethyl (2S)-2-methyl-4-{[4-({[6-(4-morpholinyl)-3-pyridinyl]sulfonyl}amino)phenyl]methyl}-1-piperazinecarboxylate (D18). MS (ES+): MH+ 432.3
Reaction SMILES: [Br-].Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([NH:34]C(=O)OC(C)(C)C)[CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([C:20]3[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:23]4[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=4[N:21]=3)[CH2:15]2)=[O:13])=[CH:5][CH:4]=1.[NH:42]1[CH:46]=[CH:45][N:44]=[CH:43]1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[N:42]1([C:3]2[CH:4]=[CH:5][C:6]([CH2:9][C@@H:10]([NH2:34])[CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH2:17][C@@H:16]([C:20]4[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:23]5[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=5[N:21]=4)[CH2:15]3)=[O:13])=[CH:7][CH:8]=2)[CH:46]=[CH:45][N:44]=[CH:43]1
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc(Br)cc3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(-n4ccnc4)cc3)C2)nc2ccccc21
Temperature: 110 °C

Procedure:
A suspension of bromide, tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (prepared from the procedure of Example 6, Step A) (45 mg, 0.088 mmol), imidazole (11 mg, 2 eq), CuI (3.3 mg, 20% mol), N,N′-dimethylethylenediamine (3.1 mg, 40% mol), potassium phosphate (K3PO4) (37.4 mg, 2 eq) in 2 mL dioxane was heated at 110° C. for 27 hrs. The mixture was filtered; the filtrate was washed with EtOAc and concentrated to give a greenish oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:9]=[C:10]([NH:13]C(=O)OC(C)(C)C)[S:11][CH:12]=2)[CH2:3][CH2:2]1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1nc(CN2CCOCC2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(CN2CCOCC2)cs1
Yield: 100 %

Procedure:
Tert-butyl 4-(morpholinomethyl)thiazol-2-ylcarbamate 90 (1.88 g, 6.28 mmol) was treated with 20 mL of 25% trifluoroacetic acid in CH2Cl2 for 18 h at room temperature. After all the solvent had been removed by concentrating and drying under high vacuum, the resulting residue was treated with a mixture of pentane/EtOAc to afford 91 (1.96 g, 100% yield) as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33]O)([O-:22])=[O:21].C(Br)(Br)(Br)[Br:36]>C(#N)C.C(OCC)(=O)C>[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][Br:36])([O-:22])=[O:21]
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCO)c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2[nH]cc(CCBr)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a solution of triphenylphosphine (2.83 g, 0.011 mol) in 100 mL of acetonitrile was added a solution of 5-nitro-3-(2-hydroxyethyl)indole (2.00 g, 0.0097 mol) in 25 mL of acetonitrile, followed by a solution of CBr4 (3.60 g, 0.011 mol) in 25 mL of acetonitrile, at 0° C. under Ar. The mixture was stirred at room temperature for 18 h and then another 0.283 g (1.1 mmol) of triphenylphosphine and 0.360 g (1.1 mmol) of CBr4 were added. After 2.5 h the mixture was diluted with ethyl acetate, washed (H2O, brine), dried (Na2SO4) and evaporated and the residue was chromatographed (SiO2 /ethyl acetate-hexane, 1:4) to give the title compound (2.27 g, 87%) as a yellow solid: IR (neat) 3370, 1334 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ11.69 (s, 1H), 8.60 (d, J=2.1 Hz, 1H), 7.98 (dd, J=9.0, 2.2 Hz, 1H), 7.54-7.49 (m, 2H), 3.76 (t, J=7.2 Hz, 2H), 3.32 (t, J=7.2 Hz, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]#[C:15][C:16]1([OH:24])[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1)[CH:2]=[CH2:3].[C-]#N.[Na+].[CH3:28][N:29]([CH3:33])[CH2:30]CO>>[CH2:1]([C:4]1[CH:9]=[C:8]([C:10]([O:12][CH2:13][CH2:28][N:29]([CH3:33])[CH3:30])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]#[C:15][C:16]1([OH:24])[CH:21]2[CH2:20][CH2:19][N:18]([CH2:23][CH2:22]2)[CH2:17]1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C(=O)OC)ccc1C#CC1(O)CN2CCC1CC2
Reactant: CN(C)CCO
Agent: [C-]#N
Agent: [Na+]
Product: C=CCc1cc(C(=O)OCCN(C)C)ccc1C#CC1(O)CN2CCC1CC2
Temperature: 90 °C

Procedure:
A mixture of 3-[2-(2-allyl-4-methoxycarbonylphenyl)ethynyl]quinuclidin-3-ol (0.64 g), sodium cyanide (50 mg) and N,N-dimethylethanolamine (10 ml) was heated at 90° C. for 24 hours. The mixture was evaporated to give an oil which was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using 10% methanol in dichloromethane containing 1% ammonia (density 0.88 g/cm3) as eluent to give 3-[2-(2-allyl-4-(2-(N,N-dimethylamino)ethoxycarbonyl)phenyl)ethynyl]quinuclidin-3-ol as a gum (0.559 g); microanalysis found: C, 66.7; H, 7.6; N, 6.7%, C23H30N2O3.0.4CH2Cl2.0.1 H2O requires 7.47; N, 6.7%; NMR (CDCl3): 1.32-1.55(1H, m), 1.55-1.88(1H, m), 1.88-2.20(3H, m), 2.33(6H, s), 2.70(2H, t), 2.65-3.15(4H, m), 3.07(1H, d), 3.33(1H, dd), 3.56(2H, d), 4.41(2H, t), 4.98-5.15(2H, m), 5.29(CH2Cl2), 5.85-6.10(1H, m), 7.43(1H, d) and 7.71-7.90(2H, m); m/Z 383 (M+H).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:22])[N:15]([CH2:19][C:20]#[N:21])[CH:16]([CH3:18])[CH3:17])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:44]2[C@H:45]([CH3:68])[C@H:46]3[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]3[C:48]=2[C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:20]([CH2:19][N:15]([CH:16]([CH3:18])[CH3:17])[C:14]([C:12]1[N:13]=[C:9]([N:7]2[CH2:6][CH:5]([S:4][C:44]3[C@H:45]([CH3:68])[C@@H:46]4[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]4[C:48]=3[C:49]([O:51][CH2:52][C:53]3[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=3)=[O:50])[CH2:8]2)[S:10][CH:11]=1)=[O:22])#[N:21]
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: CC(=O)SC1CN(c2nc(C(=O)N(CC#N)C(C)C)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)N(CC#N)C(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
To a solution of 3-acetylthio-1-[4-(N-cyanomethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]azetidine (344 mg, 1.01 mmol) (obtained as described in Reference Example 50) in dimethylformamide (1 0 ml) was added hydrazine acetate (112 mg, 1.22 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (725 mg, 1.22 mmol) in acetonitrile (20 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.70 ml, 4.04 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (10:1) to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(N-cyanomethyl-N-isopropyl-carbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (245 mg, yield 39%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>O>[Cl:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:9]=1)[O:11][C:12](=[O:14])[CH:13]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1ccc2cc(Cl)cc(Cl)c2o1
Temperature: 50 °C
Yield: 72.2 %

Procedure:
To a 2 L round bottom flask fitted with a mechanical stirrer and condenser was added 3,5-dichlorosalicylaldehyde (200 g, 1.05 mol, 1 equiv.), acetic anhydride (356 g, 3.49 mol) and triethylamine (95.0 g , 0.94 mol. 0.90 equiv.). The reaction solution was heated at reflux overnight. The dark brown reaction mixture was cooled to 50° C. and water (1 L) added with stirring. After one hour the mixture was filtered and the filtrate combined with EtOH (1 L). This mixture was heated to 45° C. for one hour, cooled to room temperature, filtered and the solid (fraction A) washed with EtOH (0.5 L). The combined EtOH solutions were concentrated by rotary evaporation to an oil (fraction B). The solid from fraction A was dissolved in methylene chloride (1.5 L) and the resulting solution passed through a pad of silica gel (1300 mL volume). The resulting dark brown solution was concentrated to an oil that was triturated with hexanes (1.3 L) to give a solid that was isolated by filtration and washed (hexanes) to give substantially pure 6,8-dichlorocoumarin (163 g). A further 31 g of product was obtained by treating the oil, fraction B, in a similar fashion; the oil was dissolved in methylene chloride (0.5 L) passed through a silica pad (0.5 L volume) and triturated with hexanes. The total isolated yield was 194 g or 86% yield of the brown solid.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(O)C>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc(Cl)cc2)C1=O
Yield: 67.3 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 4-chloroaniline (0.568 g; 4.36 mmol) in ethanol (3 mL). 1-(4-chlorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.234 g (67%) was obtained as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[CH2:15]([NH:17][C:18](=[S:21])[NH:19][NH2:20])[CH3:16]>>[CH2:15]([NH:17][C:18](=[S:21])[NH:19][N:20]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8])[CH3:16]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CCNC(=S)NN
Agent: Cl
Product: CCNC(=S)NN=c1c(=O)c2ccccc2c1=O

Procedure:
ninhydrin, 4-ethyl thiosemicarbazide hydrochloride
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([O:14]C)=[O:13])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:16]=[CH:17][C:18]([C:20]([O:22]CC)=[O:21])=[N:19][N:3]12>Cl>[O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH:16]=[CH:17][C:18]([C:20]([OH:22])=[O:21])=[N:19][N:3]12
Reactant: CCOC(=O)c1ccc2nc3ccc(C(=O)OC)cc3c(=O)n2n1
Agent: Cl
Product: O=C(O)c1ccc2nc3ccc(C(=O)O)nn3c(=O)c2c1

Procedure:
A mixture of 2-ethyl 8-methyl 10-oxo-10H-pyridazino [6,1-b]quinazoline-2,8-dicarboxylate (0.15 g, 0.46 mmol, Example 1, Step C) in 50 mL of 10% hydrochloric acid was refluxed for 24 h. The mixture was cooled and filtered to give the titled compound as a yellow solid, mp>285° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:31])[N:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=2[Cl:26])=[O:20])[C:3]=1[N+:32]([O-])=O.O.[NH4+].[Cl-]>CCO.[Fe]>[NH2:32][C:3]1[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:31])[N:23]=[C:24]([C:27]([CH3:29])([CH3:28])[CH3:30])[C:25]=2[Cl:26])=[O:20])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])=[CH:7][C:2]=1[Cl:1]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1N
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (109 mg, 0.211 mmol, prepared as described in the previous step) in EtOH (5 mL) and water (2.5 mL) was treated with NH4Cl (113 mg, 2.11 mmol) and iron powder (58.9 mg, 1.06 mmol). The mixture was heated to 60° C. for 5 h, then the EtOH was evaporated in vacuo. The remaining aqueous mixture was diluted with water (30 mL) and extracted twice with EtOAc (25 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 35 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [3-amino-4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a colorless glassy solid. Mass Spectrum (LCMS, ESI pos.): Calculated for C21H20N5OCl2F3: 486.1 (M+H); Measured: 486.2.
Reaction SMILES: [ClH:1].[CH:2]([N:15]1[CH2:18][C:17]([NH:22][CH2:23][CH2:24]CC2C=CC=CC=2)([C:19]([NH2:21])=[O:20])[CH2:16]1)([C:9]1C=CC=CC=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[ClH:1].[CH2:23]([NH:22][C:17]1([C:19]([NH2:21])=[O:20])[CH2:16][CH2:9][CH2:2][NH:15][CH2:18]1)[CH3:24]
Reactant: NC(=O)C1(NCCCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CCNC1(C(N)=O)CCCNC1

Procedure:
To a solution of 1-benzhydryl-3-(benzylethylamino)-azetidine-3-carboxylic acid amide hydrochloride salt (I-1A-3c; 0.66 g, 1.4 mmol) in methanol (25 ml) was added 20% Pd(OH)2 on carbon (30% water; 0.13 g). The mixture was placed on a Parr® shaker and then reduced (45 psi H2) at room temperature overnight. The mixture was diluted with methanol (200 ml) filtered through a 0.45 μm filter disk, and then concentrated to a solid. The residue was triturated from diethyl ether, collected by vacuum filtration, washed with ether and then dried, in vacuo, to afford I-1A-3e (298 mg, 98%): +APcI MS (M+1) 144.1; 1H NMR (400 MHz, CD2Cl2) δ 4.56 (br s, 4H), 3.00 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].O>C(OC(=O)CCC)(=O)CCC>[CH2:1]([C:6]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)[CH2:2][CH3:3]
Reactant: Nc1ccccc1N
Agent: CCCC(=O)OC(=O)CCC
Solvent: O
Product: CCCc1nc2ccccc2[nH]1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of o-phenylenediamine (2.2 g) in butyric anhydride (4.7 g) was stirred for 4 hours at 110° C. To the reaction mixture was added water, which was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium bicarbonate, dilute hydrochloric acid and water and then dried. The solvent was evaporated to dryness, and the residue was refluxed for 1.5 hour in 3N-HCl (35 ml). The reaction mixture was made basic with a 6N NaOH. The crystals were recrystallized from ethyl acetate-hexane to give colorless plates (0.9 g, 38%), m.p. 160-162° C.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[CH:2]=[CH2:3].N1C=CC=CC=1.C1COCC1.[Br:19][CH:20]([CH3:24])[C:21](Cl)=[O:22]>C(OCC)(=O)C>[Br:19][CH:20]([CH3:24])[C:21]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]=[CH2:3])=[O:22]
Reactant: C=CCOCCO
Reactant: CC(Br)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CCOCCOC(=O)C(C)Br
Temperature: 0 °C
Yield: 64.5 %

Procedure:
A 50-mL two-necked flask is purged with nitrogen and then charged with 2-allyloxyethanol (2.5 mL, 23.4 mmol), pyridine (3 mL) and THF (10 mL). The solution is cooled to 0° C., and 2-bromopropionyl chloride (2 mL, 19.52 mmol) is added dropwise slowly. The resulting mixture is stirred at that temperature for an hour, then ethyl acetate (10 mL) is added, and the resulting pyridine hydrochloride is filtered off. The filtrate is washed with dilute hydrochloric acid (10 mL), then with an aqueous solution of NaHCO3 (10 mL) and further with brine (10 mL). The organic layer is dried over Na2SO4 and the volatile matter is distilled off under reduced pressure. The crude product thus obtained is distilled under reduced pressure to give allyloxyethyl 2-bromopropionate (78.5-81 (1.3 mmHg), 2.986 g) of the formula shown below.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[O:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([Mg]Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.C(Cl)Cl>CCOCC>[C:20]1([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([O:18][CH3:19])=[C:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1c(Cc2ccccc2)ccc2ccccc12
Reactant: Cl[Mg]c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1c(Cc2ccccc2)cc(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A solution of the compound of Example 94 Part B (5.00 g 15.3 mmole) and bis-(1 3-diphenylphosphino)-propane nickel (II) chloride (0.40 g, 0.74 mmole) in dry ether was stirred at 0°. Phenylmagnesium chloride (2.0M in ether; 9.5 mL 19.0 mmole) was added dropwise and the mixture was stirred at room temperature for 2 hours. The mixture was then poured into 1.0N hydrochloric acid, and the crude product was isolated by extraction with methylene chloride. This was chromatographed to provide the title product (4.26 g, 86%) as a white solid. A small sample recrystallized from hexane melted at 103°-105°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17]>C1(C)C=CC=CC=1>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)=[O:17]
Reactant: O=C=NCCCl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(NCCCl)Nc1cccc(C(F)(F)F)c1
Yield: 96 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 3-trifluoromethyl-phenylamine (2.0 g, 12.412 mmol) in toluene (20 mL) was reacted with 1-chloro-2-isocyanatoethane (1.96 g, 18.618 mmol to give 3.2 g of pure product (96%)