Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]([CH:13]=[CH:14][N:15]=2)[N:9]=[C:10]([Cl:12])[CH:11]=1)=O)C.O.[NH2:17][NH2:18]>C(O)C>[Cl:12][C:10]1[CH:11]=[C:6]([C:4]([NH:17][NH2:18])=[O:3])[C:7]2[N:8]([CH:13]=[CH:14][N:15]=2)[N:9]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(Cl)nn2ccnc12
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(Cl)nn2ccnc12
Reaction time: 0.25 h
Yield: 57 %

Procedure:
To a solution of crude 6-chloro-imidazo[1,2-b]pyridazine-8-carboxylic acid ethyl ester (5.00 g, “22 mmol”) in 40 mL of ethanol at 0-5° C. was added 10 mL of hydrazine hydrate. Yellow solid immediately precipitated. After 15 min. at 0-5° C., the solid was isolated by Buchner filtration, rinsing well with ice-cold ethanol (250 mL total) and dried by sucking air through then in vacuo. A small amount of additional solid precipated from the filtrate and was isolated and dried similarly to the first crop. A total of 2.38 g (57% over three steps) of 6-chloro-imidazo[1,2-b]pyridazine-8-carboxylic acid hydrazide was isolated as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][N:9](C(OC(C)(C)C)=O)[C@H:10]1[CH2:15][N:14]([C:16]([O:18][CH2:19][CH:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH:13]([C:33](=[O:35])[NH2:34])[C:12]([CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][N:14]([C:16]([O:18][CH2:19][CH:20]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[CH:13]([C:33](=[O:35])[NH2:34])[C:12]([CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(OCc1ccccc1)[C@@H]1C=C(CO[Si](C)(C)C(C)(C)C)C(C(N)=O)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1=C[C@@H](NOCc2ccccc2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of (5R)-(9H-fluoren-9-yl)methyl 5-((benzyloxy)(tert-butoxycarbonyl)amino)-3-(((tert-butyldimethylsilyl)oxy)methyl)-2-carbamoyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 161, 1.19 g, 1.67 mmol) in DCM (20 mL) at room temperature was added zinc bromide (1.502 g, 6.67 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate and. The aqueous wash was extracted three to four times more with DCM. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated to afford the title compound (0.970 g, 95%) as an off white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[C:9]([C:12]3[CH:13]=[C:14]([C:17]([OH:19])=O)[S:15][CH:16]=3)=[CH:10][N:11]=[C:7]2[CH:6]=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C@@H:38]1([NH2:45])[CH2:43][CH2:42][CH2:41][CH2:40][C@@H:39]1[NH2:44]>CN(C)C=O>[NH2:44][C@@H:39]1[CH2:40][CH2:41][CH2:42][CH2:43][C@@H:38]1[NH:45][C:17]([C:14]1[S:15][CH:16]=[C:12]([C:9]2[N:8]3[C:3]([O:2][CH3:1])=[CH:4][C:5]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:6][C:7]3=[N:11][CH:10]=2)[CH:13]=1)=[O:19]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: COc1cc(-c2ccccc2)cc2ncc(-c3csc(C(=O)O)c3)n12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2)cc2ncc(-c3csc(C(=O)N[C@H]4CCCC[C@H]4N)c3)n12

Procedure:
To a solution of 4-(5-methoxy-7-phenylimidazo[1,2-a]pyridin-3-yl)thiophene-2-carboxylic acid (10.0 mg, 0.029 mmol) in N,N-dimethylformamide (1 ml) was added 1,1′-carbonyldiimidazole (7.0 mg, 0.043 mmol). After 20 minutes cis-1,2-cyclohexanediamine (0.034 ml, 0.29 mmol) was added. After 10 minutes the reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give N-[(1S,2R)-2-aminocyclohexyl]-4-(5-methoxy-7-phenylimidazo[1,2-a]pyridin-3-yl)thiophene-2-carboxamide. 1H NMR (600 MHz, DMSO-d6) δ 8.13 (s, 1H); 7.85 (d, 2H); 7.74 (d, 1H); 7.59 (s, 1H); 7.54 (d, 1H); 7.47-7.49 (m, 2H); 7.38-7.41 (m, 1H); 6.66 (d, 1H); 3.99 (s, 3H); 1.50-1.72 (m, 7H); 1.29-1.36 (m, 3H). LRMS (ESI) calculated for C25H27N4O2S [M+H]+, 447.2 found 447.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]3[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(Cl)c(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3c(Cl)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(=O)(O)[O-].[Na+].O.[Cl:11][C:12]1[N:17]=[C:16]([C:18]2[C:19](F)=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:15]2[N:26]([CH2:38][C@H:39]3[CH2:44][CH2:43][C@H:42]([CH3:45])[CH2:41][CH2:40]3)[C:27]([N:29]3[CH2:34][CH2:33][O:32][C@@H:31]4[CH2:35][CH2:36][CH2:37][C@@H:30]34)=[N:28][C:14]=2[CH:13]=1>CCO>[Cl:24][C:22]1[CH:23]=[C:18]([C:16]2[C:15]3[N:26]([CH2:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([CH3:45])[CH2:41][CH2:40]4)[C:27]([N:29]4[CH2:34][CH2:33][O:32][C@@H:31]5[CH2:35][CH2:36][CH2:37][C@@H:30]45)=[N:28][C:14]=3[CH:13]=[C:12]([Cl:11])[N:17]=2)[C:19]([N:3]([CH3:4])[CH3:2])=[N:20][CH:21]=1
Reactant: CNC
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cc(Cl)cnc4F)c32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)c1ncc(Cl)cc1-c1nc(Cl)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Temperature: 90 °C

Procedure:
To a solution of dimethylamine hydrochloride (580 mg, 7.25 mmol) and sodium bicarbonate (812 mg, 9.67 mmol) in EtOH:water (4 mL:2 mL) was added 6-chloro-4-(5-chloro-2-fluoropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic) (125 mg, 0.24 mmol). The reaction was heated to 90° C. for 5 hours. The reaction was then concentrated and diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 45% EtOAc/hexanes) afforded 5-chloro-3-{6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-4-yl}-N,N-dimethylpyridin-2-amine (racemic). MS ES calc'd. for C28H36Cl2N6O [M+H]+ 543. found 543.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br:9]Br>>[C:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH:1]([Br:9])[CH3:2]
Reactant: CCOC(=O)OCC
Reactant: BrBr
Product: CCOC(=O)OC(C)Br
Yield: 68.5 %

Procedure:
585 g Diethylcarbonate (4.92 mole) was heated by an external 1500 w iodine quartz lamp. The mixture was allowed to reflux (temperature 125°) by the heat evolved from the lamp. 318.2 g (2.0 mole) of bromine is added slowly during 3 hours through a dip-pipe at such a rate that the solution colour was yellow to light orange. The temperature dropped to ca. 120° at the beginning of the addition, but rose again slowly. When all the bromine was consumed the temperature was 137°. The reaction mixture was cooled and treated as described in Example 2. Fractional distillation afforded 1-bromoethyl ethyl carbonate in a 68.5% yield. The earlier fraction contained about 6.5% more of 1-bromoethyl ethyl carbonate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[CH:12][N:13]([C@@H:15]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:21]([O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[N:14]=[C:9]3[C:10]2=[C:4]([C:5](=O)[NH:6][N:7]=[CH:8]3)[CH:3]=1.N1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42]>O1CCOCC1>[NH2:1][C:2]1[C:11]2=[CH:12][N:13]([C@@H:15]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:21]([O:22][C:23](=[O:26])[CH2:24][CH3:25])[C@H:16]3[O:17][C:18](=[O:20])[CH3:19])[N:14]=[C:9]3[C:10]2=[C:4]([C:5](=[S:42])[NH:6][N:7]=[CH:8]3)[CH:3]=1
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3c(N)cc4c(=O)[nH]ncc(n2)c34)O[C@@H]1COC(C)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3c(N)cc4c(=S)[nH]ncc(n2)c34)O[C@@H]1COC(C)=O

Procedure:
To a solution of the compound from Step 1 (75 mg, 0.16 mmol) in dioxane (2 mL) is added pyridine (2.5 mL) followed by phosphorus pentasulfide (2 equiv). The reaction mixture is heated at reflux for 24 h. The solvent is evaporated then and the residue washed with pyridine. The combined washings are evaporated and the residue is dissolved in CHCl3 and washed with 10% aq. NaHCO3 and water and dried (Na2SO4). The evaporated residue is used as such for the next step.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23](OCC(Cl)(Cl)Cl)=[O:24])([CH3:13])[CH3:12]>C1COCC1>[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23]([O:10][CH2:9][C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)=[O:24])([CH3:13])[CH3:12]
Reactant: OCc1cccnc1
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 3.9 %

Procedure:
NaH (0.19 g, 4.80 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (5 mL), the suspension cooled to 0° C. and 3-pyridylcarbinol (0.40 mL, 4.00 mmol) was added. The suspension was stirred at 0° C. for 30 min and then added to a solution of Intermediate 2 (1.33 g, 4.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and 3-pyridylcarbinol in THF were added after 7 and 25 h, respectively. After 4 d the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL) washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5% and 10% MeOH in DCM (200 mL each)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 80% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid) and Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 40% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 in DCM to give pyridin-3-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (46.3 mg, 3.8%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:30][C:31]([F:40])([F:41])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH:35][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:24])[CH3:25])[NH:10]1)=[O:28]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCc2ccccc2C(F)(F)F)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2-trifluoromethyl-benzyl amine (52.55 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide (38 mg, 32.3%) as an off-white powder. HRMS (ES+) m/z Calcd for C31H30Cl2F3N3O+H [(M+H)+]: 588.1791. found: 588.1795.
Reaction SMILES: [I-].[K+].CC1C=CC(S(O[CH2:14][CH2:15][F:16])(=O)=O)=CC=1.[CH2:17]([N:24]1[CH2:28][CH2:27][C@@H:26]([C@@H:29]([NH2:31])[CH3:30])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([N:24]1[CH2:28][CH2:27][C@@H:26]([C@@H:29]([NH:31][CH2:14][CH2:15][F:16])[CH3:30])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](N)[C@@H]1CCN(Cc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](NCCF)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 100 °C
Yield: 50.2 %

Procedure:
Potassium iodide (0.71 g, 4.27 mmol) and 2-fluoroethyl 4-methylbenzenesulfonate (0.93 g, 4.27 mmol) (Kopka, et al., 2006) are added to a solution of (S)-1-((R)-1-benzylpyrrolidin-3-yl)ethanamine (0.83 g, 4.06 mmol) (Shroeder, et al., 1992) in DMF (10 mL). The reaction mixture is heated for 2 h at 100° C. and evaporated under reduced pressure. The residue is purified by column chromatography (chloroform-ethanol-triethylamine=30:1:1) to afford the desired product (0.51 g, 50%) as a brown oil. 1H NMR (CDCl3): δ 1.09 (d, J=6.3 Hz, 3H, methyl), 1.55 (m, 1H), 1.96 (m, 1H), 3.15-2.15 (m, 9H), 3.65 (s, 2H, —CH2Ph), 4.46 (m, 1H, —CHF), 4.61 (m, 1H, —CHF), 7.31 (m, 5H, ArH). 13C NMR (CDCl3): δ 18.1, 27.5, 43.8, 53.9, 56.7, 57.5, 60.4, 82.4, 84.6, 126.6, 128.1, 128.5, 139.0. LCMS: m/z calcd for C15H23FN2 ([M]+) 250. found 251 ([M+H]+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([CH3:28])=[N:7][C:8]3[C:13]([N:14]=2)=[C:12]([C:15]2[NH:19][C:18]4[C@H:20]([C@H:24]([OH:26])[CH3:25])[NH:21][C:22](=[O:23])[C:17]=4[CH:16]=2)[C:11]([F:27])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[Li+].[OH-:30].Cl>O1CCOCC1.O>[NH2:21][C@H:20]([C:18]1[NH:19][C:15]([C:12]2[C:11]([F:27])=[CH:10][CH:9]=[C:8]3[C:13]=2[N:14]=[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)[C:6]([CH3:28])=[N:7]3)=[CH:16][C:17]=1[C:22]([OH:23])=[O:30])[C@H:24]([OH:26])[CH3:25]
Reactant: [OH-]
Reactant: Cc1nc2ccc(F)c(-c3cc4c([nH]3)[C@H]([C@@H](C)O)NC4=O)c2nc1NC1CC1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c([C@@H](N)[C@@H](C)O)[nH]3)c2nc1NC1CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
The yellow foam (352b) (184.5 mg) in 1,4-dioxane (6.0 mL) was treated with 1.0 M aq. LiOH (3.0 mL, 3.0 mmol). The mixture was heated at 100° C. for 16 h. The mixture was lyophilized to give a yellow solid containing m/z (ESI, +ve) 614.1 (M+H). The yellow solid was dissolved in 1 mL of dioxane and treated with a solution of 4 M HCl in 1,4-dioxane (5 mL) with a few drops of water added to aid solubility. The mixture was stirred at RT for 4 h, after which time bis-deprotection was observed by LC-MS. The mixture was lyophilized to give 2-((1R,2R)-1-amino-2-hydroxypropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid (352c) as a brown solid. A solution of the 2-((1R,2R)-1-amino-2-hydroxypropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid (352c) in DMF (3.0 mL) was treated with TEA (0.20 mL, 1.44 mmol) followed by PyBOP (NovaBiochem) (300 mg, 0.57 mmol). The mixture was stirred at RT for 16 h. The mixture was concentrated, dissolved in DMSO (5.0 mL), and purified by preparative HPLC (Gradient: 10-100% MeCN in H2O, modified with 0.1% TFA) to give (R)-2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-6-((R)-1-hydroxyethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one bis(2,2,2-trifluoroacetate) (352) (54 mg, 0.089 mmol) as a red gum. LC-MS m/z 382.1, [M+H]+; 19F NMR (DMSO-d6; 376 MHz): δ −108.08 (s, 1F), −74.95 (s, 6F).
Reaction SMILES: CON(C)[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>C1COCC1>[C:11]1([C:7]2[N:6]=[C:5]([C:4]([C:23]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:17])[CH:10]=[CH:9][CH:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Reactant: CON(C)C(=O)c1cccc(-c2ccccc2)n1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cccc(-c3ccccc3)n2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
To a solution of 38c (0.210 g, 0.86 mmoL) in 5 mL THF was added a THF solution of 3,4,5-trimethoxyphenylmagnesiumbromide (0.5 N, 3.5 mL, 1.73 mmol) at 0° C. The mixture was allowed to stir for 30 min and quenched with water, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure 1c as white needle crystals (78%). 1H NMR (CDCl3) δ 8.10 (d, br, 2H), 8.02-8.00 (m, 1H), 7.97-7.96 (m, 2H), 7.66 (s, 2H), 7.49-7.43 (m, 3H), 3.97 (s, 3H), 3.89 (s, 6H); MS (ESI) m/z 372.6 (M+Na)+.
Reaction SMILES: [Li].[CH2:2](Cl)[C:3]([CH3:6])([CH3:5])[CH3:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](F)[C:10]=1[C:16]1[O:17][CH2:18][C:19](C)(C)[N:20]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:4][C:3]([CH3:6])([CH3:5])[CH2:2][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[C:10]=1[C:16]([NH:20][CH2:19][CH3:18])=[O:17]
Reactant: CC(C)(C)CCl
Reactant: CC1(C)COC(c2c(F)cccc2F)=N1
Agent: O=C([O-])O
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)c1c(F)cccc1CC(C)(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
A solution of p,p'-di-t-butyl biphenyl (5.559 g, 0.021 mol) and THF (100 mL) was stirred at 0° C. under an atmosphere of argon. Lithium wire (0.021 mol, 0.15 g) was added in small pieces and the mixture was allowed to stir at 0° C. for 24 h. The mixture was cooled to -78° C. and neopentyl chloride (2.0 g, 0.01875 mol) was added dropwise. The mixture was stirred at -78° C. for 1 h, and the compound of Example g (3.17 g, 0.015 mol) was added all at once. The mixture was continuously stirred for 4 h and 50 mL sat aq NaHCO3 was added. This mixture was extracted with three 50 mL portions of ethyl acetate. The combined extracts were washed twice with water, dried (MgSO4), and concentrated. The crude concentrate was purified by HPLC eluting with 1:4 ethyl acetate/hexanes. The oxazoline was as a clear oil in 27% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:28]3[C:29]([CH:32]=[O:33])=[CH:30][CH:31]=[C:27]3[C:8]3([CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH3:25])[CH:16]=4)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:34]=1.[Mn]([O-])(=O)(=O)=[O:36].[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:28]3[C:29]([C:32]([OH:36])=[O:33])=[CH:30][CH:31]=[C:27]3[C:8]3([CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH3:25])[CH:16]=4)[CH2:10][CH2:9]3)[O:7][C:6]=2[CH:34]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2c(C=O)ccc23)ccc1OC(C)C
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2c(C(=O)O)ccc23)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To a solution of 7-chloro-1′-(4-isopropoxy-3-methylbenzoyl)spiro-[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde (130 mg, 0.27 mmol) in acetone (1.5 mL) was added a solution of potassium permanganate (43 mg, 16 μL, 0.27 mmol) in water (1.5 mL) and acetone (1.5 mL) dropwise at 0° C. The mixture was allowed to stir at room temperature for 2 h before it was concentrated onto Celite from methanol. Column chromatography on the residue (0-20% EtOAc/CH2Cl2) gave 7-chloro-1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]-pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carboxylic acid (13%).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][C:11](=[O:25])[NH:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].I[CH3:29]>CC(C)=O>[CH3:29][S:3][C:1]([C:4]1[CH:27]=[CH:26][C:7]([C:8]([NH:10][C:11](=[O:25])[NH:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)=[NH:2]
Reactant: CI
Reactant: COC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(=N)SC)cc2)cc1
Temperature: 50 °C

Procedure:
Methyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]phenoxyacetate (870 mg) was suspended in acetone (100 ml) and iodomethane (10 ml) was added. The stirred suspension was heated to 50° C. After 24 and 48 hours respectively, two further aliquots of iodomethane (10 ml+10 ml) were added whilst stirring at 50° C. was continued. Removal of the solvents in vacuo yielded methyl 4-[3-(4-(methylthio)carbonimidoylbenzoyl)ureido]phenoxyacetate as an orange-brown solid residue which was not purified further. The residue was suspended in methanol (40 ml) and heated to 45°-50° C. with stirring before a solution of ammonium acetate (1.54 g) in methanol (20 ml) was added. After stirring overnight at 45°-50° C., extra portions of methanol (10 ml) and ammonium acetate (0.77 g) were added and the reaction mixture was heated to 70° C. with stirring. After stirring for a further 24 hours at 70° C., the solvents were removed in vacuo to yield a pale yellow solid which was crystallised, with filtration, from boiling methanol to give the title compound (208 mg) as an off-white solid: NMR Spectrum (DMSO-d6) 1.78 (3H, s), 3.71 (3H, s), 4.77 (2H, s), 6.93 (2H, d), 7.50 (2H, d), 7.91 (2H, d), 8.14 (2H d) 9.00-11.00 (3H br); Mass Spectrum m/Z 371 (M+H)+ ; Elemental Analysis: calculated for C18H18N4O5. 1.0 CH3CO2H. 0.75 H2O: C, 54.1%; H, 5.34%; N, 12.6%; found: C, 54.3%; H, 5.0%; N, 12.3%.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH:11]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:1]=[CH:13][CH:11]=[O:12]
Reactant: COc1cccc(C=O)c1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cccc(C=CC=O)c1
Temperature: 120 °C
Yield: 24.6 %

Procedure:
680 mg of m-anisaldehyde and 1.52 g of formylmethylenetriphenylphosphorane were dissolved in 10 ml of toluene and stirred under heating at 120 ° C. for 7 hours. The reaction solution was cooled to room temperature and purified by silica gel column chromatography [hexane/ethyl acetate=9/1→4/1] to give 199 mg of the title compound as a yellow oily substance.