Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]([CH3:11])[C:8]([OH:10])=O)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:49][C:50]1[CH:55]=[CH:54][C:53]([N:56]2[C:64]3[CH2:63][CH2:62][CH2:61][NH:60][C:59]=3[CH:58]=[N:57]2)=[CH:52][CH:51]=1>O.C(OCC)(=O)C.CN(C)C=O>[F:49][C:50]1[CH:51]=[CH:52][C:53]([N:56]2[C:64]3[CH2:63][CH2:62][CH2:61][N:60]([C:8](=[O:10])[CH:7]([N:6]4[C:2]([CH3:1])=[CH:3][C:4]([C:12]([F:15])([F:14])[F:13])=[N:5]4)[CH3:11])[C:59]=3[CH:58]=[N:57]2)=[CH:54][CH:55]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: Cc1cc(C(F)(F)F)nn1C(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1C(C)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Reaction time: 0.02 h
Yield: 88.8 %

Procedure:
Dimethylformamide (1 mL) was added to a mixture containing 2-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]propanoic acid (49.6 mg, 0.223 mmol) and HATU (89.1 mg, 0.234 mmol). Diisopropylethylamine (98 μL, 0.56 mmol) was added at room temperature and the reaction mixture was stirred for 1 minute. 1-(4-Fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (49.5 mg, 0.228 mmol) was added all at once and the reaction mixture was stirred at room temperature overnight. Ethyl acetate and water were then added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 20-38% ethyl acetate in hexanes) to afford the desired product as a white solid (83.5 mg, 0.198 mmol, 89%). 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.44 (ddd, J=9.2, 5.2, 2.0 Hz, 2H), 7.15 (dt, J=8.8, 2.0 Hz, 2H), 6.31 (s, 1H), 5.55 (q, J=7.2 Hz, 1H), 3.73 (ddd, J=13, 7.6, 3.2 Hz, 1H), 3.37 (ddd, J=12, 8.8, 3.2 Hz, 1H), 2.72-2.79 (m, 2H), 2.29 (s, 3H), 1.86-1.97 (m, 1H), 1.76-1.85 (m, 1H), 1.80 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C20H19N5OF4 [M+H]+ 422, found 422.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]([CH:26]([C:28]2[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=2)[OH:27])[C:23]([F:34])=[C:22]([Cl:35])[C:21]=1[N:36]1[CH2:41][C@H:40]([CH3:42])[O:39][C@H:38]([CH3:43])[CH2:37]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]([C:26]([C:28]2[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=2)=[O:27])[C:23]([F:34])=[C:22]([Cl:35])[C:21]=1[N:36]1[CH2:37][C@H:38]([CH3:43])[O:39][C@H:40]([CH3:42])[CH2:41]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(O)c3nccn3C)c(F)c2Cl)C[C@H](C)O1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3nccn3C)c(F)c2Cl)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a stirring solution of (6-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-((2R,6S)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)(1-methyl-1H-imidazol-2-yl)methanol (1.2 g, 1.93 mmol, Intermediate 73) in dichloromethane (20 mL) was added Manganese (IV) oxide (0.670 g, 7.70 mmol). The mixture was allowed to stir overnight at room temperature. The reaction was filtered through Celite®, and the filtrate concentrated under vacuum to give clear oil. The oil was purified on short bed of silica using 20-30% ethyl acetate in n-hexane to give 1.0 g (84%) the title compound as oil.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][O:7][C:8]3[CH:15]=[CH:14][C:13]([C:16](Cl)=[O:17])=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[CH3:19][NH2:20]>ClCCl.O1CCCC1>[CH3:19][NH:20][C:16]([C:13]1[CH:14]=[CH:15][C:8]2[O:7][CH2:6][C@H:5]3[CH2:1][CH2:2][CH2:3][N:4]3[C:10](=[O:11])[C:9]=2[CH:12]=1)=[O:17]
Reactant: CN
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)N1CCC[C@@H]1CO2
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)C(=O)N1CCC[C@@H]1CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzoxazepine-5-one-7-carboxylic acid chloride (0.330 g; 1.24 mmol), prepared as described in Example 17A, starting from the material described in Example 3I, in dichloromethane (3 ml) was added dropwise to a stirred 10% solution of methylamine in tetrahydrofuran. The mixture was stirred at room temperature for a further 1 h and then evaporated to dryness under reduced pressure. The residue was taken up in dichloromethane (20 mL) and washed with 0.5M HCl (2×20 mL). The dichloromethane layer was dried (MgSO4) and solvent evaporated under reduced pressure. Recrystallisation of the crude product from ethylacetate/diethylether gave the title compound (0.262 g) as a white solid. M.p. 186-189° C.; EIMS: m/z=261.0 [M+H]+
Reaction SMILES: [OH:1][CH:2]([CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Cl>>[F:28][C:29]([F:38])([F:39])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:5][CH2:6]1
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Reactant: FC(F)(F)c1cccc(CCl)c1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2cccc(C(F)(F)F)c2)CC1

Procedure:
Following the procedure of Example 5, 1-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine was reacted with 3-(trifluoromethyl)benzyl chloride to form 1-(3-trifluoromethylbenzyl)-4-(2-hydroxy-3-n-hexadecyloxypropyl)piperazine, mp 133°-135° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[C:11]4[CH:25]=[CH:24][CH:23]=[CH:22][C:12]4=[C:13]4[CH:21]=[CH:20][CH:19]=[CH:18][C:14]4=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:26]1[C:34]2[C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[S:31][C:30]=2[C:29]([C:39]2[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=2)=[CH:28][CH:27]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C1(C)C=CC=CC=1>[CH:26]1[C:34]2[C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[S:31][C:30]=2[C:29]([C:39]2[CH:40]=[C:41]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]4[CH:17]=[N:16][C:15]5[C:10](=[C:11]6[CH:25]=[CH:24][CH:23]=[CH:22][C:12]6=[C:13]6[CH:21]=[CH:20][CH:19]=[CH:18][C:14]6=5)[N:9]=4)[CH:3]=3)[CH:42]=[CH:43][CH:44]=2)=[CH:28][CH:27]=1
Reactant: Brc1cccc(-c2cnc3c4ccccc4c4ccccc4c3n2)c1
Reactant: OB(O)c1cccc(-c2cccc3c2sc2ccccc23)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1cc(-c2cccc(-c3cccc4c3sc3ccccc34)c2)cc(-c2cnc3c4ccccc4c4ccccc4c3n2)c1
Yield: 70.4 %

Procedure:
In a 200 mL three-neck flask were put 3.0 g (7.8 mmol) of 2-(3-bromophenyl)dibenzo[f,h]quinoxaline, 2.6 g (8.6 mmol) of 3-(dibenzothiophen-4-yl)phenylboronic acid obtained in Step 2, 0.24 g (0.78 mmol) of tri(ortho-tolyl)phosphine (P(o-tolyl)3), 78 mL of toluene, 7.8 mL of ethanol, and 12 mL of 2.0 M potassium carbonate aqueous solution. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To the mixture was added 35 mg (0.16 mmol) of palladium(II) acetate. The mixture was stirred at 80° C. under a nitrogen stream for 8 hours. After a predetermined period of time had elapsed, the precipitated solid was separated by filtration to give a yellow solid. The solid was washed with water and ethanol, toluene was added thereto, and the resulting mixture was stirred while being heated. The toluene solution was suction-filtered to give 3.1 g of 2-[3′-(dibenzothiophen-4-yl)biphenyl-3-yl]dibenzo[f,h]quinoxaline (abbreviation: 2mDBTBPDBq-II) as a yellow solid (yellow powder) in a yield of 71%.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:14][NH2:15])=[N:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1.[F:16][C:17]([F:32])([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)[C:18](OC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C#N>C(Cl)Cl>[F:32][C:17]([F:16])([C:18]1[N:4]2[CH:5]=[C:6]([C:8]3[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=3)[CH:7]=[C:2]([F:1])[C:3]2=[N:14][N:15]=1)[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2
Reactant: COC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: Cn1cc(-c2cnc(NN)c(F)c2)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(-c2cc(F)c3nnc(C(F)(F)c4ccc5ncccc5c4)n3c2)cn1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of 1-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)hydrazine (190 mg, 917 μmol), methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (218 mg, 917 μmol), triphenylphosphine polymer supported (241 mg, 917 μmol), DIEA (200 μl, 1146 μmol) in DCM (4 mL) was added 2,2,2-trichloroacetonitrile (92 μl, 917 μmol). The reaction vessel was then appropriately sealed and heated to 150° C. with microwaves for 15 min. The reaction was then concentrated onto dry silica under reduced pressure and product purified on silica (40 g) eluting with 1-4% of 2 M NH3 in MeOH/DCM. The product was then further purified by RP-HPLC eluting with water/ACN (0.1% TFA). Collected fractions concentrated under reduced pressure, dissolved in MeOH/DCM (5 mL) and stirred with Si-Carbonated (300 mg; 0.2 mmol) for 30 min at 23° C. Solids were then removed by filtration, and washed with MeOH (3×1 mL). The filtrate was then concentrated under reduced pressure, and product isolated as an off white solid. MS (ESI pos. ion) m/z: 395 (MH+). Calc'd exact mass for C20H13F3N6: 394.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:9]([C:13]1([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-])=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-]>[Zn].CO>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][C:13]1([CH:9]([N:8]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]([OH:12])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)C(N(Cc1ccccc1)Cc1ccccc1)C1(Oc2ccccc2[N+](=O)[O-])CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccccc1OC1(C(C(=O)O)N(Cc2ccccc2)Cc2ccccc2)CCCCC1
Temperature: 65 °C
Yield: 84.7 %

Procedure:
2-(Dibenzylamino)-2-(1-(2-nitrophenoxyl)cyclohexyl)acetic acid (0.8 g, 1.69 mmol, Eq: 1.00), NH4Cl (180 mg, 3.37 mmol, Eq: 2) and Zn (1.71 g, 26.1 mmol, Eq: 15.5) were combined with MeOH (35.0 mL) to give a grey suspension, and the mixture was heated to 65° C. for 90 min. The mixture was filtered through Celite, the filtrate was concentrated and partitioned between sat. aq. NaOAc and Et2O. The phases were separated and the organic layer washed with H2O, brine, dried over Na2SO4 and concentrated to afford 2-(1-(2-aminophenoxyl)cyclohexyl)-2-(dibenzylamino)acetic acid as light brown solid (0.6365 g, 85%). MS m/z 475.1 (MH+).
Reaction SMILES: CN(C)CC.[F:6][C:7]1[CH:41]=[CH:40][C:10]([CH2:11][N:12]2[CH2:39][CH2:38][N:15]3[C:16]4[N:37]=[CH:36][CH:35]=[CH:34][C:17]=4[N:18]([C:21]([C@@H:23]4[CH2:26][CH2:25][N:24]4[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=O)[CH2:19][CH2:20][CH:14]3[CH2:13]2)=[CH:9][CH:8]=1>O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]2[CH2:39][CH2:38][N:15]3[C:16]4[N:37]=[CH:36][CH:35]=[CH:34][C:17]=4[N:18]([CH2:21][C@@H:23]4[CH2:26][CH2:25][N:24]4[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:19][CH2:20][CH:14]3[CH2:13]2)=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)N1CCC2CN(Cc3ccc(F)cc3)CCN2c2ncccc21
Agent: CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1CN1CCC2CN(Cc3ccc(F)cc3)CCN2c2ncccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of alane-dimethylethylamine complex (0.5 M in toluene, 3.1 mL, 1.55 mmol) was added to a solution of the product of example 68A (154 mg, 0.31 mmol) in tetrahydrofuran (5.0 mL) at room temperature under nitrogen. The turbid solution was stirred at room temperature for 3 hours and then quenched by addition of methanol (1 mL), followed after 5 minutes by water (5 mL) and 25% NaOH (0.5 mL). The aqueous layer was separated and extracted with ethyl acetate (2×5 mL), and the combined organic phases were washed with brine (5 mL), dried (Na2SO4) and concentrated under vacuum to provide residue which was purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column (30×75 mm) eluted with methanol:10 mM (NH4)2CO3 in water (50:50-95:5) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.45 (s, 9H), 1.70-1.92 (m, 2H), 1.91-2.08 (m, 1H), 2.11-2.27 (m, 2H), 2.32-2.44 (m, 1H), 2.52-2.62 (m, 1H), 2.68-2.83 (m, 1H), 3.03-3.18 (m, 1H), 3.23-3.70 (m, 8H), 3.71-3.89 (m, 2H), 4.27-4.45 (m, 1H), 6.69-6.77 (m, 1H), 6.97-7.04 (m, 2H), 7.04-7.10 (m, 1H), 7.31 (dd, J=8.3, 5.6 Hz, 2H), 7.81 (dd, J=4.7, 1.4 Hz, 1H); MS (DCI) m/z 482 (M+H)+.
Reaction SMILES: C(OC([N:8]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][C:23]([O:25][C@H:26]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]3[CH2:51][CH2:50]3)[CH:38]=1)[CH2:27][C:28]1[C:33]([Cl:34])=[CH:32][N+:31]([O-:35])=[CH:30][C:29]=1[Cl:36])=[O:24])[CH:17]=[CH:16]2)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:36][C:29]1[CH:30]=[N+:31]([O-:35])[CH:32]=[C:33]([Cl:34])[C:28]=1[CH2:27][C@@H:26]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:45])[F:46])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)[O:25][C:23](=[O:24])[CH2:22][N:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(ccn2CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(ccn2CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Yield: 42.5 %

Procedure:
To a solution of (S)-4-(2-(2-(5-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (170 mg, 0.221 mmol) in DCM (10 ml), 4M HCl in dioxane (552 μl, 2.206 mmol) was added, and the mixture was reacted overnight at room temperature. The solvent was evaporated and the resulting crude was purified by preparative HPLC (Method 1) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(methylsulfonamido)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (63 mg, 0.094 mmol, 43% yield). MS/ESI+ 670.09 [MH]+, [αD]=7.68, c=0.5 in DCM. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.27 (s, 1H) 8.51 (s, 2H) 7.42 (d, 1H) 7.29 (d, 1H) 7.13-7.22 (m, 2H) 7.02 (d, 1H) 7.02 (dd, 1H) 6.91 (dd, 1H) 7.05 (t, 1H) 6.44 (dd, 1H) 6.01 (dd, 1H) 5.21 (d, 1H) 5.06 (d, 1H) 3.87 (d, 2H) 3.41 (dd, 1H) 3.21 (dd, 1H) 2.87 (s, 3H) 1.13-1.32 (m, 1H) 0.50-0.71 (m, 2H) 0.22-0.48 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[CH:10]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]#[N:12].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:10]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:11]#[N:12]
Reactant: COc1ccc(F)c(C(C#N)Cc2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CC(Cc1ccccc1)c1cc(O)ccc1F
Temperature: 25 °C

Procedure:
To a stirred and cooled (0° C.) solution of 2-(2-fluoro-5-methoxy-phenyl)-3-phenyl-propionitrile (5.68 g, 22.25 mmol) in 150 ml dichloromethane under argon was added dropwise a 1M solution of boron tribromide in dichloromethane (66.7 ml, 66.7 mmol). The reaction was allowed to warm up to room temperature. The mixture was stirred over night, poured on ice water, diluted with dichloromethane. The organic layer was separated and the aqueous layer extracted twice with dichloromethane. The combined organic layers were washed subsequently with water, saturated sodium bicarbonate solution and brine, then dried over sodium sulphate and filtered. Evaporation of solvent afforded a pale brown solid.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH:42]([CH3:44])[CH3:43])[C:38]([O:40][CH3:41])=[O:39]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](=[O:30])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH:42]([CH3:43])[CH3:44])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl)C(C)C
Agent: Cl
Product: COC(=O)[C@@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl)C(C)C

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(4-chloro-3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=2)[N:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:18]S(O)(=O)=O>>[C:8]([C:7]1[CH:6]=[N:5][N:4]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:3]2[C:2]=1[Cl:1])(=[O:18])[NH2:9]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1cc2c(Cl)c(C#N)cnn2c1
Product: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a round bottom flask was added concentrated H2SO4 (100 mL) followed by ethyl 4-chloro-3-cyanopyrrolo[1,2-b]pyridazine-6-carboxylate (10 g, 40 mmol). The reaction was stirred at room temperature under nitrogen overnight. The reaction mixture was poured onto ice cold saturated sodium carbonate solution. The aqueous solution was extracted with EtOAc (4×) and the combined organic layer was concentrated to yield 7 g (70%) of the title compound as a yellow solid. HPLC (condition S): retention time=8.04 min. LCMS (condition A): m/z=268.0 +ve. H1 NMR (400 MHz, CDCl3) δ ppm: 8.49 (1H, d, J=1.6 Hz), 8.40 (1H, s), 8.08 & 7.98 (1H, two br s), 7.12 (1H, d, J=1.6 Hz), 4.34 (2H, q, J=7.2 Hz), 1.34 (3H, t, J=7.2 Hz).
Reaction SMILES: [Na][Na].[OH:3][C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>CS(C)=O.O.C1(C)C=CC=CC=1>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Agent: [Na+]
Agent: [Na][Na]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Oc1ccc(Oc2ccc3ccccc3n2)cc1)C(=O)O
Reaction time: 0.5 h

Procedure:
The disodium salt of 2-(4-hydroxyphenoxy)propionic acid was made by dissolving the acid (9.1 gm, 0.05 mole) in 50 ml of DMSO and adding a solution of sodium hydroxide (4.4 gm, 0.11 mole) in 13 ml of water. The mixture was stirred for 30 min. and warmed to 55° C. at which time a solution of 2-chloroquinoline (8.2 gm, 0.050 mole) in 20 ml of DMSO was added. The reaction mixture was heated at 97°-108° for 1.5 hr. and then at 122°-125° for one hour longer. At the end of this time the mixture was poured into 600 ml of cold water and acidified. It was allowed to stand until solids formed which were taken up in toluene. From this 6.5 gm of 2-(4-(2-quinolinyloxy)phenoxy)propanoic acid were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=[CH:3]1.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C.Cl.[NH2:30][CH2:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[C:34](=[O:50])[N:35]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:36]2=[O:41]>CN(C=O)C>[O:49]=[C:43]1[CH:42]([N:35]2[C:34](=[O:50])[C:33]3[C:37](=[CH:38][CH:39]=[CH:40][C:32]=3[CH2:31][NH:30][C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)=[O:9])[C:36]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: Cn1cncc1C(=O)O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cncc1C(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
A mixture of 1-methyl-1H-imidazole-5-carboxylic acid (0.3 g, 2.6 mmol) and carbonyl diimidazole (0.5 g, 3.0 mmol) in DMF (30 mL) was stirred at room temperature for 3 hours. Triethylamine (0.8 g, 6.0 mmol) was added, followed by 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol). The mixture was stirred at 75° C. (oil bath) for 3 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with water (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give 3-methyl-3H-imidazole-4-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.2 g. 28%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.50-2.64 (m, 2H), 2.84-2.97 (m, 1H), 3.81 (s, 3H), 4.89 (d, J=5.6 Hz, 2H), 5.13-5.20 (dd, J=5.2 and 12.5 Hz, 1H), 7.68-7.84 (m, 5H), 8.94 (t, J=5.5 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.98, 30.93, 33.51, 37.44, 48.88, 121.88, 125.45, 127.05, 131.52, 132.29, 133.09, 134.83, 139.42, 142.08, 160.25, 166.94, 167.53, 169.82, 172.74; Anal. calcd. for C19H17N5O5+0.13H2O+0.1Et2O: C, 57.52; H, 4.54; N, 17.29. Found: C, 57.23; H, 4.27; N, 16.95.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:18]>CC(O)C>[Na+:18].[C:1]1([CH:7]([N:9]2[C:13]([C:14]([O-:16])=[O:15])=[CH:12][N:11]=[CH:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)n1cncc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(c1ccccc1)n1cncc1C(=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 17.7 parts of (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid, 3.28 parts of sodium hydroxide and 120 parts of 2-propanol is stirred and refluxed until the reaction mixture becomes homogeneous and thereafter for 1 further hour. During reflux part of the product crystallizes out. The reaction mixture is allowed to cool to room temperature and the precipitated product is filtered off. The product is washed with 2 -propanol and dried in vacuo, yielding (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid sodium salt.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[N:34][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47](O)=[O:48])[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:36][CH:37]=1.[CH3:53][NH:54][CH2:55][CH:56]([OH:58])[CH3:57]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[N:36][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47]([N:54]([CH2:55][CH:56]([OH:58])[CH3:57])[CH3:53])=[O:48])[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:34][CH:33]=1
Reactant: CNCC(C)O
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(O)CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1

Procedure:
HATU coupling of 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid with 1-(methylamino)propan-2-ol. White solid. Yield: 0.16 g