Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([OH:16])=O)=[CH:12][N:13]=2)[CH:10]=1)#[N:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:28][C:29]1[CH:30]=[C:31]([C:36]2[N:40]=[C:39]([CH:41]3[CH2:44][N:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:42]3)[O:38][N:37]=2)[CH:32]=[CH:33][C:34]=1[CH3:35]>ClCCl.N1C=CC=CC=1>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:14]([NH:28][C:29]3[CH:30]=[C:31]([C:36]4[N:40]=[C:39]([CH:41]5[CH2:44][N:43]([C:45]([O:47][CH3:48])=[O:46])[CH2:42]5)[O:38][N:37]=4)[CH:32]=[CH:33][C:34]=3[CH3:35])=[O:16])=[CH:12][N:13]=2)[CH:10]=1)#[N:2]
Reactant: N#CCCc1ccc2ncc(C(=O)O)n2c1
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccc(CCC#N)cn45)c3)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring suspension of 6-(2-cyanoethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (75) (50 mg, 0.232 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under Argon was added dropwise oxalyl chloride (22 uL, 0.256 mmol). Then, a drop of anhydrous N,N-dimethylformamide was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was concentrated and the crude solid was dried under vacuo. Methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31) (33 mg, 0.116 mmol) and anhydrous pyridine (2 mL) were added to the acid chloride. The reaction was stirred to room temperature under Argon for 20 minutes. The crude product was purified by reverse phase preparative HPLC to give methyl 3-(3-(3-(6-(2-cyanoethyl)imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F64). 1H NMR (400 MHz, d6-DMSO) δ 10.08 (s, 1H), 9.45 (s, 1H), 8.63 (s, 1H), 8.12 (d, J=1.6 Hz, 1H), 7.85 (dd, J=2.0, 5.6 Hz, 1H), 7.82 (d, J=6.8 Hz, 1H), 7.60 (dd, J=1.6, 9.2 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 4.38-4.33 (m, 2H), 4.31-4.24 (m, 1H), 4.21-4.18 (m, 2H), 3.59 (s, 3H), 3.01 (t, J=7.6 Hz, 2H), 2.91 (t, J=6.4 Hz, 2H), 2.38 (s, 3H). MS m/z 486.18 (M+1)+.
Reaction SMILES: II.Br[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].[CH:15](=[O:19])[CH:16]([CH3:18])[CH3:17].Cl>C(OCC)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH:15]([OH:19])[CH:16]([CH3:18])[CH3:17])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1Br
Reactant: CC(C)C=O
Agent: Cl
Agent: II
Solvent: CCOCC
Product: CC(C)C(O)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A Grignard is prepared from 1.77 g (73 mmol) of iodine-activated magnesium and 18.70 g (72 mmol) 1-bromo-4-chloro-2-trifluoromethyl-benzene dissolved in 150 mL diethyl ether. 5.46 g (72 mmol) isobutyraldehyde in 30 mL diethyl ether are added dropwise to the Grignard reagent at ambient temperature. After the addition has ended the reaction mixture is refluxed for 30 minutes and then stirred overnight at ambient temperature. It is combined with ice water and acidified with hydrochloric acid. The aqueous phase is separated off and extracted with diethyl ether. The organic phases are combined, dried with sodium sulphate and evaporated down. The residue is chromatographed on a silica gel column (petroleum ether/ethyl acetate=9:1). 10.5 g of oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-])=O>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[S:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2nc3cc(-c4cc5ccccc5s4)ccc3o2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(-c2nc3cc(-c4cc5ccccc5s4)ccc3o2)cc1N

Procedure:
Prepared by the method of Example 15e), from 2-(3-nitro-4-methoxyphenyl)-5-(2-benzothiophenyl)benzoxazole (200 mg, 0.50 mmol) and palladium on carbon (10%) (10 mg) in dioxane (10 ml), the subtitle compound was obtained.(40 mg, 86%). MS 373.2 m/z (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[N:14]=[CH:13][C:12]=1[C:26]([NH:28][C:29]1[CH:30]=[N:31][C:32]([C:36]2[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=2)=[C:33]([CH3:35])[CH:34]=1)=[O:27].O>N1C=CC=CC=1>[C:1]([N:39]1[CH2:40][CH:41]=[C:36]([C:32]2[N:31]=[CH:30][C:29]([NH:28][C:26]([C:12]3[CH:13]=[N:14][N:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=4)[C:11]=3[CH3:10])=[O:27])=[CH:34][C:33]=2[CH3:35])[CH2:37][CH2:38]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(C(=O)c2ccccc2)CC1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Benzoyl chloride (75 μl) was added to a solution of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (221 mg) in pyridine (2.5 ml), and stirred at 40° C. for six hours. Water was added to the reaction solution, the precipitated solid was washed with ethanol and water to give the titled compound (218 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:34][CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:15]=[C:16]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)[CH2:17]2.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH2:37][CH2:36]2)[CH:15]=[C:16]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:32])([F:33])[F:31])=[CH:25][CH:24]=1)[CH2:17]2
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C1c2c(Cl)cc(CC3CCNCC3)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(CN2CCC(Cc3cc(Cl)c4c(c3)CN(Cc3ccc(OC(F)(F)F)cc3)C4=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117.3 %

Procedure:
To a mixture of 4-Cyano-benzyl bromide (12 mg, 0.06 mmol), 7-chloro-5-piperidin-4-ylmethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (30.0 mg, 0.06 mmol) and potassium carbonate (42 mg, 0.3 mmol) was added acetonitrile (3.0 mL). The mixture was allowed to stir at room temperature overnight. Water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography provided the title compound as a brown oil (39.0 mg, 99%). 1H NMR (300 MHz, CDCl3): δ 7.60 (d, 2H), 7.27-7.59 (m, 4H), 7.17-7.20 (m, 3H), 7.05 (s, 1H), 4.77 (s, 2H), 4.22 (s, 2H), 3.53 (s, 2H), 2.80-2.84 (m, 2H), 2.58-2.60 (m, 2H), 1.91 (t, 21, 1.56-1.62 (m, 3H), 1.27-1.34 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([CH3:19])[C:11]=1[CH3:20].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:20][C:11]1[C:12]([CH3:19])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(O)ccn1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(Oc2ccnc(N)c2)ccc([N+](=O)[O-])c1C
Temperature: 75 °C

Procedure:
To a stirred solution of 2-aminopyridin-4-ol (600 mg, 5.5 mmol) and 1-fluoro-2,3-dimethyl-4-nitrobenzene (570 mg, 3.37 mmol) in DMSO (4.0 mL) was added K2CO3 (1.00 g, 7.20 mmol) and the reaction mixture heated to 75° C. for 3 days. The resulting mixture was cooled to RT and was partitioned between water (50 mL) and EtOAc (75 mL). The aq layer was separated and extracted with EtOAc (75 mL) and the combined organic extracts were washed with water (3×50 mL) and brine (50 mL) and then dried and evaporated in vacuo. The residue was recrystallized from DCM to afford the title compound, Intermediate C2, as a tan solid (25 mg, 28%): Rt 1.40 min (Method 2); m/z 260 (M+H)+ (ES+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=[O:16])[C:10]=1[CH2:17][NH:18][C:19]([C:21]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][C:33]([N:36]3[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][C@H:37]3[CH3:49])=[N:34][CH:35]=2)[CH:27]=[C:26]2[C:22]=1[C:23]([CH3:53])=[CH:24][N:25]2[CH:50]([CH3:52])[CH3:51])=[O:20]>C(Cl)Cl>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11](=[O:16])[C:10]=1[CH2:17][NH:18][C:19]([C:21]1[C:22]2[C:23]([CH3:53])=[CH:24][N:25]([CH:50]([CH3:52])[CH3:51])[C:26]=2[CH:27]=[C:28]([C:30]2[CH:35]=[N:34][C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][C@H:37]3[CH3:49])=[CH:32][CH:31]=2)[CH:29]=1)=[O:20]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)C[C@H]4C)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNC[C@H]4C)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
Added trifluoroacetic acid (1 ml, 12.98 mmol) to a solution of (R)-tert-butyl 4-(5-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1-isopropyl-3-methyl-1H-indol-6-yl)pyridin-2-yl)-3-methylpiperazine-1-carboxylate (57 mg, 0.091 mmol) in DCM (3 mL) and let stir at RT for 1 hour. Concentrated on rotovap. Partitioned between DCM and sat'd Na2CO3, separated and washed DCM phase with water, brine, dried (MgSO4), filtered and rotovapped off DCM. Obtained 25 mg of the title compound as a tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (d, 2H), 1.46-1.59 (m, 6H), 2.21 (s, 3H), 2.27 (s, 3H), 2.44 (s, 3H), 2.83 (dd, J=12.13, 3.54 Hz, 1H), 2.96-3.29 (m, 4H), 3.90 (br. s., 1H), 4.47-4.76 (m, 5H), 6.00 (s, 1H), 6.51 (d, J=8.59 Hz, 1H), 7.05 (s, 1H), 7.45 (s, 1H), 7.68 (dd, J=8.72, 2.40 Hz, 1H), 8.43 (d, J=2.27 Hz, 1H), 10.11-12.70 (m, 1H). LCMS: [M+H]+ 527.5.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].ClN1C(=O)[CH2:18][CH2:17][C:16]1=O>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:17]([CH3:18])[CH3:16])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Solvent: CC#N
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A portion of residue 3 (4.19 g, ˜7.45 mmol) was dissolved in acetonitrile (50 mL) and treated with N-chlorosuccinimide (1.19 g, 8.94 mmol) at room temperature. The temperature was raised to 65° C. and the mixture stirred overnight. When LC/MS showed complete conversion of starting material, the mixture was cooled to room temperature and partitioned between water (150 mL) and ethyl acetate (150 mL). The organic layer was separated and the organic phase washed twice with 2 N Na2CO3 and brine, dried over Na2SO4 and concentrated under vacuum to give an off white solid. The product was purified by preparative reverse phase HPLC to give pure desired product 4 (1.31 g, 29% from s.m.) as a white foamy solid upon solvent evaporation and high vacuum drying. LRMS (M+H+) m/z 598.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@@H:7]([CH:26]([CH3:28])[CH3:27])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43]Cl)[CH:38]=1.Cl.N1C=CC=CC=1CCl>CN(C=O)C.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:29])[C@@H:7]([CH:26]([CH3:27])[CH3:28])[N:8]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH2:43][C:39]1[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCc1cccnc1
Reactant: CC(C)[C@@H](NS(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: ClCc1ccccn1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](C(=O)OC(C)(C)C)N(Cc1cccnc1)S(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of N-[4-(4-bromophenoxy)benzenesulfonyl]-D-valine t-butyl ester (980 mg, 2.0 mol) in 5 mL of DMF was added potassium carbonate (1.53 g, 11.1 mol), 3-picolyl chloride hydrochloride (414 mg, 2.53 mol), and Kl (67 mg, 0.4 mol). The reaction was stirred at room temperature overnight. An additional 220 mg of picolyl chloride hydrochloride was added, and the reaction was stirred for 3 h. Water (25 mL) and ethyl acetate (50 mL) were added, and the layers were separated. The ethyl acetate fraction was washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica, eluting with 35% ethyl acetate in hexane, to give 1.07g (92%) of N-[4-(4-bromophenoxy)benzenesulfonyl]-N-(pyridin-3-yl)methyl-D-valine t-butyl ester as a tan foam.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:11](O)=[O:12])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O.C(N(CC)CC)C>[OH:12][CH2:11][C:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)C1(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(CO)CC1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Under ice cooling, to a tetrahydrofuran solution (20 ml) of 1-(tert-butoxycarbonyl)cyclopropanecarboxylic acid (1.79 g) and triethylamine (1.48 ml) was added dropwise isobutyl chlorocarbonate (1.37 ml), followed by stirring for 1 hour. Under ice cooling, the supernatant was added dropwise to a mixed solvent solution of sodium borohydride (1.09 g) in tetrahydrofuran (20 ml) and water (5 ml), and stirred for 30 minutes. A 10% aqueous citric acid solution was added, and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford tert-butyl 1-(hydroxymethyl)cyclopropanecarboxylate (1.28 g).
Reaction SMILES: N([O-])=[O:2].[Na+].[Cl:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([CH3:16])[C:7]=1[C:8](N)=[O:9]>O.S(=O)(=O)(O)O>[Cl:5][C:6]1[N:14]=[C:13]([Cl:15])[CH:12]=[C:11]([CH3:16])[C:7]=1[C:8]([OH:2])=[O:9]
Reactant: O=N[O-]
Reactant: Cc1cc(Cl)nc(Cl)c1C(N)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)nc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.9 %

Procedure:
A solution of sodium nitrite (2.73 g, 39.6 mmol) in water (15 mL) was added slowly to a solution of commercially available (Maybridge) 2,6-dichloro-4-methyl-nicotinamide (4.5 g, 22 mmol) in concentrated sulfuric acid resulting in evolution of heat and brown gas. The mixture was stirred at room temperature for 15 min, and then heated to 60° C. for 7 h. The solution was cooled to 0° C. and then water (15 mL) was added. The resulting white precipitate was collected by filtration and washed with hexane. The aqueous filtrate was extracted with EtOAc (3×) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was combined with the white precipitate to afford 2,6-dichloro-4-methyl-nicotinic acid (4.39 g, 97%) as a white solid: LCMS RT: 1.20 min, MH+: 206.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:17][O-:18].[Na+]>CS(C)=O>[ClH:2].[CH3:17][O:18][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNC1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(S(=O)(=O)C2CCNC2)cc1

Procedure:
A solution of 15.5 g (0.060 mole) of 3-[(4-chlorophenyl)sulfonyl]pyrrolidine hydrochloride and 9.0 g (0.167 mole) of sodium methoxide in 200 ml of dimethylsulfoxide was stirred at 100° C. for 2 hours. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and water. The methylene chloride solution was dried over magnesium sulfate and the solvent was removed in vacuo to give an oil, the free base of the title compound. The hydrochloride salt was prepared, recrystallizing from methanol-diethyl ether to give 9.1 g (55%) of white crystalline solid, m.p. 181°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O>>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: COC(=O)CN
Reactant: COCCOc1cccc(C=O)c1
Product: COCCOc1cccc(CNCC(=O)OC)c1
Yield: 55 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 3-(2-methoxyethoxy)benzaldehyde. Yield 55%. MS M+H calculated 254.1. Found 254.1
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:20]([CH3:22])[CH3:21])[C:9]([CH:18]=O)=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][OH:26].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH:20]([CH3:21])[CH3:22])[C:9]([CH2:18][NH:23][CH2:24][CH2:25][OH:26])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1C=O
Reactant: NCCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)c1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1CNCCO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
To a suspension of 7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carbaldehyde (40 mg) in ethanol (1 mL) was added 2-aminoethanol (11.8 mg), sodium cyanoborohydride (12.1 mg), and acetic acid (1 drop) in an ice-water bath. After 10 minutes, the mixture was stirred at ambient temperature. After 2 hours, sodium cyanoborohydride (11.8 mg) was added and the reaction mixture was acidified to pH4 with acetic acid (5 drops). After stirring overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by p-TLC (chloroform-methanol=10-1) to give 2-({[7-chloro-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazin-3-yl]methyl}amino)ethanol as pale yellow oil (21 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A solution of diethyl (3-methoxy-4-nitrophenyl)propanedioate (3.8 g, 12.219 mmol) in 30 mL of methanol and 20 mL of water was added KOH (2.05 g, 36.657 mmol) and the mixture was heated to 70° C. for 4 hours. Cooled to ambient temperature and removed the solvents under reduce pressure. The residue was added 100 mL of water and adjusted to pH=2 with conc. HCl. Extracted with EtOAc and the organic layer was washed with water, brine and dried over anhydrous sodium sulfate, concentrated to give (3-methoxy-4-nitrophenyl)acetic acid. 1H-NMR (400 MHz, MeOD) δ ppm 7.75 (d, J=8.6 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 6.98 (dd, J=7.8 Hz, J=1.6 Hz, 1H), 3.93 (s, 3H), 3.70 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]2([CH3:15])[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[O:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O.C(OCC)(=O)C>[F:35][C:19]([F:18])([F:34])[O:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH:26]2[CH2:27][CH2:28][N:29]([C:2]3[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]4([CH3:15])[CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9]4)=[CH:4][CH:3]=3)[CH2:30][CH2:31]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reactant: CC1(COc2ccc(Br)cc2)COC(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(COc2ccc(N3CCC(Oc4ccc(OC(F)(F)F)cc4)CC3)cc2)COC(C)(C)O1
Yield: 93.2 %

Procedure:
4-[(4-Bromophenoxy)methyl]-2,2,4-trimethyl-1,3-dioxolane (156 mg, 0.518 mmol), 4-[4-(trifluoromethoxy)phenoxy]piperidine (135 mg, 0.517 mmol), palladium acetate (1.2 mg, 0.0053 mmol), tri-tert-butylphosphine tetraphenylborate (2.7 mg, 0.0052 mmol), sodium tert-butoxide (55 mg, 0.57 mmol), and toluene (2 mL) were mixed and stirred under reflux for 2 hours. Ethyl acetate and water were added to the reaction mixture, followed by extraction. The organic layer was washed with water twice. A residue was obtained by concentrating the organic layer under reduced pressure, and the resulting residue was then subjected to chromatography refining (methylene chloride) using silica gel, obtaining 232 mg of the objective compound (yield: 93%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([OH:7])=[O:6].[N+](=[CH2:18])=[N-]>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Cl:15])[CH:9]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Reactant: C=[N+]=[N-]
Product: CON=C(C(=O)OC)c1ccc(O)c(Cl)c1

Procedure:
2-Methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.) and diazomethane (1.5 g.) were reacted and the product was purified by column chromatography according to a similar manner to that of Preparation 5-3) (b) to give crystals of methyl 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetate (syn isomer) (3.0 g.).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([NH:10][C:11]([CH3:16])([C:13]([OH:15])=O)[CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[N:3]=1.CCN(C(C)C)C(C)C.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[N:31]1([C:13](=[O:15])[C:11]([NH:10][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)=[N:5][CH:6]=2)=[O:9])([CH3:12])[CH3:16])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32]1
Reactant: CC(C)(NC(=O)c1cnc(-n2cccn2)nc1O)C(=O)O
Reactant: c1ccc2c(c1)CCN2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1cnc(-n2cccn2)nc1O)C(=O)N1CCc2ccccc21
Reaction time: 3.5 h

Procedure:
To the product of Example 188 (100 mg, 0.343 mmol), DIPEA (0.15 mL 0.86 mmol), 2,3-dihydro-1H-indole (0.04 ml, 0.36 mmol) and HOBt (55.2 mg, 0.36 mmol) in 1.4 mL DMF was added EDC (69.1 mg, 0.36 mmol). The reaction aged at rt for 3.5 h. The reaction was diluted with EtOAc and washed with aq HCl (2 M) and water. The organic portion was partially concentrated and the product was allowed to crystallize. The mixture was diluted with 80% EtOAc/20% hexane before the product was isolated by filtration. It was then washed with 80% EtOAc/20% hexane to afford the title compound. HPLC/MS: 393.0 (M+1); Rt=2.63 min.