Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32](OC)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1.O>CCOCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32]([C:2]5[S:3][CH:4]=[CH:5][N:6]=5)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2nccs2)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 87.5 %

Procedure:
2-Bromothiazole (0.643 mL, 7.14 mmol) in dry ether (7 mL) was added to n-butyllithium (2.5 M in Hexanes) (2.92 mL, 7.31 mmol) in dry ether (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (1.0 g, 2.339 mmol) in dry ether (15 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at −78° C. Water (60 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with dichloromethane (3×75 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark orange oil. The crude product was purified by column chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate as an off-white solid (984 mg). LCMS (Method F, ES-API): RT 2.64 min, m+H=480.9; 1H NMR (400 MHz, CDCl3): δ 8.06 (1H, d, J=3.0 Hz), 7.64 (1H, s), 7.48-7.43 (2H, m), 7.31 (1H, s), 7.20-7.14 (2H, m), 6.55 (1H, s), 5.60 (1H, br s), 4.49 (1H, d, J=15.0 Hz), 4.21 (1H, br s), 3.28-3.25 (1H, m), 2.86-2.81 (3H, m), 2.49 (1H, d, J=14.5 Hz), 1.55 (9H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([O-:24])=[O:23].N1C(C)=CC=CC=1C.O.C(=O)(O)O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:31][C:28]3[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C(O)O
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: N#Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OCc1ccccc1
Temperature: 156.5 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
To the 7-benzyloxy-4-chloro-6-cyanoquinoline (2.60 g, 8.83 mmol) described in WO98/13350 there were added 4-nitrophenol (2.46 g, 17.7 mmol) and lutidine (2.06 ml, 17.7 mmol), and the mixture was heated and stirred at 155-158° C. for 2 hours. After returning the reaction system to room temperature, it was dissolved in tetrahydrofuran, saturated bicarbonate water was added and stirred therewith for 10 minutes, the mixture was concentrated under reduced pressure, the precipitated solid was filtered out and subjected to silica gel column chromatography (Fuji Silicia NH Type, eluent-hexane:ethyl acetate=50:50→ethyl acetate alone), the fraction containing the target substance was concentrated and the obtained solid was washed with diethyl ether. It was then dried under reduced pressure to obtain the title compound (1.84 g, 4.63 mmol, 52.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:8](=[O:9])[O:7][CH2:6]2.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8](=[O:9])[O:7]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1OC)C(=O)OC2
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)C(Br)OC2=O

Procedure:
5,6-Dimethoxyphthalide (5.82 g; 0.03 mole.), N-bromosuccinimide (5.34 g; 0.03 mole.) and α-azo-isobutyronitrile (0.1 g.) were gently refluxed in dry carbon tetrachloride (150 ml.) for 2 hours.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][O:27][C:28](=[O:41])[CH2:29][CH2:30][NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:26][O:27][C:28](=[O:41])[CH2:29][CH2:30][NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([O:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:35][CH:34]=1
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Reactant: OC(CC1CCCCC1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCNC(=O)c1ccc(OC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1
Reaction time: 8 h
Yield: 31.2 %

Procedure:
A solution of (±)-2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethanol (0.184 g, 0.527 mmol), 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (0.136 g, 0.608 mmol), and triphenylphosphine (0.208 g, 0.791 mmol) in toluene (8.0 mL) is treated with 1,1′-(azodicarbonyl)dipiperidine (ADDP, 0.206 g, 0.817 mmol) and stirred overnight. The reaction mixture is filtered through Celite® diluted with EtOAc, washed with water (2×), brine (1×), dried over MgSO4, filtered, and conc. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 25% EtOAc to 100% EtOAc giving (±)-3-{4-[2-cyclohexyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-ethoxy]-benzoylamino}-propionic acid methyl ester (0.091 g, 31%) as a white foam. MS (ES): 554.0 [M+H]+.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:39]3[CH:38]=[CH:37][N:36]=[C:35]([Cl:34])[CH:40]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccnc(Cl)c1)N1CCC(N2CCCCC2)CC1
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 2-chloropyridine-4-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a yellow solid (35%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]([NH:8]S(C(C)(C)C)=O)[CH3:7])=[N:2]1.[ClH:15]>CO>[ClH:15].[O:1]1[CH:5]=[CH:4][C:3]([CH:6]([NH2:8])[CH3:7])=[N:2]1
Reactant: CC(NS(=O)C(C)(C)C)c1ccon1
Agent: Cl
Solvent: CO
Product: CC(N)c1ccon1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a round-bottomed flask, 2-methyl-propane-2-sulfinic acid (1-isoxazol-3-yl-ethyl)-amide (652 mg, 2.71 mmol) was dissolved in methanol (5 ml) and hydrogen chloride (4.0 M in 1,4-dioxane, 1.4 ml, 5.6 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 15 min then concentrated to give 1-isoxazol-3-yl-ethylamine hydrochloride as an off-white solid which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:15])=[CH:4][CH:3]=1.IC.[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:1][C:2]1[C:11]([CH2:12][CH:13]=[CH2:14])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:15])=[CH:4][CH:3]=1
Reactant: C=CCc1c(O)ccc2c1C(=O)CCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)ccc2c1C(=O)CCC2
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
160 mg of 3,4-dihydro-7-hydroxy-8-(2-propenyl)-1(2H)-naphthalenone (CAS No. 122076-30-6), 140 mg of iodomethane, and 400 mg of potassium carbonate were dissolved in 15 ml of acetone. The reaction solution was then stirred at 70° C. for 1.5 hours. The mixture was filtered and then washed with acetone. The organic layer was then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography, so that 140 mg of the subject compound was obtained from an ethyl acetate-hexane eluate (1:10).
Reaction SMILES: S([O-])(O)=O.[Na+].[C:6](=O)(O)[O-].[Na+].[C:11]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)(=[O:13])[CH3:12].ClCC(O)=O.[OH-].[Na+].Cl>O>[C:11]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:6])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CCC(Cc2ccc(S(=O)(=O)Cl)cc2)CC1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(O)CCl
Agent: O=S([O-])O
Solvent: O
Product: CC(=O)N1CCC(Cc2ccc(S(C)(=O)=O)cc2)CC1
Yield: 81.7 %

Procedure:
To a solution of sodium hydrogensulfite (4.57 g) and sodium bicarbonate (6.10 g) in water (40 mL) was added 4-[(1-acetyl-4-piperidinyl)methyl]benzenesulfonyl chloride (11.46 g) at 75° C. under stirring, and the mixture was stirred at 75° C. for an hour. Chloroacetic acid (5.14 g) and an aqueous solution of 50% sodium hydroxide (4.4 mL) was added to the reaction solution and stirred for 20 hours under reflux with heat. 1N Hydrochloric acid (20 ml) was added to the reaction mixture at 0° C., and the reaction mixture was extracted with ethyl acetate (60 mL, 30 mL). The organic phase was washed with saturated brine (10 mL×2), dried over magnesium sulfate (anhydrous), and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 150 g, ethyl acetate/methanol=1/0→9/1). The objective fraction was concentrated under reduced pressure to give the title compound as a colorless oil (8.76 g).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@@H:10]([CH2:18][N:19]([CH:36]([CH3:38])[CH3:37])[C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH2:9]1)C1C=CC=CC=1.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][C:53]=1[O:54][CH3:55])[C:48](O)=[O:49].CC#N.O.CC#N>O>[CH:36]([N:19]([CH2:18][C@@H:10]1[C@H:11]([CH2:13][N:14]([CH:15]([CH3:17])[CH3:16])[C:48](=[O:49])[C:47]2[CH:51]=[CH:52][C:53]([O:54][CH3:55])=[C:45]([O:44][CH2:43][CH2:42][CH2:41][O:40][CH3:39])[CH:46]=2)[CH2:12][NH:8][CH2:9]1)[C:20](=[O:35])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=1)([CH3:38])[CH3:37]
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Reactant: COCCCOc1cc(C(=O)N(C[C@H]2CN(Cc3ccccc3)C[C@H]2CNC(C)C)C(C)C)ccc1OC
Solvent: CC#N
Solvent: O
Product: COCCCOc1cc(C(=O)N(C[C@H]2CNC[C@H]2CN(C(=O)c2ccc(OC)c(OCCCOC)c2)C(C)C)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described in Example 361 by coupling N-[(3R*,4R*)-1-benzyl-4-(isopropylamino-methyl)-pyrrolidin-3-ylmethyl]-N-isopropyl4-methoxy-3-(3-methoxy-propoxy)-benzamide and 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid in step J. MS (LC-MS): 658.3 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.20 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21](OC)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH:30]=1.C[Al](C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][C:19]([C:21]([N:27]([CH3:26])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH:30]=3)=[O:22])=[N:18][N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1
Reactant: COC(=O)c1nnc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)o1
Reactant: CNCc1cccc(CN2CCCC2)c1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nnc(C(=O)N(C)Cc3cccc(CN4CCCC4)c3)o2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BK using methyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3,4-oxadiazole-2-carboxylate (150 mg, 0.41 mmol), methyl-(3-pyrrolidin-1-ylmethyl-benzyl)-amine (99 mg, 0.48 mmol), trimethylaluminium (2 M in toluene, 0.44 mL) and THF (15 mL).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[O:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1>>[O:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(Br)cc1
Product: Brc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 100 °C
Yield: 67.8 %

Procedure:
4-Bromoaniline (3.9 g, 0.0227 mol) was added to a solution of 2-chlorobenzoxazole (1.16 g, 0.00755 mol) in xylenes and the reaction mixture was heated at 100° C. for 2 hours. It was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL), the organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was triturated in n-heptane and the precipitate collected by filtration and dried to yield N-(1,3-benzoxazol-2-yl)-N-(4-bromophenyl)amine (1.48 g, 0.00512 mol) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.Cl.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]Cl>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22])[CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2
Reactant: O=S(=O)(c1cccc(O)c1)n1ccc2cc(F)ccc21
Reactant: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCOc1cccc(S(=O)(=O)n2ccc3cc(F)ccc32)c1

Procedure:
5-Fluoro-1-(3-hydroxybenzenesulfonyl) indole was treated in a similar procedure as given in the Example 1 with 3-dimethylaminopropylchloride hydrochloride (2.48 mmol, 0.393 grams), with some non-critical variations to obtain the above derivative.
Reaction SMILES: ClC1C=CC(S(N[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](CCCCCC2C=NC=CC=2)(C(OCC)=O)[C:19]([O:21]CC)=[O:20])(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>Cl.C(O)(=O)C>[C:19]([OH:21])(=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCOC(=O)C(CCCCCCNS(=O)(=O)c1ccc(Cl)cc1)(CCCCCc1cccnc1)C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCC(=O)O

Procedure:
A solution of 1.4 g of ethyl 8-(p-chlorophenylsulfonamido)-2-[5-(3-pyridyl)-pentyl]-2-(ethoxycarbonyl)-octanoate in 50 ml of 6N HCl and 10 ml of acetic acid is heated to reflux for 23 h after which time it is evaporated to give an oil. This is treated with water, the solution is neutralized with solid sodium bicarbonate to a pH of 6.4 and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, filtered and concentrated to give crude product which is further purified by chromatography on silica gel [(1) ethyl acetate as eluent, (2) preparative thin layer chromatography with ethyl acetate/acetic acid 99.5:0.5] to give 8-(p-chlorophenylsulfonamido)-2-[5-(3-pyridyl)pentyl])-octanoic acid as an oil, NMR (CDCl3): delta 7.77 (d,2H), 7.4 (d,2H), 2.85 (t,2H), 2.55 (t,2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[Br:13]N1C(=O)CCC1=O>ClCCl.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:13])=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)cc1[N+](=O)[O-]
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClCCl
Product: COc1ccc(CBr)cc1[N+](=O)[O-]
Yield: 78.2 %

Procedure:
To a solution of 4-methoxy-3-nitrotoluene (5.02 g) and N-bromosuccinimide (5.51 g) in dichloromethane (50 mL) was added 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) (463 mg). The mixture was heated under reflux for 8 hours. The solution was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with n-hexane-ethyl acetate (20:1) to give 4-methoxy-3-nitrobenzyl bromide as a pale yellow powder (5.78 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:4]=[CH:3]1.[Cl:15]N1C(C)(C)C(=O)N(Cl)C1=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CCCCCCC>CN(C=O)C>[Cl:15][C:3]1[N:2]([CH3:1])[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:4]=1
Reactant: COC(=O)c1ncn(C)c1C(=O)OC
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)n(C)c1C(=O)OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a colorless solution of dimethyl 1-methyl-1H-imidazole-4,5-dicarboxylate (500 mg, 2.42 mmol, Eq: 1.00) in DMF (5.00 mL) was added under a nitrogen atmosphere 1,3-dichloro-5,5-dimethylhydantoin (487 mg, 2.42 mmol, Eq: 1.00). The reaction mixture was heated to 80° C. and stirred for 2 h, cooled down to ambient temperature, poured into saturated sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layers were washed with brine (5 mL), dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) to give the product as colorless oil (415 mg, 1.78 mmol, 73.7%). MS: M=233.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[NH:7][C:8]([C:10]([NH:12][C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17]C)=[O:16])=[O:11])=[N:9][C:5]=2[CH:4]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[NH:7][C:8]([C:10]([NH:12][C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([OH:17])=[O:16])=[O:11])=[N:9][C:5]=2[CH:4]=1
Reactant: COC(=O)c1ccccc1NC(=O)c1nc2cc(OC)c(OC)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2nc(C(=O)Nc3ccccc3C(=O)O)[nH]c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a stirred solution of methyl 2-(5,6-dimethoxy-1H-benzo[d]imidazole-2-carboxamido)benzoate (200 mg, 0.56 mmol) in THF (10 mL) and MeOH (5 mL) was added 2N NaOH solution (1.4 mL) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by addition of 1N HCl solution and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 2-(5,6-dimethoxy-1H-benzo[d]imidazole-2-carboxamido)benzoic acid (90 mg, 47.1%). 1H-NMR (400 MHz, DMSO-d6) δ 3.82 (s, 6H), 6.97 (s, 1H), 7.13-7.34 (m, 2H), 7.64 (m, 1H), 8.08 (d, J=9.6 Hz, 1H), 8.78 (d, J=7.6 Hz; 1H), 12.90 (s, 1H), 13.27 (s, 1H); LC-MS (ES-API); rt 8.74 min; m/z calculated for C17H15N3O5 [M−H]− 340.1, found 340.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)[N:10]=1.CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH:23]([CH3:24])[CH3:25])=[N:21][N:22]=3)[N:19]=2)=[CH:12][N:11]([CH:26]2[CH2:30][CH2:29][N:28]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:27]2)[N:10]=1
Reactant: CC(C)c1nnc2ccc(-c3cn(C4CCNC4)nc3-c3ccc(F)cc3F)nn12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nnc2ccc(-c3cn(C4CCN(S(C)(=O)=O)C4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
To a round bottom flask was added 6-(3-(2,4-difluorophenyl)-1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.105 g, 0.256 mmol, Example #Q.1.1.1), DCM (5 mL) and DIPEA (0.054 mL, 0.31 mmol). Then methanesulfonyl chloride (0.020 mL, 0.26 mmol) was added. The reaction mixture was stirred at ambient temperature for about 10 min. The reaction mixture was purified directly by flash chromatography (40 g RediSep® silica gel; DCM/MeOH gradient from 1:0 to 9:1) to give the title compound (0.120 g, 96%): LC/MS (Table 1, Method g) Rt=2.28 min; MS m/z: 488.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].Cl.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH2:13])[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(CCC(=O)O)cc1F

Procedure:
A mixture of 5.0 g. of 3-fluoro-4-nitrocinnamic acid and 100 mg. of 10% palladium-on-carbon in 200 ml. of ethanol containing 5 drops of 5.5 N ethanolic hydrogen chloride is treated with hydrogen in a Parr apparatus at room temperature for 3 hours. The mixture is then filtered through Celite and the filtrate is concentrated, affording 3-fluoro-4-aminohydrocinnamic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)=[O:4].O[Li].O>O1CCCC1.O>[F:27][C:24]([F:25])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH2:12][CH2:13]1)=[O:28]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a suspension of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid methyl ester (1.000 g, 2.535 mmol) in a mixture of tetrahydrofuran-water (1:1, 5 mL), LiOH.H2O (0.106 g, 2.535 mmol) was added in one portion. The mixture was stirred at room temperature overnight. The clear solution was then cooled to 0° C. and quenched with 1 N HCl solution to pH 4-5. The solid separated was filtered. The residue was washed with cold water and dried under vacuum to obtain 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (0.771 g, 2.027 mmol, 80%) as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.82 (t, J=9.6 Hz, 2H), 7.74 (t, J=7.4 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.4 Hz, 1H), 7.27 (t, J=9.6 Hz, 1H), 3.87-3.60 (m, 6H), 3.31-3.10 (m, 2H), 13C NMR (75 MHz, DMSO-d6) δ 166.8, 165.7, 160.0, 143.7, 134.9, 134.9, 133.4, 130.1, 129.0, 128.0, 127.1, 127.0, 127.0, 126.0, 125.9, 125.5, 122.4, 112.5, 46.3, 44.3, 44.1. MS (ES+) m/z 381.2 (M+1).