Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>CO.C(Cl)Cl>[C:16]1([S:15][C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:1][NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=4)[CH:4]=3)[NH:8][C:7]=2[C:12]([NH2:14])=[O:13])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(CNc3cccc(C(F)(F)F)c3)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (50 mg, 0.17 mmol) with 3-trifluoromethylaniline (80 mg, 0.50 mmol) as described in General Procedure X to afford Iac (36 mg, 48.3%) as an ivory colored solid, tlc Rf=0.5 (5% MeOH/CH2Cl2), m/z obs=442 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:12][C:13]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([Cl:24])[C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:12][C:13]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([Cl:24])[C:14]=1[CH2:15][O:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn2cccc(O)c2n1
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn2cccc(OCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
A mixture of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (207 mg), 2,6-dichloro-3-nitrobenzyl bromide (400 mg) and potassium carbonate (580 mg) in N,N-dimethylformamide (8 ml) was stirred for 2 hours at 60° C. The mixture was cooled and diluted with water. The separated oil was extracted with dichloromethane. The organic layer was washed with water, dried, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 8-(2,6-dichloro-3-nitrobenzyloxy)-2-methylimidazo[1,2-a]pyridine (120 mg) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:29][CH2:28]4)=[C:23]([NH2:26])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:38]#[N:39])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.C(N(CC)C1C=CC=CC=1)C.[C:51](Cl)(=[O:53])[CH3:52]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:27]4[CH2:28][CH2:29][CH:30]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[CH2:31][CH2:32]4)=[C:23]([NH:26][C:51](=[O:53])[CH3:52])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:38]#[N:39])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: CC(=O)Cl
Reactant: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(N4CCC(N5CCCC5)CC4)c(N)cc23)cc1Cl
Solvent: CCN(CC)c1ccccc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N1CCC(N2CCCC2)CC1
Yield: 87.8 %

Procedure:
By the procedure of Example 27, 0.1 g (0.18 mmol) of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-amino-7-(4-pyrrolidin-1-yl piperidin-1-yl)quinoline-3-carbonitrile is reacted with 0.3 ml (1.9 mmol) of N,N-diethyl aniline and 0.04 ml (0.56 mmol) of acetyl chloride in 1.5 mL of NMP. The crude residue is purified by silica gel chromatography (gradient 95:5 methylene chloride/methanol to 4:1 methylene chloride/methanol) to give 95 mg of N-[4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-3-cyano-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinolin-6-yl]acetamide as a beige solid, mp 243-255° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[NH:6][C:7](=[O:14])[C:8]3[CH:9]=[CH:10][CH:11]=[N:12][C:13]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)(=O)=O>C(#N)C.CN(C)C=O>[O:14]=[C:7]1[NH:6][C:5]2[CH:15]=[CH:16][C:2]([O:1][CH:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]3)=[CH:3][C:4]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: O=c1[nH]c2ccc(O)cc2c2ncccc12
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3[nH]c(=O)c4cccnc4c3c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.7 %

Procedure:
The compound (60 mg, 0.28 mmol) prepared in step 2 and potassium carbonate (120 mg, 0.85 mmol) were dissolved in acetonitrile (6 ml)/N,N-dimethylformamide (3 ml), added with t-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (240 mg, 0.85 mmol). The resulting mixture was stirred for 3 days at 100˜110° C. and cooled to room temperature. After extraction with chloroform, the reaction mixture was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (chloroform:methanol=10:1) to obtain the title compound (65 mg, yield: 58%, white solid).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[Cl:12][CH2:13][SiH:14]([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[C:5]([NH:4][CH2:1][CH2:2][CH2:3][Si:14]([CH2:13][Cl:12])([CH3:16])[CH3:15])([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11]
Reactant: C[SiH](C)CCl
Reactant: C=CCNC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCC[Si](C)(C)CCl
Temperature: 70 °C

Procedure:
A 250 mL 3-necked round bottom flask equipped with reflux condenser nitrogen inlet, thermometer heating mantle, pressure equalizing addition funnel and magnetic stirrer was charged with 14.36 g (91.3 mmol) of t-butyl N-allylcarbamate and 150 mL of toluene. The olefin and solvent were stirred and heated to about 70° C., then 10 microliters of Karstedt's catalyst (5% Pt solution, about 30 ppm Pt based on olefin) was added. A solution containing 12 g (110.5 mmol) of chloromethyldimethylsilane in 20 mL toluene was added cautiously over about 30 minutes at a rate sufficient to maintain the reaction temperature between about 80 and about 100° C. After addition was completed, the temperature was stirred and heated at about 85° for about 1 hour. GC-MS indicated complete reaction of the olefin to form the silylated compound, N-Boc-3-aminopropylchloromethyldimethylsilane. The solution was transferred to a 500 ml single neck round bottom flask and the solvent and excess silane were stripped via rotary evaporation to yield 25 g of crude product (quantitative yield based on olefin).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8](=[O:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.N1CCCC1.Cl>CO>[O:10]=[C:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[O:1][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(=O)c1ncccc1O
Agent: Cl
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ncccc1O2
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
A solution of 1-(3-hydroxy-2-pyridyl)ethanone (2.4 g, 18 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.5 g, 18 mmol) and pyrrolidine (1.5 mL, 18 mmol) in MeOH (12 mL) was stirred at 80° C. for 2 hours. After cooling to room temperature 1M aqueous HCl was added until pH 4 was reached and the reaction mixture was stirred for further 30 minutes. Methanol was evaporated, the remaining mixture was poured into water, and the pH adjusted to pH 7 with saturated aqueous sodium carbonate. The aqueous phase was extracted with ethyl acetate (3×), washed with brine (3×), dried over sodium sulfate and evaporated to dryness. Purification by silica gel chromatography (50-100% ethyl acetate in hexane) afforded tert-butyl 4′-oxo-3′,4′-dihydrospiro-[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate (2.2 g, 40%) as an orange oil that solidified upon standing. ESI-MS m/z talc. 318.2, found 319.3 (M+1)+; Retention time: 1.16 minutes (3 min run).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:14]=[C:13](Cl)[C:12]2[C:7](=[CH:8][C:9]([O:18][CH3:19])=[C:10]([O:16][CH3:17])[CH:11]=2)[N:6]=1>CO>[Cl:4][C:5]1[N:14]=[C:13]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][C:9]([O:18][CH3:19])=[C:10]([O:16][CH3:17])[CH:11]=2)[N:6]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2nc(Cl)nc(OC)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.1 %

Procedure:
Sodium methoxide (0.12 g, 2.2 mmole) was added to a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (0.52 g, 2 mmol) in methanol (20 mL) at 25° C. The mixture was stirred at 25° C. for 12 h and was concentrated in vacuo to give a white solid residue. Purification of the residue by flash column chromatography (gradient elution 30 to 60% EtOAc/hexanes) provided the title compound (0.51 g, quantitative yield): TLC (Rf =0.50; CH2Cl2); 1H NMR (CDCl3) δ 7.33 (s, 1H), 7.21 (s, 1H), 4.20 (s, 3H), 4.01 (s, 6H); 13C NMR (CDCl3) δ 166.9, 156.1, 154.3, 149.8, 149.5, 109.0, 106.2, 101.4, 56.4, 56.3, 55.0; HRMS (FAB) m/z 255.0531 (M+H)+ (C11H11N2O3Cl requires 255.0536); Anal. (C11H11N2O3Cl·1/2H2O·1/4CH3OH) C, H, N.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:25][C:26]([CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)=[O:27])[CH:23]=3)[NH:18][N:17]=2)=[CH:12][CH:11]=1>ClCCl>[C:1]([N:30]1[CH2:31][CH2:32][CH2:33][CH:28]([C:26]([NH:25][C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[C:16]3[C:13]2[CH:12]=[CH:11][N:10]=[CH:15][CH:14]=2)=[O:27])[CH2:29]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc2[nH]nc(-c3ccncc3)c2c1)C1CCCNC1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3ccncc3)c2c1)C1CCCN(C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
In a flask, dichloromethane (0.023mL) was added to benzoyl chloride. The reaction was cooled to 0° C., and a solution of N-(3-(pyridin-4-yl)-1H-indazol-5-yl)piperidine-3-carboxamide (0.014 g, 0.044 mmol) in dichloromethane (0.020 mL) was dropwise added to the benzoyl chloride solution. The reaction stirred for 6 hrs from 0° C. to room temperature. The reaction was quenched with water (1 mL) and extracted with dichloromethane (3×1 mL). The extracts were combined and dried with sodium sulfate. The crude product was purified using prep LC/MS. LC-MS: 426.1 [M+H]. LC/MS RT=2.998 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:18]([OH:21])[CH2:19][Br:20])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O.C1COCC1>C1(C)C=CC=CC=1>[NH2:1][C:4]1[CH:5]=[C:6]([C@H:18]([OH:21])[CH2:19][Br:20])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc([C@H](O)CBr)ccc1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1cc([C@H](O)CBr)ccc1OCc1ccccc1
Yield: 69.6 %

Procedure:
A solution of the product of Step A) (18.7 g, 53.1 mmol) in toluene (40 mL) and THF (40 mL) was added to a Parr shaker bottle containing Pt2O (370 mg). This mixture was shaken under H2 (50 psi, 344.74 kpa) until the reaction was complete (18 h). The catalyst was removed by filtration, and the filtrate was concentrated to an oil. Column chromatography (1 kg silica gel packed in and eluted with CH2Cl2/MeOH, 19:1) gave 11.9 g (69.6%) of the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][N:7]=1)=[O:5].[CH3:14][O:15][CH:16]([O:20][CH3:21])[CH:17](Br)[CH3:18]>C1COCC1.O.C(=O)=O>[Br:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([C:4](=[O:5])[CH2:18][CH2:17][CH:16]([O:20][CH3:21])[O:15][CH3:14])[CH:11]=1
Reactant: CON(C)C(=O)c1cc(Br)ccn1
Reactant: COC(OC)C(C)Br
Agent: O=C=O
Solvent: O
Solvent: C1CCOC1
Product: COC(CCC(=O)c1cc(Br)ccn1)OC
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To a solution of (1) (8.86 g, 36.2 mmole) in 250 mL of anhydrous THF in a 3-neck flamed dried round bottom flask at −70° C. (acetone-dry ice bath) is slowly added the Grignard reagent prepared from bromopropionaldehyde dimethyl acetal (16.5 g, 90.4 mmol) and Mg turnings (4.39 g, 181 mmol) in anhydrous THF (250 mL), maintaining internal temperature around −68° C. to −70° C. After stirring at −70° C. for 2 hours, the reaction mixture is diluted with 200 mL of water with the dry ice bath removed. The mixture is poured into a separatory funnel, and the mixture is extracted 3 times with ethyl acetate (150 mL). The organic layers are combined and dried over Na2SO4 and the solvent evaporated leaving a thick yellow oil (11 g, 100% crude yield, MS ES+258.02).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14].C([Li])CCC.Cl[CH:21]([SiH3:23])Cl>CCCCCC.O>[CH3:21][SiH:23]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1
Reactant: Cc1ccccc1C
Reactant: [SiH3]C(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: C[SiH]1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 1 L rb flask equipped with a Teflon covered magnetic stirring bar and a reflux condenser was placed potassium tert-butoxide (36 g; 0.32 mol), o-xylene (17 mL; 0.15 mol) and 700 mL of hexanes. n-Butyllithium (128 mL; 2.5M) in hexane was added to the above mixture via a syringe. The red color of the o-xylene dianion appeared. The resulting mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temp. The suspension of the dianion was transferred via a cannula to a sintered glass filter. The solvent was removed by suction filtration. The precipitated dianion was rinsed with fresh hexane. It was then resuspended in 500 mL of hexane and the suspension returned via a cannula to the original apparatus. Freshly distilled dichloromethylsilane (17 mL; 0.16 mol) was added. The mixture was stirred overnight a room temperature. 50 mL water was added. The organic layer was washed three times with water, dried over anhydrous calcium chloride, filtered and the solvents removed by evaporation under reduced pressure. The residue was purified by fractional distillation through a 15 cm vacuum jacketed Vigreux column. A central fraction, b.p. 43°-44° C./0.7 mmHg, was obtained. Yield: 5.5 g(25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:38]([CH:35]4[CH2:36][CH2:37][NH:32][CH2:33][CH2:34]4)=[O:39])[CH2:21][CH2:20]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(CCC1CCNCC1)[C@@H]1CCc2ccc(OC)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC1CCN(C(=O)C2CCNCC2)CC1)[C@@H]1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.5 %

Procedure:
Under an inert atmosphere ((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-(2-piperidin-4-yl-ethyl)-propyl-amine (200 mg, 0.61 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (139 mg, 0.61 mmol), EDCl (117 mg, 0.61 mmol), HOBT (82 mg, 0.61 mmol), triethylamine (0.17 mL, 1.2 mmol), and dichloromethane (35 mL) were combined. The mixture was stirred at room temperature for 48 h and then concentrated in-vacuo. The residue was taken-up in EtOAc (50 mL) and washed with water (30 mL), 1 N NaOH (30 mL), brine (30 mL), and dried (MgSO4). The solution was filtered and concentrated to afford an oil. The oil was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine (260 mg) which was deprotected with 10 mL trifluoroacetic acid, as described herein, to afford (4-{2-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-ethyl}-piperidin-1-yl)-piperidin-4-yl-methanone (200 mg) 116[M+H]+=478.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(NCCOc2ccc(Cl)cc2Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCOc2ccc(Cl)cc2Cl)cc1

Procedure:
A solution of 15 g of ethyl p-{[2-(2,4-dichlorophenoxy)ethyl]amino}benzoate and 15 g of potassium hydroxide in 200 ml. of 95% ethanol is refluxed for 3 hours. The solution is cooled, diluted with water, acidified with concentrated hydrochloric acid and filtered. The solid is recrystallized from ethanol to give crystals, mp 203°-205° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]([C:35](=[O:37])[CH3:36])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CNCCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CN(C(C)=O)CCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid ethyl ester (0.6 g, 1.24 mmol) in CH2Cl2 (10 mL) and TEA (0.378 mL, 2.73 mmol) at 0° C. was added acetyl chloride (0.1 mL, 1.36 mmol). The reaction was allowed to warm to 25° C. over 19 h. The reaction was then taken up in CH2Cl2 (50 mL) and washed with 1N HCl (5 mL) and water (5 mL). The organics were washed with saturated aqueous sodium chloride (30 mL), dried over MgSO4, filtered and concentrated. The residue was purified with Biotage Flash 40S chromatography, eluting with 1:1 ethyl acetate-hexanes, to provide 1-acetyl-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid ethyl ester as a white solid (0.6 g, 92%). MS: 526 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][CH3:12])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:11][CH3:12])[N:7]=[C:8]([NH:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)[CH:9]=1)=[O:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCn1nc(N)cc1C(=O)OC
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(NCc2ccc(F)cc2)cc1C(=O)OC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 5-amino-2-ethyl-2H-pyrazole-3-carboxylic acid methyl ester (527, 1.00 g, 5.91 mmol) in acetonitrile (27.5 mL) were added 4-fluorobenzaldehyde (528, 0.660 mL, 6.26 mmol), triethylsilane (4.77 mL, 0.0298 mol) and trifluoroacetic acid (2.38 mL, 0.0310 mol). The reaction was stirred at 80° C. for 4 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (529, 1.00 g, 61%).
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.N([O-])=O.[Na+].N.[ClH:15]>O>[Br:8][C:7]1[C:2]([Cl:15])=[N:3][CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: Cl
Reactant: Cc1cnc(N)c(Br)c1
Agent: N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cnc(Cl)c(Br)c1
Reaction time: 1.5 h

Procedure:
The product from (a) (145 g) was dissolved in concentrated hydrochloric acid (750 ml) and water (450 ml) and the solution cooled to -10° C. Sodium nitrite (54 g) in cold water (450 ml) was added dropwise with stirring over a period of 90 minutes while the mixture was kept at -5° C. The solution was stirred for a further 2 hours, and then basified with concentrated ammonia, keeping the temperature below 20° C. The solid which separated was washed with water, dried, dissolved in ether (1500 ml) and washed with cold sodium hydroxide solution (1M; 1 liter). The ether solution was washed twice with water (1 liter portions), dried, and evaporated to give the required 3-bromo-2-chloro-5-methylpyridine.
Reaction SMILES: [OH:1][CH:2]([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[CH:6]2.CN(C)C(=O)C>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:16][NH:15][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:21]=3)=[O:1])[CH:4]=2)[CH:9]=1)=[O:14]
Reactant: CNC(=O)c1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
6-[Hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide (10.0 g, 19.1 mmol) and manganese dioxide (6.6 g, 75.9 mmol) were added to N,N-dimethylacetamide (85 mL), and the mixture was stirred at 60° C. for 2 hr. The insoluble material was filtered off at the same temperature, and washed with N,N-dimethylacetamide (40 mL). The filtrate and washing were combined and cooled to 40° C., water (60 mL) was added dropwise thereto, and the mixture was stirred at room temperature. The obtained crystals were collected by filtration, and washed with water (50 mL). The wet crystals were dried under reduced pressure to give crude crystals (9.5 g). Ethyl acetate (100 mL) was warmed to 40° C., and the crude crystals (9.5 g) were added thereto. The obtained mixture was warmed to 50° C., and stirred for 0.5 hr. The solvent (20 mL) was evaporated under reduced pressure. The residue was allowed to cool to room temperature, and diisopropyl ether (80 mL) was added dropwise thereto, and the mixture was stirred at the same temperature. The obtained crystals were collected by filtration, and washed with a mixed solvent (30 mL) of diisopropyl ether/ethyl acetate (1:1, volume ratio). The obtained wet crystals were dried under reduced pressure to give N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (8.9 g, 17.1 mmol). yield 89%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(CC)CC>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:13]1[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)CCCCl)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
3-Chloropropanesulfonyl chloride (1.0 g, 5.6 mmol) dissolved in CH2Cl2 (20 mL) and cooled to ˜0° C. was treated dropwise with a solution of 1-methylpiperazine (566 mg, 5.6 mmol) and Et3N (572 mg, 5.6 mmol) in CH2Cl2 (10 mL). Following complete addition, the mixture was allowed to warm to rt and stir an additional 2 h. The solvent was evaporated under reduced pressure, the residue triturated with EtOAc (30 mL), vacuum filtered and the solid washed well with EtOAc. The filtrate was concentrated under reduced pressure and the oil residue dried under high vacuum to give the title compound (1.27 g, 93%): 1H NMR (CDCl3) δ: 2.17-2.26 (2H, m), 2.49 (3H, s), 2.75-2.77 (4H, m), 3.02-3.07 (2H, m), 3.46-3.49 (4H, m), 3.60 (2H, t).