Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([S:27](Cl)(=[O:29])=[O:28])[CH2:24][CH2:25][CH3:26].C(=O)(O)[O-].[Na+].[OH-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[S:27]([CH2:23][CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28]
Reactant: Fc1ccc(NCc2cccnc2)c(F)c1
Reactant: CCCCS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCS(=O)(=O)N(Cc1cccnc1)c1ccc(F)cc1F

Procedure:
A 4.4 g. portion of 3-(2,4-difluorophenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and to it were added 4.1 g. of potassium carbonate and 4.7 g. of butanesulfonyl chloride. The mixture was stirred under gentle reflux for several days, and was then cooled and diluted with 20 ml. of aqueous sodium bicarbonate and 5 ml. of aqueous sodium hydroxide. Some additional dichloromethane was added, and the suspension was shaken and the organic layer separated. It was washed with aqueous sodium bicarbonate and dried over magnesium sulfate, and it was then evaporated to a smaller volume and was chromatographed on a silica gel column, eluting with dichloromethane. The chromatography was repeated twice to obtain 0.38 g. of the desired product.
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:38]([F:39])=[CH:37][C:10]3[N:11](CC4C=CC(C5C=CC=CC=5)=CC=4)[C:12]([O:14][CH2:15][CH:16]4[CH2:18][CH:17]4[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:13][C:9]=3[C:8]=2[F:40])=[CH:3][CH:2]=1.C1CC=CCC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[C:1]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:38]([F:39])=[CH:37][C:10]3[NH:11][C:12]([O:14][CH2:15][CH:16]4[CH2:18][CH:17]4[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:13][C:9]=3[C:8]=2[F:40])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CC1COc1nc2c(F)c(-c3ccc(-c4ccccc4)cc3)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1=CCC=CC1
Solvent: CCO
Product: CCOC(=O)C1CC1COc1nc2c(F)c(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1

Procedure:
To a solution of ethyl 2-({[5-(biphenyl-4-yl)-1-(biphenyl-4-ylmethyl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}methyl)cyclopropanecarboxylate (0.270 g, 0.439 mmol) and Pd(OH)2 (0.080 g, 0.114 mmol) in 3.6 mL of EtOAc and 1.8 mL of EtOH was added 1,4-cyclohexadiene (1.06 mL, 11.3 mmol). The resulting black suspension was microwaved at 130° C. for 2 h, and then filtered through a Celite™ pad, and washed with 100% EtOAc. The resulting filtrate was concentrated. Purification of the resulting crude product by reverse phase Gilson™ HPLC (50-100% AcCN/H2O) afforded the desired product. LCMS: calculated for C26H22F2N2O3 448.46, observed m/e 448.9 (M+H)+ (Rt 2.37/4 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[O:13]=[C:14]1[C:19]2=[CH:20][NH:21][C:22]([CH:23]=O)=[C:18]2[CH2:17][CH2:16][NH:15]1.N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:23][C:22]1[NH:21][CH:20]=[C:19]2[C:18]=1[CH2:17][CH2:16][NH:15][C:14]2=[O:13]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 5-methoxy-1,3-dihydro-indol-2-one (32.6 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (32.8 mg, 0.2 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH3:8][S:9][CH2:10]Cl.C(N(CC)CC)C>>[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:8][S:9][CH3:10])=[O:4]
Reactant: CCC(C)C(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: CCC(C)C(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting 2-methylbutyric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 75°-77° C./12 mm Hg, nD20 1.4505.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]=O)=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1>>[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5c(c4)OCCO5)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][CH2:9][C:10](=[O:13])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=C1CCC(c2ccccc2)(c2ccccc2)CC1
Yield: 98.1 %

Procedure:
To a Parr hydrogenation bottle was added 4,4-diphenyl-2-cyclohexen-1-one (0.91 g, 3.66), dissolved in methanol (20 mL), followed by the addition of 10% Pd/C (0.2 g). This mixture was hydrogenated at 50 psi overnight. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo to give 0.90 g of 4,4-diphenyl-cyclohexanone. MS (EI) calcd: M+H=251.1; found: 251.1.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])=[CH:5][N:4]=1.[CH3:18][N:19]([CH2:21][C:22]1[O:26][C:25]([CH2:27][S:28][CH2:29][CH2:30][NH2:31])=[CH:24][CH:23]=1)[CH3:20]>N1C=CC=CC=1>[CH3:20][N:19]([CH2:21][C:22]1[O:26][C:25]([CH2:27][S:28][CH2:29][CH2:30][NH:31][C:3]2[NH:8][C:7](=[O:9])[C:6]([CH:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH3:11])=[CH:5][N:4]=2)=[CH:24][CH:23]=1)[CH3:18]
Reactant: CSc1ncc(C(C)c2cccnc2)c(=O)[nH]1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: c1ccncc1
Product: CC(c1cccnc1)c1cnc(NCCSCc2ccc(CN(C)C)o2)[nH]c1=O

Procedure:
Equimolar amounts of 2-methylthio-5-[1-(3-pyridyl)ethyl]-4-pyrimidone and 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine in pyridine are boiled under reflux for 48 hours and evaporated to dryness. The residue is purified to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(1-(3-pyridyl)ethyl)-4-pyrimidone.
Reaction SMILES: ClC1C=CC=CC=1Cl.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24](=[O:25])[CH:23]3[CH:18]([CH2:19][CH:20]=[C:21]4OC5C=CC=CC=5[CH:22]43)[C:17]2=[O:33])=[CH:12][CH:11]=1.C([C:36]1[C:42](=O)[C:41](Cl)=[C:40](Cl)[C:38](=[O:39])[C:37]=1C#N)#N>C(Cl)(Cl)Cl>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24](=[O:25])[C:23]34[C:37]5[CH:36]=[CH:42][CH:41]=[CH:40][C:38]=5[O:39][C:22]3=[CH:21][CH:20]=[CH:19][CH:18]4[C:17]2=[O:33])=[CH:12][CH:11]=1
Reactant: Cc1ccc(N2C(=O)C3CC=C4Oc5ccccc5C4C3C2=O)cc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2C(=O)C3C=CC=C4Oc5ccccc5C43C2=O)cc1
Yield: 36.2 %

Procedure:
15 ml of o-dichlorobenzene was added to a mixture of 0.50 g of 2-(4-methylphenyl)-3a,4,10b,10c-tetrahydro-1H-benzofuro[3,2-e]isoindole-1,3(2H)-dione and 0.75 g of DDQ. The mixture was refluxed for 4 hours. The reaction mixture was mixed with 50 ml of chloroform. The resulting mixture was washed with an aqueous 10% potassium carbonate solution and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from methanol to obtain 0.18 g (yield: 36%) of 2-(4-methylphenyl)-1H-benzofuro-[3,2-d]isoindole-1,3(2H)-dione as light yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:3]=2)=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: N#Cc1ccc(Cl)nc1OC1CCCC1
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1OC1CCCC1
Temperature: 69 °C
Yield: 100.3 %

Procedure:
To a mixture of 6-chloro-2-cyclopentyloxy-nicotinonitrile (1.32 g, 5.92 mmol) and 2-bromo-5-hydroxy-benzaldehyde (1.43 g, 7.10 mmol) in DMF (10 mL) was added potassium carbonate (1.22 g, 8.88 mmol). The resulting mixture was heated at 69° C. overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (100 mL), washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give white solid, which was purified by flash chromatography on silica gel using 10-25% EtOAc/hexanes as eluent to yield the title compound (2.30 g, quantitative) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.24 (d, J=8.2 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.70 (s, 1H), 7.60-7.46 (m, 1H), 6.79 (d, J=8.2 Hz, 1H), 4.95 (br. s., 1H), 1.87-1.50 (m, 6H), 1.52-1.30 (m, 2H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[CH:18]=[C:17]([CH2:19][CH3:20])[O:16][N:15]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:31])=[N:25][C:26]=2Cl)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH2:41]([CH:43]([NH2:46])[CH2:44][CH3:45])[CH3:42]>C(O)(C)C>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[CH:18]=[C:17]([CH2:19][CH3:20])[O:16][N:15]=2)[O:7][C@H:6]1[N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][C:24]([Cl:31])=[N:25][C:26]=2[NH:46][CH:43]([CH2:44][CH3:45])[CH2:41][CH3:42])(=[O:3])[CH3:2]
Reactant: CCc1cc([C@H]2O[C@@H](n3cnc4c(Cl)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Reactant: CCC(N)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cc([C@H]2O[C@@H](n3cnc4c(NC(CC)CC)nc(Cl)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)no1
Temperature: 50 °C

Procedure:
(2R,3R,4 R,5R)-4-(acetyloxy)-2-(2,6-dichloro-9H-purin-9-yl)-5-(5-ethylisoxazol-3-yl)tetrahydrofuran-3-yl acetate (125 mg) was dissolved in isopropanol (5 ml) and the solution was treated with diisopropylethylamine (0.06 ml) followed by 1-ethylpropylamine (0.044 ml). The mixture was heated at 50° C. under nitrogen for 16 h. The solvent was removed in vacuo and the mixture partitioned between ethyl acetate and 1 M hydrochloric acid. The organic layers were washed with saturated sodium bicarbonate solution and brine, dried (MgSO4) and evaporated in vacuo. Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with (i) dichloromethane, (ii) ether and (iii) ethyl acetate, gave the title compound as a colourless oil (108 mg). TLC SiO2 (ether) Rf=0.26.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:9]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:8][S:7][CH:6]=1.S(=O)(=O)(O)O.[C:25]([OH:29])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:3](=[O:2])[CH2:4][C:5]1[C:9]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:8][S:7][CH:6]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)Cc1cscc1Nc1c(Cl)cccc1Cl
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Product: CC(C)(C)OC(=O)Cc1cscc1Nc1c(Cl)cccc1Cl

Procedure:
316 mg (1 mmole) of 4-(2,6-dichloroanilino)-3-thiophenacetic acid methyl ester are warmed to 60° in 20 ml of tert.-butanol and 2 ml of concentrated sulfuric acid for 2 hours. The excess alcohol is distilled off. Chromatography on a column (silica gel/methylene chloride) gives, in the first fraction, 4-(2,6-dichloroanilino)-3-thiophenacetic acid tert.-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2]
Reactant: CCOc1cc(N)c2ncccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: CCOc1cc(NS(=O)(=O)c2ccccc2)c2ncccc2c1
Yield: 32.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-ethoxyquinolin-8-amine (Intermediate 47) (150 mg, 0.8 mmol), benzenesulfonyl chloride (170 mg, 0.96 mmol) and DMAP (cat.) gave the title compound (85 mg, 33%) after purification by column chromatography with n-hexane/DCM (1:0-0:1) as the eluent and recrystallisation from DCM/n-pentane.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:29])[CH2:15][O:16][C:17]3[C:18]([CH2:24][CH2:25][C:26](O)=[O:27])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C@H:9]([CH3:30])[CH2:8]2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:29])[CH2:15][O:16][C:17]3[C:18]([CH2:24][CH2:25][C:26]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:27])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C@H:9]([CH3:30])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(CCC(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(CCC(=O)NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.6 %

Procedure:
To a solution of 3-(3-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-6-methyl-pyridin-2-yl)-propionic acid (0.10 g, 0.23 mmol) in methylene chloride (2 mL) was added 4-dimethylaminopyridine (0.032 g, 0.27 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.051 g, 0.27 mmol), methanesulfonamide (0.025 g, 0.27 mmol) and triethylamine (0.037 mL, 0.27 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 0.2 M hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.051 g, LRMS: 521.5).
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[C:22]([CH3:23])=[CH:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH:19]=2)[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CC(N(C)C)=O.O>[CH:1]1([CH:7]([C:18]2[C:22]([CH3:23])=[CH:21][N:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[CH:19]=2)[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:35]([CH3:34])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution (10 mL) of 4-(cyclohexyl{4-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methoxy)benzoic acid (0.43 g) synthesized above in dimethylacetamide were added ethyl 3-(methylamino)propanoate (0.14 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g) and 1-hydroxybenzotriazole monohydrate (0.23 g) at room temperature, and the mixture was stirred at 60° C. for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was purified by silica gel chromatography (ethyl acetate:hexane=1:1, volume ratio) to give a methyl ester form of the title compound (0.44 g). This was dissolved in ethanol (2 mL), 1N sodium hydroxide (1.5 mL) was added and the mixture was stirred at room temperature for 1 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.5 mL) was added to the residue to give the title compound (0.40 g, 78%) as an amorphous form.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=1)=[O:4].[C:23]1([C:29]2[N:30]=[C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[S:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:23]1([C:29]2[N:30]=[C:31]([N:34]3[CH2:39][CH2:38][N:37]([C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:21])[F:22])=[CH:11][CH:10]=4)=[O:20])[CH2:36][CH2:35]3)[S:32][CH:33]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Nc1ccc(NC(=O)C(F)(F)F)cc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1ccc(NC(=O)C(F)(F)F)cc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 39.9 %

Procedure:
A solution of 2,2,2-trichloroethyl {4-[(trifluoroacetyl)amino]phenyl}carbamate (200 mg, 0.527 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (129 mg, 0.527 mmol), diisopropylethylamine (0.184 ml, 1.05 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 100 mg (39.8%) of the desired product as a solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH:8]=O)(=[O:3])[CH3:2].N1CCCCC1.C(O)(=O)[CH2:21][C:22]([OH:24])=[O:23].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:21][C:22]([OH:24])=[O:23])[CH:10]=[CH:11][C:12]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: O=C(O)CC(=O)O
Reactant: CC(=O)Nc1cc(C=O)ccc1C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C=CC(=O)O)ccc1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a solution of 3-acetamido-4-methylbenzaldehyde (14 g, 79 mmol) in pyridine (210 mL) is added piperidine (3.9 mL, 39.4 mmol) and malonic acid (15.26 g, 146.6 mmol). The mixture is heated to 100° C. for 4 hours, then stirred at room temperature overnight. The solution is concentrated in vacuo, then diluted with water. Cold 1 N HCl is added to the slurry until pH is ca. 4. The solid product (16.178 g, 73.8 mmol) is collected and washed generously with water. The title compound (16.178 g, 73.8 mmol) is then dried over P2O5 under vacuum overnight to yield a white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.CCOC(C)=O.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[O:10])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccccn1
Reactant: Fc1cc(I)ccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=c1ccccn1-c1ccc(I)c(F)c1
Temperature: 130 °C

Procedure:
A mixture of 2,5-diiodofluorobenzene II-4 (2.00 g, 5.75 mmol), 2-hydroxypyridine 1-7 (0.546 g, 5.75 mmol), 8-hydroxyquinoline (0.083 g, 0.57 mmol) and K2CO3 (1.00 g, 7.25 mmol) in DMSO (10 mL) was degassed before being charged with CuI (0.109 g, 0.57 mmol). The mixture in a sealed tube was heated at 130° C. overnight. Water and EtOAc were added. The mixture was filtered. The organic layer was separated, then applied to a silica gel column, which was eluted with 0-70% EtOAc in hexane to give 1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 (0.820 g). MS 315.8 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH:40]1[O:45][C:44]2[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=2[O:42][CH2:41]1>CN(C)C=O>[O:45]1[CH:40]([CH2:39][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[CH2:41][O:42][C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]1=2
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: BrCC1COc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CC4COc5ccccc5O4)CC3)C2=O)c1
Temperature: 55 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
To a solution of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.23 g, 0.55 mmol) and potassium carbonate (0.114 g, 0.83 mmol) in N,N-dimethylformamide (5 mL), was added 2-(bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine (0.082 mL, 0.55 mmol, d=1.533). After stirring at 55° C. for 18 hours, the reaction mixture was filtered, concentrated and isolated by preparatory TLC (7% methanol/dichloromethane) to obtain the title compound (0.17 g, 54%); 1H NMR (DMSO-d6): δ 1.52 (s, 9H), 1.63 (d, 2H, J=12 Hz), 2.54-2.60 (m, 2H), 2.65 (d, 2H, J=6 Hz), 2.81-2.93 (m, 6H), 3.99-4.04 (m, 1H), 4.37 (dt, 2H, J=10.4 and 2.4 Hz), 4.60 (d, 2H, J=11.2 Hz), 6.76-6.88 (m, 7H), 7.23 (t, 2H, J=8.8 Hz), 7.48-7.55 (m, 2H), 7.79 (m, 1H), 7.83 (dt, 1H, J=7.2 and 2 Hz); MS for C34H39N3O5 m/z 570.12 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:17]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:6]=1.CO.Cl.O1CCOCC1>>[NH2:17][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[CH:6]=1)[CH2:2][OH:1]
Reactant: Cn1cc(-c2cccc(C[C@@H](CO)NC(=O)OC(C)(C)C)c2)cn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(C[C@H](N)CO)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of Step A (0.45 g, 1.4 mmol) was combined with methanol (2.0 mL, 49 mmol) and 4.0 M HCl in dioxane (6.0 mL, 24 mmol). The reaction mixture was stirred at rt for 30 min yielding the titled compound. LC-MS found: 232.2 (m+1).