Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[N:7][C:8]([C@@H:18]([NH2:20])[CH3:19])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:10]=2)[CH:5]=[CH:4]1.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24](Cl)[N:23]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[C:25]([C:29]#[N:30])=[C:24]([NH:20][C@H:18]([C:8]2[N:7]=[C:6]3[CH:5]=[CH:4][N:3]([CH3:2])[C:11]3=[CH:10][C:9]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:19])[N:23]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccccn1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1-c1ccccn1
Temperature: 25 °C

Procedure:
A solution of (S)-1-(1-methyl-6-(pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine hydrochloride (50 mg, 0.198 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (50.4 mg, 0.297 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.104 mL, 0.594 mmol) in acetonitrile (6 mL), was heated in a microwave reactor at 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was concentrated, re-dissolved in DMF, and purified by preparative HPLC (basic mode) using a 20-30% CH3CN gradient in H2O. The desired fractions were combined and solvent was removed in vacuo. The residue was purified again by preparative HPLC (basic mode) using a 25-35% CH3CN gradient in H2O. The pure fractions were combined and the solvent was removed in vacuo to give the title compound as a colorless film (24 mg, 31%). 1H NMR (500 MHz, CD3OD) δ ppm 1.59 (d, J=7.32 Hz, 3 H), 4.04 (br s, 3 H), 5.84 (q, J=7.32 Hz, 1 H), 6.88 (d, J=3.42 Hz, 1 H), 7.62-7.68 (m, 1 H), 7.90 (d, J=7.81 Hz, 1 H), 8.08 (d, J=2.93 Hz, 1 H), 8.16 (td, J=7.81, 1.95 Hz, 1H), 8.66 (s, 1H), 8.83 (d, J=4.88 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C20H19N9, 386. found 386.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=2)=[CH:8][CH:7]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[O:13][CH:14]=[C:15]([C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[N:16]=2)=[CH:10][CH:11]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1coc(-c2ccc(OCCCCl)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1coc(-c2ccc(OCCCCl)cc2)n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A solution of 2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-4-carboxylic acid i34 (0.5 g, 1.57 mmol, 1 eq), morpholine (0.15 g, 1.73 mmol, 1.1 eq) and triethylamine (0.44 ml, 3.14 mmol, 2 eq) in dichloromethane (20 ml) is cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.33 g, 1.73 mmol, 1.1 eq) and 1-hydroxybenzotriazole (0.04 g, 0.31 mmol, 0.2 eq) are added to the solution and the mixture is stirred 24 h at room temperature. The mixture is then washed with water and a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to give 0.54 g of 4-({2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}carbonyl)morpholine i35.
Reaction SMILES: [CH3:1][O:2][C:3]([N:6]1[N:10]=[N:9][C:8]([CH3:11])=[N:7]1)([CH3:5])[CH3:4].C([Li])CCC.CON(C)[C:20](=[O:39])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C@H:29]2[CH2:34][CH2:33][C@H:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:31][CH2:30]2)=[CH:23][CH:22]=1>C1COCC1>[C:35]([CH:32]1[CH2:31][CH2:30][CH:29]([NH:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:20](=[O:39])[CH2:11][C:8]3[N:9]=[N:10][N:6]([C:3]([O:2][CH3:1])([CH3:5])[CH3:4])[N:7]=3)=[CH:22][CH:23]=2)[CH2:34][CH2:33]1)([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(C)(C)n1nnc(C)n1
Reactant: CON(C)C(=O)c1ccc(CN[C@H]2CC[C@H](C(C)(C)C)CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(C)(C)n1nnc(CC(=O)c2ccc(CNC3CCC(C(C)(C)C)CC3)cc2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
To a solution of 2-(1-methoxy-1-methylethyl)-5-methyl-2H-tetrazole (893 mg, 5.7 mmol) in THF (10 ml) cooled to −78° C. on a dry-ice-acetone bath was added dropwise a solution of n-butyl lithium in hexanes (3.6 ml, 1.6 M, 5.7 mmol). The mixture was stirred at −78° C. for 30 min, and at 0° C. for an additional 30 min, then recooled to −78° C. This solution was then slowly transferred (by cannulation) to a solution of N-methoxy-N-methyl-trans-4-{[4-tert-butylcyclohexylamino]methyl}benzamide (760 mg, 2.3 mmol) in THF (15 ml) maintained at −78° C. The reaction mixture was stirred for 30 min at −78° C. and then quenched by the addition of methanol (2 ml). Solvent was removed by rotary evaporation, and the residue was dissolved in ethyl acetate (100 ml). The organic phase was washed once with saturated aqueous sodium hydrogen carbonate (100 ml); dried over anhydrous sodium sulphate and taken to dryness by rotary evaporation to leave 1.0 g (100%) of the title material as an clear oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH3:18].Cl[CH2:20][S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:20][S:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:14])=[CH:11][C:10]=1[CH3:18]
Reactant: ClCSc1ccccc1
Reactant: COc1ccc(C(=O)O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)OCSc2ccccc2)cc1C
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
Cesium carbonate (13.00 g, 40.0 mmol) is added to a solution of 4-methoxy-3-methyl benzoic acid (6.65 g, 40.0 mmol) in dry DMF (50 ml) at ambient temperature. The mixture is stirred at 65° C. for 20 minutes and cooled to 0° C., before chloromethyl phenylsulfide (5.76 g, 36 mmol) in dry DMF (10 ml) is added dropwise. Stirring is continued at 0° C. for 30 minutes, then at ambient temperature for 2 hours and finally at 70° C. for 1 hour, before water is added and the product extracted into diethyl ether. The ether solution is washed with 1M sodium hydroxide and 4 times with brine, dried (MgSO4) and evaporated. The crude product is used in Intermediate 8 without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]([OH:20])=O)=[C:13]2[CH:12]=[C:11]([CH3:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[C:54]([O:58][C:59](=[O:68])[NH:60][C:61]([CH2:66][NH2:67])([CH3:65])[CH2:62][CH2:63][CH3:64])([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[C:54]([O:58][C:59](=[O:68])[NH:60][C:61]([CH3:65])([CH2:62][CH2:63][CH3:64])[CH2:66][NH:67][C:18]([C:17]1[C:16]([CH3:21])=[N:15][N:14]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]([CH3:22])=[CH:12][C:13]=12)=[O:20])([CH3:57])([CH3:56])[CH3:55]
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Reactant: Cc1cc(OCc2ccccc2)n2nc(C)c(C(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3ccccc3)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65 %

Procedure:
A solution of 240 mg (0.81 mmol) of 7-benzyloxy-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 139A) in 12 ml of tetrahydrofuran was admixed with 132 mg (0.97 mmol) of 1-hydroxy-7-azabenzotriazole and 186 mg (0.97 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred at room temperature for 10 minutes. The resulting mixture was admixed with 0.422 ml (2.43 mmol) of N,N-diisopropylethylamine and 210 mg (0.97 mmol) of rac-(1-aminomethyl-1-methylbutyl)carbamic acid tert-butyl ester from Example 152A. The mixture was stirred at room temperature for a further 18 hours, and the contents were then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was removed and washed with water and aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (mobile phase: cyclohexane/ethyl acetate, gradient 0% to 50%), which gave 370 mg (65% yield, 71% pure) of the target compound, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[C:3]=1[CH2:14][C:15]([OH:17])=[O:16].[CH3:18]S(O)(=O)=O>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=2)[C:3]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: N#Cc1ccc2c(CC(=O)O)c(O)ccc2c1
Reactant: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)Cc1c(O)ccc2cc(C#N)ccc12
Temperature: 40 °C
Yield: 172.6 %

Procedure:
A solution containing 18.2 g of 2-hydroxy-6-cyano-1-naphthylacetic acid, 250 ml of methanol and 3 g of methanesulfonic acid was stirred at 40° C. to perform dissolution, followed by stirring at room temperature for 2 days. Then, 5 g of active carbon was added, followed by stirring for 30 minutes. Thereafter, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. To the residue was added 50 ml of 50% hydrous methanol, and then the precipitate was collected by filtration to obtain 13 g of the desired product.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:19])[CH:17]=[CH2:18]>CCCCCC.C(OCC)(=O)C>[C:1]([C:9]1([CH2:18][CH2:17][C:16]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCc1ccc(OC)cc1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)CCC2(C(=O)c3ccccc3)CCCCC2=O)cc1
Yield: 65.5 %

Procedure:
The title compound was prepared in 65.5% yield after chromatography (silica gel, hexane/ethyl acetate 4:1) from 2-benzoylcyclohexanone and p-methoxybenzyl acrylate using a similar method to that used in Preparation 2. (M+ 394.13, 53%). Rf 0.39 (silica, hexane/ethyl acetate (2:1). 1H-NMR (300 MHz, CDCl3): =1.38-1.49 (m, 1 H), 1.68-1.82 (m, 3H), 1.98-2.57 (m, 7H), 2.82-2.91 (m, 1H), 3.82 (s, 3H), 5.03 (s, 2H), 6.87 (d, 2H), 7.26 (d, 2H), 7.42 (t, 2H), 7.56 (t, 1H), 7.88 (d, 2H) ppm. Analysis %: Found: C, 73.05; H, 6.74; C24H26 O5 requires C, 73.08; H, 6.64.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>C1COCC1>[Cl:9][C:3]1[C:2]2[NH:1][C:10]([OH:11])=[N:8][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: Nc1ccnc(Cl)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Oc1nc2ccnc(Cl)c2[nH]1
Yield: 86.5 %

Procedure:
1.1 A solution of 17.23 g of 3,4-diamino-2-chloropyridine and 19.46 g of 1,1′-carbonyldiimidazole in THF is stirred at room temperature for 16 hours. The product is separated off and dried, giving 17.6 g of 4-chloro-3H-imidazo[4,5-c]pyridin-2-ol (“1”).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[C:21]=1[S:27]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:28])=[O:29]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (0.5 mmol) to obtain 5-chloro-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino) phenyl)-1,3-dimethyl-1H-pyrazole-4-sulfonamide. 1H NMR (300 MHz, CDCl3)) δ 2.1 (s, 3H), 3.6 (s, 3H), 5.8 (s, 1H), 5.95 (dt, 1H), 7.0 (q, 1H), 7.2 (d, 1H), 7.3 (m, 2H), 7.4 (dd, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].[CH2:9]([Mg]Br)[CH3:10].CCOCC>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:8])[CH2:9][CH3:10]
Reactant: O=Cc1ccccn1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a stirred solution of 2-pyridine carboxaldehyde (4.0 g, 37.34 mmol) in THF (50 mL) at 0° C., add 3M ethyl magnesium bromide in ether (18.7 mL, 56.0 mmol), continue stirring for 30 min at 0° C. and then at ambient temperature for 2 h. Add water (200 mL), extract three times with EtOAc, dry over anhydrous Na2SO4, filter through a short pad of silica gel and concentrate in vacuo to give the desired intermediate as a yellow oil (3.39 g, 66%).
Reaction SMILES: O=O.[C:3]([O:6][CH:7]=[C:8]([CH3:11])[CH:9]=[CH2:10])(=[O:5])[CH3:4].[C:12]([OH:15])(=[O:14])[CH3:13]>>[C:3]([O:6][CH:7]([O:6][C:3](=[O:5])[CH3:4])[C:8]([CH3:11])=[CH:9][CH2:10][O:14][C:12](=[O:15])[CH3:13])(=[O:5])[CH3:4]
Reactant: C=CC(C)=COC(C)=O
Reactant: CC(=O)O
Agent: O=O
Product: CC(=O)OCC=C(C)C(OC(C)=O)OC(C)=O
Yield: 58.8 %

Procedure:
12,000 parts by volume of oxygen are introduced in the course of 4 hours into a solution, at 95° C., of 63 parts of 1-acetoxy-2-methyl-1,3-butadiene in 600 parts of glacial acetic acid, in which 25 parts of the catalyst prepared as described in Example 1a are suspended. The reaction mixture is worked up as described in Example 1b and fractional distillation gives 71.8 parts of 1,1,4-triacetoxy-2-methyl-2-butene (representing 58.8% conversion) of boiling point 118°-124° C./0.7 mbar and 19.5 parts of 4-acetoxytiglic aldehyde (representing 27.4% conversion) of boiling point 102°-107° C./25-27 mbar.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]([C:9]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[O:10])([CH3:8])[CH3:7].[CH3:21]SC.CI>>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][C:9]1([C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)([CH3:8])[CH3:7])[CH2:21][O:10]1
Reactant: CC(C)(C(=O)CCc1ccc(Cl)cc1Cl)C1OCCO1
Reactant: CSC
Solvent: CI
Product: CC(C)(C1OCCO1)C1(CCc2ccc(Cl)cc2Cl)CO1

Procedure:
In accordance with Example 3, reaction of 83 g (0.262 mol) of b 2,4-dichlorophenylethyl 2-(1,3-dioxolan-2-yl)-prop-2-yl ketone with 28.2 g (0.455 mol) of dimethyl sulphide/60 g of methyl iodide gives 90 g of 2-(2,4-dichlorophenylethyl)-2-[2-(1,3-dioxolan-2-yl)-prop-2-yl]-oxirane as an oil, which is directly reacted further. ##STR103##
Reaction SMILES: [CH3:1][NH2:2].[C:3]([N:8]=[C:9]=[O:10])(=[O:7])[C:4]([CH3:6])=[CH2:5]>C(Cl)(Cl)Cl.ClCCCl>[C:3]([NH:8][C:9]([NH:2][CH3:1])=[O:10])(=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: C=C(C)C(=O)N=C=O
Reactant: CN
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)NC
Yield: 99.9 %

Procedure:
To a solution of methylamine (0.35 g; 11.29 mmol) in chloroform (30 ml), a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (2 ml) was dropwise added under nitrogen stream while cooling with ice. After completion of the addition, chloroform, 1,2-dichloroethane and methylamine were evaporated under reduced pressure to give 1-methacryloyl-3-methylurea (1.42 g), which was recrystallized from a mixture of benzene and hexane to give colorless plates. M.P., 112°-113.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][CH:18]2[OH:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)(Cl)(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][C:18]2=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc([N+](=O)[O-])c2c1CCCC2O
Agent: O=[Cr](=O)(Cl)Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCOc1ccc([N+](=O)[O-])c2c1CCCC2=O
Yield: 76.4 %

Procedure:
5-[3'-(t-Butoxycarbonylamino)propyloxy]-1-hydroxy-8-nitro-1,2,3,4-tetrahydronaphthalene (2.46 g) is dissolved in dry methylene chloride (110 ml), and thereto are added molecular sieves 3A (6.73 g) and pyridinium dichlorochromate (1.5 equivalent), and the mixture is refluxed. After the reaction is completed, the mixture is diluted with ether, and the insoluble materials are removed by filtration through a pad of Celite. The filtrate is concentrated, and the residue is purified by silica gel column chromatography to give the title compound (1.87 g) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C[N:31]1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH4+].[OH-]>O.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([NH2:31])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)O)ccc1F
Agent: COc1nc(Cl)nc(OC)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(N)=O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A 250 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (2.58 g, 6.1 mmol), 4-methylmorpholine (2.0 mL, 18.3 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.28 g, 7.3 mmol) and tetrahydrofuran (30 mL). After stirring the mixture for 30 min at 25° C., NH4OH (15.0 mL) was added. The mixture was stirred for 30 min and diluted with water. The product precipitated from solution. The precipitated was filtered and washed with water and diethyl ether to give the title compound (2.55 g, 8%) as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 8.10 (m, 1H), 7.9 (dd, J=2.1 and 5.2 Hz, 1H), 7.65 (q, 6.7 and 8.5 Hz, 1H), 7.56 (t, J=9.1 Hz, 1H), 7.35 (td, J=2.4 and 8.2 Hz, 1H), 7.17 (td, J=2 and 6.6 Hz, 1H), 6.78 (s, 1H), 5.36 (s, 2H), 2 (s, 3H) ppm. ES-HRMS m/z 423. 0719 (M+H calcd for C20H15ClF3N2O3 requires 423.0718).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]2[C:4]=1[CH2:5][C:6]1[C:7]3[CH:8]2[CH2:9][N:10](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][C:12]=3[CH:13]=[CH:14][CH:15]=1.CO.P([O-])([O-])(O)=O.[Na+].[Na+]>O>[CH3:1][O:2][C:3]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]2[C:4]=1[CH2:5][C:6]1[C:7]3[CH:8]2[CH2:9][NH:10][CH2:11][C:12]=3[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc2c(c1OC)Cc1cccc3c1C2CN(S(=O)(=O)c1ccc(C)cc1)C3
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1OC)Cc1cccc3c1C2CNC3
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of compound 14 (440 mg, 1.01 mmol), dry methanol (10 mL) and disodium hydrogen phosphate (574 mg, 4.04 mmol) was stirred under nitrogen at room temperature. To this mixture was added 6.20 g of 6% Na--Hg in three portions and the reaction was heated at reflux for 2 h. After cooling, water (200 mL) was added and the mixture was extracted with ether (3×200 mL). The ether layers were combined, dried (MgSO4), filtered (Celite), and evaporated to give an oil that solidified under vacuum. After rotary chromatography 142 mg (50%) of compound 15 was obtained as an oil. The oil quickly darkened on exposure to air and was used immediately for the next step. A small portion of the oil was treated with ethereal HCl and the hydrochloride salt of compound 15 was recrystallized from ethanol-ether: mp (HCl salt) 190° C. (dec); 1H NMR (CDCl3, base) δ3.13 (dd, 1H, J=10.8, 12 Hz, H-1a), 3.50 (dd, 1H, J=3.4, 17.4 Hz, H-1b), 3.70 (m, 1H, H-11b), 3.839 (s, 3H, OCH3), 3.842 (s, 3H, OCH3), 4.03 (dd, 1H, J=6, 12 Hz, H-7a), 4.08 (s, 2H, H-3), 4.33 (d, 1H, J=17.4 Hz, H-7b), 6.78 (d, 1H, J=8.24 Hz, ArH), 6.92 (m, 3H, ArH), 7.11 (t, 1H, J=7.5 Hz, ArH), 7.18 (d, 1H, J=7.5 Hz, ArH); MS (CI) m/z 282 (100); HRCIMS Calculated for C18H19NO2 : 282.1494; Found 282.1497.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NCCN1CCCC1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N-(2-aminoethyl)pyrrolidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-(pyrrolidin-1-yl)ethyl)terephthalamide.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=399.1, tR (minutes, Method G)=2.57
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[CH:7]([CH:8]=1)[C:6]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH2:9][N+:10]([O-])=O)[CH2:5]2.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:10][CH2:9][C:6]1([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][CH:4]2[CH:7]1[CH:8]=[C:2]([CH3:1])[CH2:3]2
Reactant: CC1=CC2C(C1)CC2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC1=CC2C(C1)CC2(CN)CC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 10.5 %

Procedure:
Tert-butyl [3-methyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (1.12 g, 3.99 mmol) was dissolved in ethanol (20 mL) and water (10 mL). To the solution, iron powder (892.8 mg, 15.9 mmol) and ammonium chloride (211.5 mg, 3.99 mmol) were added, and the mixture was stirred for 4 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N solution of hydrochloric acid in ethyl acetate (5 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (105.8 mg, 28%).