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[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([N:22]1[CH2:21][CH2:20][N:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24][CH2:23]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN([C@H](C)[C@](O)(Cn2cncn2)c2ccc(F)cc2F)CC1
Temperature: 120 °C
Yield: 24.4 %

Procedure:
A mixture of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane IV (1.0 g, 4.0 mmol), ethyl piperazine-1-carboxylate (1.2 ml, 8 mmol) and potassium carbonate in DMF (5 ml) was heated at 120° C. for 18 h. After cooling the reaction mixture was poured onto crushed ice and extracted with ethyl acetate (3×30 ml). The combined extract was washed with water, brine, dried (MgSO4) and concentrated and the resulting product was purified on a column of silica gel (hexane/EtOAc, 1:1) to give the title compound as off-white solid (400 mg, 24%).
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]([CH3:5])[CH3:4].[CH3:7][C:8](=[CH:11][CH2:12][CH3:13])[CH:9]=[O:10]>CCOCC>[CH3:7][C:8]([CH:9]([OH:10])[CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:11][CH2:12][CH3:13]
Reactant: CCC=C(C)C=O
Reactant: CC(C)CBr
Agent: [Mg]
Solvent: CCOCC
Product: CCC=C(C)C(O)CC(C)C

Procedure:
The Grignard reagent obtained by reacting 11.8 g (0.49 g-atoms) of magnesium in 50 ml of ether with 67.13 g (0.49 mol) of isobutyl bromide in 250 ml of ether is reacted with 40.0 g (0.41 mol) of 2-methyl-2-pentenal in 100 ml of ether. The fractional distillation of the crude product (94 g) over a 20 cm Widmer column gives 44.4 g (69.4%) of olfactorily good 4,7-dimethyl-3-octen-5-ol of boiling point 47°-48° C./0.04 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[C:4]([F:24])[CH:3]=1.[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[C:11]1[N:20]([CH3:23])[C:21](=[O:22])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:24])=[CH:9][C:10]2=1)(=[O:27])[CH3:26]
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2F)cc2c3ccccc3n(C)c21
Reactant: CC(=O)Cl
Product: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3F)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in preparation 1.9B above, with compound A 3-(4-chloro-2-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and acetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.Cl[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:10]=[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1cc(F)ccn1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cn2ccc(F)cc2n1
Yield: 17.7 %

Procedure:
A mixture of 4-fluoropyridin-2-amine (1.0 g, 8.92 mmol) and ethyl 4-chloro-3-oxobutanoate (1.46 mL, 10.7 mmol) in THF (20 mL) was stirred at about reflux overnight. The residue was concentrated and was chromatographed on the C18 ISCO Combiflash system using the following gradient: A: Water (0.1% NH4HCO3); B: Methanol; 10% B to 60% B over 20 min to give 350 mg product as brown oil (350 mg, yield: 17.6%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13].S(Cl)([Cl:18])(=O)=O>C(Cl)(Cl)Cl>[Cl:18][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:12]([OH:14])=[O:13])[CH:4]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(O)c1ccc2ccccc2c1O
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(Cl)c2ccccc2c1O

Procedure:
To a suspension of 30.0 g 1-Hydroxy-naphthalene-2-carboxylic acid in 600 ml chloroform a mixture of 14.9 ml sulfuryl chloride and 20 ml chloroform was added dropwise. After stirring the reaction for 8 h at room temperature the precipitated product was isolated by filtration, washed with dichloromethane and recrystallized from isopropanol/water to yield 25.1 g of 4-chloro-1-hydroxy-naphthalene-2-carboxylic acid as off-white solid.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.Cl.[CH3:30][N:31]([CH3:38])[CH2:32][CH2:33][CH2:34][C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:30][N:31]([CH3:38])[CH2:32][CH2:33][CH2:34][C:35]([N:26]1[CH2:25][CH:24]=[C:23]([C:21]2[NH:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]5[N:6]=[CH:5][S:4][C:8]=5[CH:9]=4)[C:15]=3[CH:22]=2)[CH2:28][CH2:27]1)=[O:36]
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Reactant: CN(C)CCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCCC(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C

Procedure:
To a solution of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine trihydrochloride (50.0 mg, 0.11 mmol) in DMF (3 mL) was added 4-(dimethylamino)butyric acid hydrochloride (17 mg, 0.13 mmol), TBTU (42 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.11 mL). The reaction mixture was left to stir at rt over the weekend. The crude mixture was concentrated in vacuo and purified via MDP, which afforded the title compound as a tan solid. MS (ES+): m/z: 461.99 (100) [MH+]. HPLC: tr=1.82 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, DMSO-d6): δ=1.63-1.68 (m, 2H), 2.10 (s, 3H), 2.11 (s, 3H), 2.18-2.24 (m, 2H), 2.33-2.43 (m, 2H), 2.54-2.56 (m, 2H), 3.67-3.72 (m, 2H), 4.15 (bs, 1H), 4.21 (bs, 1H), 6.45 (s, 1H), 6.84 (d, J=6.4 Hz, 1H), 7.87 (dd, J=1.6, 8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.34 (s, 1H), 8.92 (s, 1H), 9.23 (s, 1H), 9.61 (s, 1H), 12.02 (d, J=11.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[S:8](Cl)(Cl)=[O:9]>ClCCl>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][S:8](=[O:9])[O:4][CH2:3]1
Reactant: CC(C)(CO)CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)COS(=O)OC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of 2,2-dimethyl-propane-1,3-diol (1 g) in dichloromethane (5 mL) is added dropwise at 0° C. thionylchloride (735 μL). The mixture is stirred for 3 hours at 40° C. and then partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The organic phase is washed with brine and dried (MgSO4). The solvent is evaporated to give the title compound. Yield: 1 g; TLC: rf=0.65 (silicagel, cyclohexane/ethyl acetate 3:1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH:36][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1)[CH3:31]
Reactant: CCOC(=O)CCN
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with beta-alanine ethyl ester hydrochloride using BOP reagent in tetrahydrofuran to give the title compound as a light brown solid, MS (ESI+): m/z=475.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:22])[CH2:19][C:20]#[N:21])[CH3:16].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18](=[O:22])[C:19](=[C:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)[C:20]#[N:21])[CH3:16]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of 1-benzyl-piperidin-4-one (75.1 g, 0.40 mol) in toluene (400 ml), cyano-acetic acid ethyl ester (50.6 ml, 0.48 mol) and acetic acid (18.2 ml, 0.32 mol) are added at ambient temperature. The reaction mixture is refluxed for 4 h, quenched with ice-water and extracted with diethyl ether. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester in quantitative yield.
Reaction SMILES: Cl.[C:2]1([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:24][CH2:23][CH2:22][C@@H:21]4[C@H:16]([O:17][CH2:18][CH2:19][NH:20]4)[C:14]=3[CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:20]1[CH2:19][CH2:18][O:17][C@@H:16]2[C:14]3[CH:15]=[C:10]([O:9][CH2:8][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:11]=[CH:12][C:13]=3[O:24][CH2:23][CH2:22][C@@H:21]12)(=[O:34])[CH3:33]
Reactant: c1ccc(COc2ccc3c(c2)[C@H]2OCCN[C@@H]2CCO3)cc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCO[C@@H]2c3cc(OCc4ccccc4)ccc3OCC[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3.47 g of trans-10-phenylmethoxy-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine hydrochloride, 50 ml of triethylamine and 25 ml of methylene chloride is cooled in ice and 1.0 ml of acetyl chloride dissolved in 25 ml of methylene chloride is added dropwise thereto. The solution is stirred overnight at room temperature, washed with a dilute hydrochloric acid solution and dried over anhydrous magnesium sulfate. The drying agent is removed via filtration and the filtrate evaporated to yield trans-4-acetyl-10-phenylmethoxy-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][C:18]([F:21])([F:20])[F:19])=[O:5])[CH3:2].[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][C:18]([F:21])([F:20])[F:19])=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc2c(OC(F)(F)F)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC(F)(F)F)cccc2c1NC1CCCC1

Procedure:
4-Chloro-8-trifluoromethoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with cyclopentylamine following general procedure B to afford 4-cyclopentylamino-8-trifluoromethoxy-quinoline-3-carboxylic acid ethyl ester (220 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (180 mg) following general procedure E. The above ethylamide (0.54 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-cyclopentyl-3-ethyl-7-trifluoromethoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (60 mg). LCMS: m/z 394 [M+1]+.
Reaction SMILES: [C:1]([CH2:3][C:4](=[NH:8])OCC)#[N:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C(O)C>[NH2:8][C:4]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[CH:3][C:1]#[N:2]
Reactant: C1COCCN1
Reactant: CCOC(=N)CC#N
Solvent: CCO
Product: N#CC=C(N)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In anhydrous ethanol (10 ml) was dissolved ethyl 2-cyanoacetimidate (1.0 g), followed by addition of morpholine (0.78 g). The mixture was stirred at room temperature for 4 hours, and the separated crystals were collected by filtration. This crystal crop was used as it was in the next reaction.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][C:32](=[O:34])[C:31]2[CH:30]=[CH:29][C:28]([S:27][CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:36][CH:35]=2)[CH2:39][CH2:38]1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 87.4 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 47 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([OH:24])=[O:23])[CH:16]=1)[CH3:2].[CH3:25][CH2:26]O>S(=O)(=O)(O)O>[CH2:25]([O:23][C:22](=[O:24])[CH2:21][C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:13])([F:12])[F:14])=[CH:10][C:5]=2[CH2:4][NH:3][CH2:1][CH3:2])[CH:20]=[CH:19][CH:18]=1)[CH3:26]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)OCC)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (0.34 mmol) in EtOH (7 mL) was added sulfuric acid (3-4 drops), and the reaction was stirred at 50° C. overnight. Once no starting material was seen by analytical LCMS, the mixture was filtered over a pad of Celite and rinsed with EtOH. The filtrate was concentrated to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[CH2:4][C@@H:3]1[OH:13].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].C(N(CC)CC)C>CO>[F:14][C:15]([F:22])([F:21])[C:16]([NH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[CH2:4][C@@H:3]1[OH:13])=[O:17]
Reactant: CCOC(=O)C(F)(F)F
Reactant: COc1ccc2c(c1)[C@@H](N)[C@@H](O)C2
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)[C@@H](O)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Step AE (1): To a solution of (1R,2S)-1-amino-6-methoxy-2,3-dihydro-1H-inden-2-ol (500 mg) [E. N. Jacobsen, et. al Organic Synthesis 1999, 76, 46-56] in methanol (10 mL) was added ethyl trifluoroacetate (0.83 mL) followed by triethylamine (0.65 mL), and the reaction mixture was stirred at rt for 12 h. The solvents were removed in vacuo to give 2,2,2-trifluoro-N-((1R,2S)-2-hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-yl)acetamide as an oil. HPLC retention time: 1.77 min (method B). MS (ESI) (M+Na)+ 298.13.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:4]=[N:3][CH:2]=1.O=S(Cl)Cl.[Cl:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:20][C:21]([F:30])([F:31])[O:22][C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)[CH:8]=2)=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(-c2cncnc2)c1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cccc(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-pyrimidin-5-yl-benzoic acid (100 mg, 0.50 mmol) and SOCl2 (73 μL, 1.0 mmol) was heated under reflux for 4 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (5 mL) and slowly added to a mixture of 4-(chlorodifluoromethoxy)aniline (106 mg, 0.55 mmol) and TEA (140 μL, 1.0 mmol) in DCM (5 mL). The mixture was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was suspended in EtOAc (10 mL), filtered through a 10 μm Isolute® fritted cartridge and the filtrate was evaporated to dryness under reduced pressure to give the crude product which was purified by preparative HPLC to afford the title compound. LC-MS (Condition 4) tR=1.15 min, m/z=375.8 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=9.05 Hz, 2H) 7.73 (t, J=7.82 Hz, 1H) 7.92 (m, 2H) 8.06 (t, J=6.97 Hz, 2H) 8.37 (t, J=1.96 Hz, 1H) 9.24-9.29 (m, 3H) 10.52 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:20][NH2:21])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH3:2].Cl[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][C:26]([I:32])=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH2:20][NH:21][C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][C:26]([I:32])=[CH:25][N:24]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Reactant: CCOc1cc(CN)ccc1OCc1ccc(OC)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CNc2ncc(I)cc2[N+](=O)[O-])ccc1OCc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a stirred solution of (3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (2.75 g, 9.54 mmol) in acetonitrile (50 mL) was added 2-chloro-5-iodo-3-nitropyridine (2.85 g, 10.01 mmol) and N,N-diisopropylethylamine (1.85 g, 14.31 mmol). The resulting yellow mixture was heated to reflux. After 3 h, the red-brown solution was allowed to cool to room temperature, resulting in the formation of a precipitate. The solids were isolated by filtration and washed with water (200 mL). The moist solids were dissolved in dichloromethane (100 mL), and a small amount of water separated and was removed. The solution was dried over magnesium sulfate, filtered, and concentrated to provide 4.34 g (85%) of N-(3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-3-nitropyridin-2-amine as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:15]=[CH:14][N:13]=1)[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[C:16]([C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)[CH:15]=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OS(=O)(=O)C(F)(F)F)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccc(F)cc2)ccn1
Yield: 71.4 %

Procedure:
Compound II (54 mg, 0.113 mmol), Pd(PPh3)4 (13 mg, 0.011 mmol), 4-fluorophenylboronic acid (32 mg, 0.23 mmol) and potassium carbonate (63 mg, 0.45 mmol) were stirred in toluene (1.5 mL) and water (0.7 mL) at 120° C. under microwave irradiation (300 W) for 30 min. The reaction mixture was then poured onto brine (5 mL) and extracted with EtOAc (3×5 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 then 80:20) to furnish III as a colourless oil (34 mg, 71%).
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Reactant: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2cccnc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.19 mL, 1.09 mmol) and 3-aminopyridine (175 mg, 1.36 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (42 mg, 22% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][CH2:5][N:6]([C:21]1[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][N:22]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.C>C(O)(=O)C.C(O)(C)C.[Fe]>[CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:27][C:26]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]1=2
Reactant: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CN(C)CCCN1c2ccccc2C(c2ccccc2)=Nc2cccnc21
Reaction time: 1 h

Procedure:
To a stirred solution of 3.3 g of crude [2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone obtained in Example (8c) in 20 ml of acetic acid at 65° C. was added portionwise 6.6 g of iron powder. The reaction was exothermic at the beginning, the temperature rising to 90° C. Thereafter the temperature was controlled at 85° C. for 1 hr. The mixture was filtered through celite and washed with acetic acid and methanol. The filtrate and washes were combined and evaporated and the residue was dissolved in methanol. The solution was filtered to remove insoluble iron acetate. The filtrate was evaporated and the residue dissolved in water/methylene chloride and made basic with sodium hydroxide and potassium carbonate. The mixture was mixed with celite and filtered through celite. The aqueous layer of the filtrate was extracted twice with methylene chloride which had been used to wash the cake. The combined methylene chloride solution was washed once with NaCl solution, dried and treated with charcoal, filtered and evaporated to give a black foam weighing 1.63 g (46%). The foam was dissolved in isopropyl alcohol. The solution was treated with charcoal and the mixture was filtered into a solution of 0.7 g fumaric acid in isopropyl alcohol. This solution was again treated with charcoal and filtered. Chemical ionization mass spectral analysis and thin-layer chromatography confirmed the presence of the title compound.