Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([OH:18])[CH:3]([OH:17])[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:12]=[N:13][C:14]([CH3:16])=[N:15][C:6]1=2.C(N(CC)CC)C>[Pd].C(O)C>[OH:17][CH:3]([CH2:2][OH:18])[CH2:4][N:5]1[C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:12]=[N:13][C:14]([CH3:16])=[N:15][C:6]1=2
Reactant: Cc1ncc2c(n1)N(CC(O)C(O)Cl)C(=O)CO2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ncc2c(n1)N(CC(O)CO)C(=O)CO2
Yield: 18.9 %

Procedure:
The solution of 2 g of γchloro-8-(2,3-dihydroxypropyl)-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one and 0.739 g of triethylamine in 50 ml of abs. ethanol is hydrogenated in the presence of 0.20 g of 5% palladium-on-charcoal catalyst at room temperature and atmospheric pressure. Then the catalyst is filtered out, the filtrate is evaporated, the residue is taken up in water and extracted with chloroform. The organic phase is dried and evaporated. The residue is triturated with petroleum ether and dried to give 0.33 g (19%) of the product, m.p.: 70°-72° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:19][CH:20]=2)=[CH:9][C:8]=1[CH3:29])C.[Li+].[OH-]>>[CH2:31]([O:30][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:19][CH:20]=2)=[CH:9][C:8]=1[CH3:29])[C:4]([OH:33])=[O:3])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2csc(-c3ccc(OC)cc3)n2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCCc2csc(-c3ccc(OC)cc3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid as colorless liquid.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][O:10][CH3:11])[CH:5]=[N:4][C:3]=1[C:12]1[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][N:13]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[N:6]([CH2:7][CH2:8][CH2:9][O:10][CH3:11])[CH:5]=[N:4][C:3]=2[C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][N:13]=2)=[CH:23][C:22]=1[F:30]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: COCCCn1cnc(-c2cc(C#N)ccn2)c1Br
Product: COCCCn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from 2-[5-bromo-1-(3-methoxypropyl)-1H-imidazol-4-yl]pyridine-4-carbonitrile and 4-chloro3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C19H16ClFN4O, 372. Found, 371, 373.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:23]4[CH2:24][CH:20]([CH2:21][CH2:22]4)[C:19]=3[CH2:25][C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=3)[C:29]([OH:31])=[O:30])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:23]4[CH2:24][CH:20]([CH2:21][CH2:22]4)[CH:19]3[CH2:25][C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=3)[C:29]([OH:31])=[O:30])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(CC2=C(c3nc(-c4ccccc4)c(-c4ccccc4)o3)C3CCC2C3)c1
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1cccc(CC2C3CCC(C3)C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of 3-{[3-(4,5-diphenyloxazol-2-yl)bicyclo-[2.2.1]hept-2-en-2-yl]methyl}benzoic acid (0.3 g) and 10% Pd/C (0.1 g) in methanol (20 ml) was stirred under H2 for 8 hours. The catalyst was filtered off and filtrate was evaporated in vacuo to give 3-{[3-(4,5-diphenyloxazol-2-yl)-bicyclo[2.2.1]hept-2-yl]methyl}benzoic acid (0.27 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH:7](C(C)(C)C)[N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:18]#[N:19])=[N:9]1)([CH3:4])([CH3:3])[CH3:2].C(C1C2C(=CC=C(O[CH2:38][C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)C=2)N(CC(OC)=O)N=1)(=O)C>>[C:18]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:38][C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[CH:12]=2)[N:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[N:9]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)C(n1nc(C#N)c2cc(O)ccc21)C(C)(C)C
Reactant: COC(=O)Cn1nc(C(C)=O)c2cc(OCc3ncccn3)ccc21
Product: CC(C)(C)OC(=O)Cn1nc(C#N)c2cc(OCc3ncccn3)ccc21

Procedure:
The title compound was prepared from tert-butyl (3-cyano-5-hydroxy-indazol-1-yl)-acetic acid tert-butyl ester in a similar manner as described in step G of Scheme A4 for the preparation of methyl 2-(3-acetyl-5-(pyrimidin-2-ylmethoxy)-1H-indazol-1-yl)acetate. MS (LC-MS): 366.0 [M+H]+, tR (HPLC conditions e): 4.63 min.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[N:15]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)=[C:20]([O:36][CH3:37])[CH:19]=2)[CH3:17])[C:9]2=[N:10][CH:11]=[C:12]([I:14])[CH:13]=[C:8]2[N:7]=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O>[I:14][C:12]1[CH:13]=[C:8]2[N:7]=[C:6]([NH2:5])[N:15]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:27]=[N:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=4)=[C:20]([O:36][CH3:37])[CH:19]=3)[CH3:17])[C:9]2=[N:10][CH:11]=1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1C(C)c1ccc(OCc2ccc(C(F)(F)F)nc2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(C)n2c(N)nc3cc(I)cnc32)ccc1OCc1ccc(C(F)(F)F)nc1
Temperature: 160 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a stirred solution of ethyl(6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (1.53 g, 2.39 mmol), in ethanol (10 mL)/water (4 mL) was added potassium phosphate tribasic (2.07 g, 9.54 mmol). The mixture was irradiated in a microwave reactor at 150° C. After 1 h, the mixture was subjected to an additional round of microwave heating (160° C., 30 min). After a total of 90 min, the mixture was diluted with water (100 mL) and extracted with dichloromethane (2×50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 1.31 g (97%) of 6-iodo-3-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine as an orange foamy solid.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.Cl.[CH2:23]([NH:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(O)C>[CH2:23]([N:30]1[C:15](=[O:17])[C:14]2[C:13](=[O:19])[C:12]3[CH:11]=[CH:10][C:9]([Cl:20])=[CH:8][C:7]=3[NH:6][C:5]=2[C:3]([OH:4])=[N:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
To a stirred suspension of dimethyl-7-chloro-4-hydroxyquinoline-2,3-dicarboxylate (5.00 g, 16.90 mM) and benzylhydrazine dihydrochloride (46.15 g, 236.50 mM) in ethanol (100 mL) was added triethylamine (75.8 mL, 541.0 mM). The mixture was heated to give a brown solution which was refluxed for 40 hours during which time a precipitate formed. The suspension was cooled to room temperature and filtered to give the benzylhydrazine salt of the title compound as an impure yellow solid. Multiple crystallizations from ethanolic hydrogen chloride and methanol gave the title compound (0.370 g, 6%) as a white powder, mp 347-350° C.; MS(CI): 354 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15](N(C)C)[S:14][C:13]=2[CH:20]=1)C1C=CC=CC=1.Cl.[N:22]1([CH2:27][CH2:28][O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=O)=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1.[CH2:39]1[CH2:43][O:42][CH2:41][CH2:40]1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:34][C:33]3[CH:37]=[CH:38][C:30]([O:29][CH2:28][CH2:27][N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:31][CH:32]=3)=[C:15]([C:30]3[CH:38]=[CH:39][C:43]([O:42][CH2:41][CH2:40][CH2:24][C:23]#[N:22])=[CH:32][CH:31]=3)[S:14][C:13]=2[CH:20]=1
Reactant: C1CCOC1
Reactant: O=C(Cl)c1ccc(OCCN2CCCC2)cc1
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Agent: Cl
Product: N#CCCCOc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Yield: 38 %

Procedure:
By essentially following the proceedure described in Example 16, Part A, the title compound was prepared as an oil starting from 6-benzyloxy-2-dimethylaminobenzo[b]thiophene and 4-[2-(1-pyrrolidinyl)ethoxy]benzoyl chloride hydrochloride in 38% yield following MPLC (SiO2; 15% then 20% then 30% THF with 5% TEA in hexanes).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C:10]([NH:12][C@@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([C@@:16]1([CH3:19])[CH2:18][O:17]1)=[O:15])=[O:11].[C:31]([O:35][C:36]([NH:38][C@@H:39]([CH3:43])[C:40](O)=[O:41])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:28]1([CH2:27][C@H:9]([NH:8][C:40](=[O:41])[C@@H:39]([NH:38][C:36](=[O:37])[O:35][C:31]([CH3:33])([CH3:32])[CH3:34])[CH3:43])[C:10]([NH:12][C@@H:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C@@:16]2([CH3:19])[CH2:18][O:17]2)=[O:15])=[O:11])[CH2:30][CH2:29]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@]1(C(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)CC2CC2)CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC1CC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@]1(C)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To (S)-2-amino-3-cyclopropyl-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (657 mg, 1.59 mmol) was added (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (601 mg, 3.18 mmol), HATU (1.40 g, 3.67 mmol), and DMF (5 mL). The mixture was cooled to 0° C. and DIEA (1.11 mL, 6.36 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (0-80% ethyl acetate/heptane) provided tert-butyl ((S)-1-(((S)-3-cyclopropyl-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (380 mg, 49%) as a colorless solid. MS (EI) for C26H37N3O6, found 488.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30](Cl)=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][CH:7]=2)=[O:31])=[CH:26][CH:25]=1
Reactant: COC(=O)CCCC=C(c1cccnc1)c1cccc(N)c1
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCC=C(c1cccnc1)c1cccc(NC(=O)COc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.25 g of methyl 6-(3-aminophenyl)-6-(3-pyridyl)-hex-5-enoate are dissolved in 30 ml of methylene chloride. At 0° C., 1.65 g of 4-chlorophenoxyacetic acid chloride and 2.5 ml of triethylamine are added successively to this solution which is then stirred for 2 hours at ambient temperature. The reaction mixture is washed with water and then evaporated down. The residue is dissolved in a mixture of 20 ml of ethanol and 16 ml of 0.5N sodium hydroxide solution and stirred for 24 hours at ambient temperature. The reaction mixture is evaporated down at ambient temperature, water is added and the resulting mixture is washed with ethyl acetate. The aqueous phase is neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated down and the residue is recrystallised from ethyl acetate/diisopropyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([C:14]([OH:16])=[O:15])[OH:13].CCCCCCC.C(OCC)(=O)C>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[S:8][CH2:7][CH2:6][C@@:5]2([C:14]([OH:16])=[O:15])[OH:13]
Reactant: O=C(O)C1(O)CCSc2c(Cl)cc(Cl)cc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=C(O)[C@@]1(O)CCSc2c(Cl)cc(Cl)cc21

Procedure:
The enantiomers of 6,8-dichloro-4-hydroxychromane-4-yl-carboxylic acid (2.17 g, 7.77 mmol; from step (v) above) were separated using chiral chromatography (Kromasil TBB; heptane: ethyl acetate: formic acid) affording 0.74 g of the faster moving, not wanted S-enantiomer, and 0.72 g (66%) of the slower moving sub-title compound. ee=98.4%
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].C(N(CC)CC)C.[CH:26]1([CH2:29][NH:30][CH2:31][CH3:32])[CH2:28][CH2:27]1>C(COC)OC>[CH:26]1([CH2:29][N:30]([CH2:31][CH3:32])[C:6]2[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=2[N+:8]([O-:10])=[O:9])[CH2:28][CH2:27]1
Reactant: CCNCC1CC1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCN(CC1CC1)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Yield: 69.9 %

Procedure:
To a stirred solution of 15.0 grams (0.05 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride and 4.97 grams (0.05 mole) of triethylamine in 200 ml. of dimethoxyethane was added, dropwise, 4.28 grams (0.05 mole) of N-cyclopropylmethyl-N-ethylamine at room temperature over a period of 2.5 hours. The resultant mixture was then heated under reflux for 16 hours. The solvent was removed by evaporation under reduced pressure and the residue then dissolved in a mixture of chloroform and water. The organic layer was separated and was washed with water, dilute hydrochloric acid, dilute sodium bicarbonate, and then water. After drying over anhydrous sodium sulfate, the organic solution was evaporated to dryness. The residue was dissolved in hexane and filtered and then evaporated to dryness to give 12.85 grams of the product as as dark, viscous amber liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:21][N:22]1[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[N:24]=[C:23]1S(C)(=O)=O.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:23]4[N:22]([CH3:21])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[N:24]=4)=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Cn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a stirred solution of 4-(6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenol (120 mg) in DMF (4 mL) was added NaH (60% in oil, 11.84 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (104 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from EtOH/hexane to give the title compound (80 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[C:31](=[O:33])[N:30]([CH3:34])[CH2:29][CH2:28]3)=[CH:4][C:5]([NH:8][C:9]2[C:10]([CH3:21])=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>CCOC(C)=O>[NH3:6].[Cl:1][C:2]1[C:3]([NH:22][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=2[C:31](=[O:33])[N:30]([CH3:34])[CH2:29][CH2:28]3)=[CH:4][C:5]([NH:8][C:9]2[C:10]([CH3:21])=[N:11][NH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1Nc1cc(Nc2cccc3c2C(=O)N(C)CC3)c(Cl)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1n[nH]cc1Nc1cc(Nc2cccc3c2C(=O)N(C)CC3)c(Cl)cn1
Product: N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Using the general procedure of Example 12, tert-butyl 4-[[5-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]-3-methylpyrazole-1-carboxylate, 68 mg was obtained from tert-butyl 4-amino-3-methylpyrazole-1-carboxylate. To a stirred solution of tert-butyl 4-[[5-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]-3-methylpyrazole-1-carboxylate (68 mg) in EtOAc (0.6 ml) was added HCl/EtOAc (4M, 1.0 ml) and the mixture stirred at room temperature for 2.5 hours. The reaction mixture was diluted with EtOAc (5 ml) and quenched with aq. potassium bicarbonate (0.53 g, 3 ml). The aqueous phase was extracted with EtOAc (2×5 ml), the combined organic extracts dried (Na2SO4), filtered and concentrated under reduced pressure. Purification via a ‘catch and release’ method (2 g isolute flash SCX-2, eluting with 100% MeOH then methanolic ammonia 0.5M→7M) afforded the title compound which was combined with a second batch; 59 mg. 1H NMR spectrum (methanol-d3) 2.03 (s, 3H), 2.84 (t, 2H), 3.00 (s, 3H), 3.46 (t, 2H), 6.47 (s, 1H), 6.72 (dd, 1H), 7.19 (dd, 1H), 7.23 (dd, 1H), 7.44 (bs, 1H), 7.71 (s, 1H); Mass spectrum: ESI+ MH+ 383.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1F.[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.N1C=CC=CC=1>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:21])[CH2:10][CH2:11][C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(F)c(F)c1
Reactant: c1c[nH]cn1
Solvent: CS(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CCC(=O)CCC(=O)c1ccc(-n2ccnc2)c(F)c1
Yield: 68.5 %

Procedure:
Ethyl 7-(3,4-difluorophenyl)-4,7-dioxoheptanoate (351 mg) was treated with imidazole (241 mg) and pyridine (395 mg) in DMSO (3 mL) at 150° C. over 7 h with a micro-wave heating. The resultant mixture was diluted with water (12 mL) and was extracted with EtOAc (20 mL×3). After removal the solvents, the mixture was purified by flash silica gel chromatography, eluting with EtOAc, to afford the desired product -ethyl 7-(3-fluoro-4-(1H-imidazol-1-yl)phenyl)-4,7-dioxoheptanoate (279 mg, 68%) as light brown solids.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C([NH:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][N:26]=1)=[O:24])C1C=CC=CC=1>>[CH2:9]([C:33]1[C:25]([C:23]([NH2:22])=[O:24])=[N:26][CH:27]=[C:28]([C:29]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:31])[CH:32]=1)[C:3]1[CH:4]=[CH:5][CH:7]=[CH:8][CH:2]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccccc2)nc1
Product: NC(=O)c1ncc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1Cc1ccccc1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to benzylamine via Procedure G. Crude methyl 6-(benzylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 300 mg of 6-(benzylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(benzylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield-benzyl-N5-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide. MS (Q1) 443.1 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=2[CH:9]([CH3:11])[CH:10]=1.[Li:12]CCCC>CCCCC>[CH3:1][C-:2]1[C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][C:8]=2[C:9]([CH3:11])=[CH:10]1.[Li+:12]
Reactant: CC1=CC(C)C2=C1CCCC2
Reactant: [Li]CCCC
Solvent: CCCCC
Product: Cc1c[c-](C)c2c1CCCC2
Product: [Li+]
Reaction time: 12 h
Yield: 97 %

Procedure:
7,9 dimethylbicyclo-[4.3.0]-nona-1(6),7-diene (5.0 g, 33.5 mmol) was added to 100 mL of pentane. To this solution nBuLi (2.7M, 13 mL) was added dropwise, and the mixture was stirred for 12 hours. The resulting white precipitate was collected via filtration, washed with pentane and dried under reduced pressure to give 5.02 g (97 percent) of product.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:2][CH2:3][O:4][C:5]2[CH:20]=[CH:19][C:8]3[C:9]([C:12]4[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=4)=[N:10][S:11][C:7]=3[CH:6]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: C1CNC1
Product: Brc1ccc(-c2nsc3cc(OCCN4CCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and azetidine were converted to yield 6-(2-Azetidin-1-yl-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole, MS: 390 (MH+, 1Br).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[CH2:5].F[B-](F)(F)F.[N:13]#[O+:14].[C:15](#[N:17])[CH3:16]>>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][C:4]1[N:17]=[C:15]([CH3:16])[N:13]([OH:14])[CH:5]=1
Reactant: N#[O+]
Reactant: CC#N
Reactant: C=CCC(C)(C)C
Agent: F[B-](F)(F)F
Product: Cc1nc(CC(C)(C)C)cn1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,4-Dimethyl-1-pentene (59 g, 0.6 mol) was added to a 10° C. suspension of nitrosonium tetrafluoroborate (66 g, 0.56 mmol) in acetonitrile (600 mL) After stirring vigorously at ambient temperature for 30 minutes, acetonitrile was removed in vacuo to afford 4-(2,2-dimethylpropyl)-2-methyl-1H-imidazol-1-ol which was used in the subsequent step without further purification.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[O:4]1[CH:5]=[CH:6][C:2]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[CH:3]1
Reactant: Brc1ccoc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1ccc(-c2ccoc2)cc1
Temperature: 150 °C
Yield: 59.2 %

Procedure:
In a microwave vial, 3-bromo-furan(590 mg, 4.02 mmol), 4-formyl phenylboronic acid (600 mg, 4.02 mmol) and 7 ml of actonitrile were mixed. 8 ml of 1N aqueous sodium carbonate was then added to the mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 7 minutes with microwave irradiation. After cooling, 50 ml of ethyl acetate was added, the organic layer was separated, washed with water, dried over sodium sulfate. The organic solvent was evaporated to give crude product, which was purified by ISCO to give 410 mg of 4-furan-3-yl-benzaldehyde, yield: 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[C:4]([N+:17]([O-])=O)[CH:3]=1>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH:6][CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NCCCn1ccnc1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(Cl)ccc1NCCCn1ccnc1
Reaction time: 16 h
Yield: 48.8 %

Procedure:
4-chloro-N-[3-(1H-imidazol-1-yl)propyl]-2-nitroaniline (11, 5 g, 17.8 mmol) was dissolved in 100 mL methanol (MeOH) and Palladium on activated carbon (10%, 120 mg, 0.1 eq.) was added under nitrogen atmosphere. The solution was hydrogenated at 1 bar for 16 hours. The reaction was filtered over celite and the filtrate concentrated in vacuo and purified by flash chromatography (gradient 0 to 10% methanol in CH2Cl2) to give 4-chloro-N1-[3-(1H-imidazol-1-yl)propyl]benzene-1,2-diamine (12, 2.18 g, 49%) as a solid; LCMS m/z=251 (M+H)+