Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].O>CN1CCCC1=O>[N:25]([C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1c(N=[N+]=[N-])nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 110 °C
Reaction time: 12 h
Yield: 64.5 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 7.40 g, 20.0 mmol) and sodium azide (2.60 g, 40.0 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was stirred at 110° C. for 12 hr. After cooling, water was added to the mixture, which was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (4.90 g, 12.9 mmol, 64%) as a pale yellow solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19]3=[N:22][C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:24][N:18]3[C:17]2=[O:33])=[CH:12][CH:11]=1>CN(C=O)C>[Cl:1][C:24]1[N:18]2[C:17](=[O:33])[N:16]([C:13]3[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=3)[CH2:21][CH2:20][C:19]2=[N:22][C:23]=1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)cn21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O=C1N(c2ccc(F)cc2)CCc2nc(COc3ccccc3)c(Cl)n21
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 24.6 %

Procedure:
N-chlorosuccinimide (30.5 mg, 0.23 mmol) was added to a stirred solution of 6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (0.1 g, 0.3 mmol) in DMF (3.25 mL). The mixture was stirred at 150° C. for 20 minutes under microwave irradiation. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 15/85). The desired fractions were collected and the solvents evaporated in vacuo to yield 3-chloro-6-(4-fluoro-phenyl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (21 mg, 27% yield) as a white solid. 1H NMR (400 MHz, CDCl3) 8 ppm 3.27 (t, J=6.6 Hz, 2H), 3.99 (t, J=6.6 Hz, 2H), 4.99 (s, 2H), 6.95-7.01 (m, 1H), 7.01-7.07 (m, 2H), 7.09-7.17 (m, 2H), 7.27-7.36 (m, 4H).
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:6][C:7](=[O:17])[C:8](CC)(CC)P(O)(O)=O)C.[CH2:18](/[C:20](=[CH:23]\[CH2:24][CH3:25])/[CH:21]=O)[CH3:19].O>CO>[CH2:18](/[C:20](=[CH:23]\[CH2:24][CH3:25])/[CH:21]=[CH:8]/[C:7]([O:6][CH3:4])=[O:17])[CH3:19]
Reactant: CCOC(=O)C(CC)(CC)P(=O)(O)O
Reactant: CC/C=C(/C=O)CC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC/C=C(/C=C/C(=O)OC)CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
To a 28 wt % solution of sodium methoxide in methanol (25.7 g) at 10° C. were added dropwise diethyl phosphonoacetic acid ethyl ester (25.3 g) and (E)-2-ethyl-2-pentenal (11.5 g) successively under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 3 hours, poured into chilled water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (dichloromethane) to give 13.4 g of methyl (E,E)-4-ethyl-2,4-heptadienoate as an oil.
Reaction SMILES: Cl.C(O)C.C(OC([NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:20][CH:19]=1)=O)C1C=CC=CC=1>O.[C].[Pd]>[CH2:33]([N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][NH2:15])=[CH:19][CH:20]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)CCCOc1ccc(CCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCN(CCCC)CCCOc1ccc(CCN)cc1
Reaction time: 1.5 h
Yield: 85.2 %

Procedure:
Conc. hydrochloric acid (2.1 ml) and g of 10% palladium-carbon (Pd-C) were added to 100 ml of an ethanol solution containing 5.4 g of N-benzyloxycarbonyl-2-[4-(3-dibutylaminopropyloxy)phenyl]ethylamine. The mixture was subjected to catalytic reduction at normal temperature under normal pressure for 1.5 hours. After removing the catalyst by filtration, the filtrate was condensed and the residue was dissolved in water. The aqueous solution was washed with diethyl ether and made alkaline with potassium carbonate, and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure to give 3.2 g of 2-[4-(3-dibutylaminopropyloxy)phenyl]ethylamine (yield: 85%, oily product).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)(=[O:20])=[O:19]
Reactant: OCCN1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(CCO)CC1
Temperature: 0 °C
Yield: 480.1 %

Procedure:
2-Piperazin-1-yl-ethanol (1.30 g, 1.0 mmol) and triethylamine (2.8 mL, 2 mmol) were dissolved in methylene chloride (20 mL). The solution was cooled to 0° C. and methanesulfonyl chloride (0.78 mL, 1 mmol) was added dropwise. The mixture was warmed to r.t., and the solvent was removed under reduced pressure. The residue was purified via silica gel chromatography (10% methanol in ethyl acetate) to afford the title compound (1.0 g, 48%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccccc2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(-c2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.50 g of ethyl 4-chloro-2-ethoxybenzoate, 0.31 g of phenylboric acid, 85 mg of 1,1-bis(diphenylphosphino)ferrocene dichloronickel and 1.4 g of potassium phosphate were dissolved in 8 ml dioxane, followed by stirring at 95° C. for 1 hour in a nitrogen atmosphere. After cooling the reaction solution to room temperature, ethyl acetate and water were added thereto. The mixture was filtered through Celite, and the mother liquor was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (9:1), ethyl 2-ethoxy-4-phenylbenzoate was obtained. Then, the resulting ethyl 2-ethoxy-4-phenylbenzoate was dissolved in 4 ml ethanol, and 2 ml of 1N sodium hydroxide was added thereto, followed by stirring at room temperature for 6 hours. The reaction mixture was ice-cooled and neutralized with 1N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was evaporated, to give 0.22 g of 2-ethoxy-4-phenylbenzoic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])(C)(C)C.[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]([OH:29])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccccn1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccn2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 2-bromopyridine (1.58 g) in 50 mL of anhydrous tetrahydrofuran at -78° C. was added tert-butyl lithium (6.5 mL of 1.7M) and the reaction mixture was stirred at -78° C. for 1 hour. At the end of this period, a solution of 1-benzyloxycarbonyl-4-oxopiperidine (2.34 g) in 20 mL of anhydrous tetrahydrofuran was added and the reaction mixture was allowed to stir at -78° C. for an additional 1 hour. Upon warming the reaction mixture to room temperature, aqueous ammonium chloride was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with sodium chloride, dried over magnesium sulfate and evaporated to afford the crude product. This a material was purified by column chromatography; elution with 1:1 hexane:ethyl acetate afforded the named product (1.0 g); MS: 313; NMR: 6.63 (m, 3), 1.94 (m, 2), 3.37 (m, 2), 4.13 (m, 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([CH2:13][O:14][C:15]2[N:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH:22]3[O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)=[CH:17][N:16]=2)[O:10][N:9]=1>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([CH2:13][O:14][C:15]2[N:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH:22]3[O:34][CH2:35][C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=3)=[CH:17][N:16]=2)[O:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(OCc3nc(-c4ccccc4Cl)no3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: Clc1ccccc1-c1noc(COc2ncc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)n1

Procedure:
In an analogous manner to that described in Example 125 (h), from tert-butyl (3RS,4RS)-4-[2-[3-(2-chlorophenyl)-[1,2,4]oxadiazol-5-ylmethoxy]-pyrimidin-5-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained 2-[3-(2-chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethoxy]-5-[(3RS,4RS)-3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-pyrimidine in the form of an amorphous yellowish solid; MS: 528 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:12])=[C:6]([OH:11])[C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2].[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[C:18](/[O:11][C:6]1[C:7]([F:10])=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[C:5]=1[F:12])\[CH3:19])[CH3:14]
Reactant: CC#CC(=O)OCC
Reactant: CCOc1ccc(F)c(O)c1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1c(F)ccc(OCC)c1F
Yield: 67.4 %

Procedure:
To a stirred mixture of 3-ethoxy-2,6-difluoro-phenol (4.26 g, 0.024 mol) and ethyl-2-butynoate (5.48 g, 0.049 mol) in tetrahydrofuran (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.73 g, 0.025 mol) slowly. After addition was complete the mixture was stirred at reflux for 6 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by ISCO column chromatography (Teledyne Isco RediSep Flash Column 120 g, 0% to 20% ethyl acetate/hexanes) which afforded (E)-3-(3-ethoxy-2,6-difluoro-phenoxy)-but-2-enoic acid ethyl ester (4.63 g, 66%) as a white crystalline solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9]1[N:15]([CH3:27])[C:16](=[O:26])[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:18][C:8]2=1)=O.[C:28]([O:34][CH2:35][C:36]([NH2:38])=[S:37])(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[C:16](=[O:26])[N:15]([CH3:27])[C:9]3[N:10]([CH3:14])[C:11]4[C:7]([C:8]=3[CH:18]=2)=[CH:6][C:5]([C:3]2[N:38]=[C:36]([CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[S:37][CH:2]=2)=[CH:13][CH:12]=4)=[CH:24][CH:23]=1
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(C(=O)CBr)ccc3n(C)c21
Reactant: CC(C)(C)C(=O)OCC(N)=S
Product: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4csc(COC(=O)C(C)(C)C)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 3 above, with compound B 6-(2-bromoacetyl)-3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and 2-amino-2-thioxoethyl pivalate
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20](O)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7].[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:26]2[CH2:27][CH2:28][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:25]2)=[O:21])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COCC(COC)n1cc(C(=O)O)c(=O)c2cc(I)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COCC(COC)n1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Intermediate 78, 500 mg, 1.12 mmol) and tert-butyl piperazine-1-carboxylate (312 mg, 1.67 mmol) in dichloromethane (50 mL) was added hydroxybenzotriazole (HOBT) (183 mg, 1.12 mmol) and N-methyl morpholine (484 mg, 4.79 mmol). The reaction mixture was stirred for 1 h at room temperature and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl) (390. mg, 2.15 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight. The reaction mixture was quenched with dilute hydrochloric acid (2N, 30 mL) and the layers were separated. The organic layer was washed with saturated sodium bicarbonate solution (40 mL), water (60 mL) and finally with brine successively and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to afford tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate 400 mg (57%) as thick oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH:42]3[CH2:44][CH2:43]3)=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[C:37]([CH:42]3[CH2:43][CH2:44]3)=[N:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2C2CC2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3C3CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K29) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow oil (255 mg, 61%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>CN(C=O)C>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: NCc1ccccc1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1C(F)(F)F)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-(trifluoromethyl)benzylamine (61.6 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (90.9 mg, 96%): m.p. 125-127° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[S:39][CH:40]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:37]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[S:39][CH:40]=2)=[N:8]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
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: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2nn(-c3c(F)cccc3F)c3ccnc(OC)c23)cs1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg) obtained in Step C of Example 35 in DMF (4 mL)/water (0.40 mL) were added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (98.3 mg), tetrakis(triphenylphosphine)palladium(0) (28.2 mg) and potassium carbonate (67.5 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (44.9 mg).
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([CH3:13])[CH:7]=[CH:6][N:5]=1)[CH3:2].C(=O)(O)[O-].[Na+]>Cl>[NH2:10][C:9]1[C:4]([S:3][CH2:1][CH3:2])=[N:5][CH:6]=[CH:7][C:8]=1[CH3:13]
Reactant: CCSc1nccc(C)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCSc1nccc(C)c1N
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
2-Ethylthio-4-methyl-3-nitropyridine (10.0 g, 50.4 mmol) was added slowly with stirring to a solution of 57 g (0.25 mole) of stannous chloride in 250 mL of concentrated aqueous hydrochloric acid. An exothermic reaction took place. The solution was held at 70° C. for 30 min, cooled, and then poured slowly into saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with ember and the extract was dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 5.8 g (68 percent of theory) of a light yellow oil that solidified upon standing. This solid was recrystallized from hexane to obtain 3.2 g of the title compound as a white solid melting at 37°-38° C.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.Br[C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=O>>[CH3:26][O:25][C:22]1[CH:21]=[C:18]2[C:17]([C:12]3[CH:11]=[CH:10][CH:9]=[C:4]4[C:5](=[O:7])[O:14][C:1](=[O:13])[C:2](=[CH:19]2)[C:3]=34)=[CH:24][CH:23]=1
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Reactant: COc1ccc(Br)c(C=O)c1
Product: COc1ccc2c(c1)cc1c3c(cccc32)C(=O)OC1=O

Procedure:
As described in example 50, the following compounds were prepared from dimethyl homophthalate and 2-bromo-5-methoxybenzaldehyde (Handford, B. O.; Whalley, W. B. J. Chem. Soc. 1963, 3896):
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:25][CH3:26])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=O)=[CH:3][CH:2]=1.[NH2:33][OH:34]>C(O)C>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C@H:21]([O:25][CH3:26])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[N:33][OH:34])=[CH:3][CH:2]=1
Reactant: NO
Reactant: CO[C@@H](Cc1ccc(C(=O)CCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C(CCCCOc2ccc(-c3ccccc3)cc2)=NO)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-{4-[5-(Biphenyl-4-yloxy)-pentanoyl]-phenyl}-2-methoxy-propionic acid from Example 52, (1 eq) was mixed with Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with Ethyl Acetate and concentrated to give the title product as a mixture of two oximes. MS(ES) for C27H29NO5 [M+H]+: 448.2.2, [M−H]−: 446.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8](=[O:11])(=[O:10])[NH2:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]([C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1)=[O:14].[CH2:22]([NH:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24]>>[NH2:9][S:8]([C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH3:24])[N:18]=[CH:17][N:16]=2)=[O:14])=[C:2]([CH3:1])[CH:7]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CCCNCCC
Product: CCCN(CCC)c1cc(C(=O)Nc2ccc(S(N)(=O)=O)cc2C)ncn1
Yield: 87 %

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (2-methyl-4-sulfamoyl-phenyl)-amide (Intermediate 17) and dipropylamine (Aldrich), the title compound was obtained as a white solid in 87% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C(N(CC)C(C)C)(C)C.[Br:20][CH2:21][C:22](Br)=[O:23]>C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][C:22](=[O:23])[CH2:21][Br:20]
Reactant: O=C(Br)CBr
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)c(NC(=O)CBr)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a stirred solution of 2,4,6-trimethylaniline (1 g, 7.40 mmol) in methylene chloride (25 mL) at -50° C. was added successively N,N-diisopropylethylamine (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl bromide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed -40° C. On completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether (70 mL) and poured into 1N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title compound (1.51 g, 80%).