Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][CH3:27])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: COc1ccccc1B(O)O
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Product: COc1ccccc1-c1ccc(C(=O)Nc2ccc3nc(N(C)CCN(C)C)sc3c2)cc1

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.15 g, 0.31 mmol) and 2-methoxyphenyl boronic acid (0.060 g, 0.38 mmol) to afford 0.050 g (35%). LC/MS, Retention time=4.49 min; (m/z): calcd for C26H28N4O2S (M+H)+: 461.6; found: 461.0.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C@@H:11](NC)[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]([N:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].C([O-])(O)=O.[Na+].C[C:39]#[N:40]>>[CH2:1]([N:9]1[CH2:13][CH2:12][C@H:11]([CH2:39][NH:40][CH2:17][C:18]([N:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: O=C(CBr)N(c1ccccc1)c1ccccc1
Reactant: CN[C@@H]1CCN(C(=O)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CNC[C@H]1CCN(Cc2ccccc2)C1)N(c1ccccc1)c1ccccc1

Procedure:
To a solution of (R)-(1-benzoyl-pyrrolidin-3-yl)-methyl-amine(0.32 g, 1.68 mmol) in dry CH3CN (10 ml) was added 2-bromo-N,N-diphenyl acetamide(0.49 g, 1.68 mmol) and NaHCO3 (0.28 g, 3.36 mmol) under nitrogen. The reaction mixture was refluxed overnight. After cooling, the solvent was evaporated. The residue was taken up with water (5 ml) and extracted with CHCl3 (3×25 ml). The organic was dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give 680 mg of desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]=[C:12]([C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)[C:13](=O)[CH2:14][O:15][CH3:16])[C:6]#[N:7].[NH2:24][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][C:27]#[N:28].CC(C)([O-])C.[K+]>C(O)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([CH:11]2[C:12]([C:18]3[S:19][CH:20]=[C:21]([CH3:23])[N:22]=3)=[C:13]([CH2:14][O:15][CH3:16])[NH:24][C:25]([C:29]([F:32])([F:31])[F:30])=[C:26]2[C:27]#[N:28])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:7]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: COCC(=O)C(=Cc1ccc(C#N)cc1OC)c1nc(C)cs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COCC1=C(c2nc(C)cs2)C(c2ccc(C#N)cc2OC)C(C#N)=C(C(F)(F)F)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.305 mmol) of the compound from example 14A, 41 mg (0.335 mmol) of 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation in analogy to U.S. Pat. No. 3,635,977 and K. Krespan, J. Org. Chem. 34, 42-45 (1969)] and 5.1 mg (0.05 mmol) of potassium tert-butoxide are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude material is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 18 mg (13% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=C(F)C=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.Cl[CH2:83][C:84]([NH2:86])=[O:85].C(=O)(O)[O-].[Na+]>C(O)C.CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:83][C:84]([NH2:86])=[O:85])[CH2:30][CH2:31]5)=[N:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: NC(=O)CCl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)cc(F)c6)c5)c4c3)cn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)nc4)cnc32)cc1
Yield: 91.5 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 2 compound of example 133) (100 mg, 0.16 mmol) was alkylated using 2-chloroacetamide (30 mg, 0.32 mmol), sodium bicarbonate (40 mg, 0.48 mmol) and ethanol/acetone (3/3 mL) to get 100 mg (91.7%) of the titled compound after purification by column (Silica gel 60/120) using 5% methanol in dichloromethane as eluent. MS: m/z=683.3 (M+1).
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C@H:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][C@H:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (51.7 mg, 0.187 mmol) in dry dichloromethane (2 mL) was added a solution of tert-butyl (4S)-4-aminoazepane-1-carboxylate (69 mg, 0.275 mmol), triethylamine (0.090 mL, 0.646 mmol), HOBT (42.5 mg, 0.278 mmol), and EDC (54.7 mg, 0.285 mmol) sequentially at room temperature under nitrogen. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was purified by HPLC on a 30×100 mm Waters Sunfire column eluted with 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes to afford the title compound as a white solid after lyophilization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([O:12][CH2:13][CH2:14][CH3:15])[CH:4]=1.[F:16][B-:17]([F:20])([F:19])[F:18].[CH2:21]([O+](CC)CC)[CH3:22]>ClCCl>[F:16][B-:17]([F:20])([F:19])[F:18].[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[NH:9])[O:8][CH2:21][CH3:22])=[C:5]([O:12][CH2:13][CH2:14][CH3:15])[CH:4]=1
Reactant: CC[O+](CC)CC
Reactant: CCCOc1cc(OC)ccc1C(N)=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCOc1cc(OC)ccc1C(=N)OCC
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 4-methoxy-2-propoxybenzamide (15 g) and triethyloxonium tetrafluoroborate (0.08 mol) in dichloromethane (180 ml) was stirred at ambient temperature for about 60 hours. The reaction mixture was evaporated under reduced pressure and the residue was washed with diethyl ether to yield crude ethyl 4-methoxy-2-propoxybenzimidate tetrafluoroborate, 20.52 g which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=1>N1C=CC=CC=1.O.C(OCC)(=O)C.[Cu]>[CH3:33][S:32][C:29]1[CH:30]=[CH:31][C:26]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)=[CH:27][CH:28]=1
Reactant: CSc1ccc(Br)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)cc2)cc1
Agent: [Cu]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1ccc(-n2ncc(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(F)cc3)c2=O)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of the product from Example 11, 4-(4-Fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (344 mg, 1.0 mmol), 4-bromothioanisole (812 mg, 4.0 mmol), and copper (70 mg, 1.1 mmol) in 20 mL of pyridine was stirred at reflux under a nitrogen atmosphere for 18 hours. After cooling to room temperature, the reaction mixture was diluted with a mixture of water and ethyl acetate. The two layers were filtered through Celite®, and separated. The organic layer was washed with 10% aqueous citric acid, with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography (silica gel, 93:7 dichloromethane/ethyl acetate) to provide the title compound as a foam (yield: 380 mg, 81.5%). 1H NMR (300 MHz, CDCl3) δ 2.55 (s, 3H), 3.05 (s, 3H), 6.98 (t, J=9 Hz, 2H), 7.22 (dd, J=9 Hz, 6 Hz, 2H), 7.38 (dd, J=8 Hz, 2 Hz, 4H), 7.64 (d, J=9 Hz, 2H), 7.91 (d, J=9 Hz, 2H), 7.98 (s, 1H). MS (DCI/NH3) m/z 467 (M+H)+. Anal. calc. for C24H19FN2O3S2.0.5H2O: C, 60.63; H, 4.21; N, 5.90. Found: C, 60.72; H, 3.96; N, 5.70.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:38]=[CH:37][C:24]2[C:25](Br)=[CH:26][CH2:27][N:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]=2[CH:22]=1.[CH2:39]([OH:42])[C:40]#[CH:41].Cl>[Pd](Cl)Cl.C(NCC)C>[ClH:20].[Cl:20][C:21]1[CH:38]=[CH:37][C:24]2[C:25]([C:41]#[C:40][CH2:39][OH:42])=[CH:26][CH2:27][N:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:23]=2[CH:22]=1
Reactant: C#CCO
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCC=C2Br
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: OCC#CC1=CCN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 40 ml of 98% diethylamine, 44.3 mg (0.25 mmole) of palladium chloride, 131.2 mg (0.5 mmole) of triphenylphosphine, 47.6 mg (0.25 mmole) of cuprous iodide, 3.5 g (10.5 mmole) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine and 5 ml of propargyl alcohol was stirred at room temperature under nitrogen for 7 hr. The mixture was concentrated at reduced pressure to dryness. The residue was dissolved in methylene chloride, and washed with water. The methylene chloride solution was dried over anhyrous sodium sulfate and concentrated at reduced pressure to dryness. Purification by column chromatography (silica gel, 20 g; eluent 20% ether in methylene chloride) gave a colorless oil. The oil was dissolved in an excess of methanolic hydrogen chloride and concentrated at reduced pressure to dryness. The residue crystallized from a mixture of methanol and ether to give a tan solid, mp 228°-229° C. dec.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][C@H:6]1[CH2:9][CH2:8][C@H:7]1[OH:10].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:10][C@@H:7]1[CH2:8][CH2:9][C@@H:6]1[O:5][C:4]1[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=1[C:2]([F:15])([F:16])[F:1])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of C7 (484 mg, 2.08 mmol), triethylamine (0.87 mL, 6.3 mmol) and dichloromethane (30 mL) was cooled to 0° C. and methanesulfonyl chloride (0.32 mL, 4.2 mmol) was added drop-wise over 15 minutes. After an additional 30 minutes at 0° C., the reaction was quenched with saturated aqueous sodium bicarbonate solution (50 mL), and the mixture was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a colorless oil. Yield: 640 mg, 2.06 mmol, 99%. 1H NMR (400 MHz, CDCl3) δ 7.60 (br dd, J=7.8, 1.2 Hz, 1H), 7.45-7.51 (m, 1H), 7.06 (br dd, J=7.7, 7.6 Hz, 1H), 6.88 (br d, J=8.4 Hz, 1H), 5.26-5.32 (m, 1H), 5.01-5.06 (m, 1H), 2.95 (s, 3H), 2.53-2.63 (m, 1H), 2.37-2.46 (m, 1H), 2.18-2.30 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1([CH3:17])[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[C:14]3([CH3:17])[CH2:16][CH2:15]3)=[CH:3][C:2]=2[F:1])[CH2:31]1
Reactant: CC1(n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)CC1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Product: CC1(n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCC(N)C4)c(F)c32)CC1

Procedure:
To 1.24 g (4.27 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-(1-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.77 (4.27 mmol) of 3-[(t-butoxycarbonyl)amino]pyrrolidine and 0.63 g (4.27 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene. The mixture was refluxed for one hour, cooled, filtered, and the solids washed with ether. The solids were dissolved in 10 ml of acetic acid at 100° C. and 2 ml of 3N hydrochloric acid was added. This mixture was heated at 100° for four hours, concentrated, triturated with 2-propanol, and the solid filtered, washed with ether, and dried (24 hours, 80° C., 125 mmHg) to give 0.90 g of 7-(3-amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-1-(1-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid as the hydrochloride salt, mp >300° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:4]([CH3:24])[CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:4]([CH3:24])[CH:3]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3ccc(F)cc3C)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(F)ccc1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 109.2 %

Procedure:
In THF/methanol (2:1, v/v, 120 ml) was dissolved methyl (2-(4-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.32 g, 3.97 mmol). To the resulting solution was added 1N NaOH (40 ml). After stirring at room temperature for 12 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(4-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetic acid (1.38 g, 100%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=O.OC1C=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:18]=1>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:21]=[CH:20][C:19]([C:30]([F:33])([F:32])[F:31])=[C:15]2[CH2:14][O:13][C:11]2[CH:10]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:19]([C:30]([F:31])([F:32])[F:33])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CCc1ccc(O)cc1C(F)(F)F
Reactant: Nc1ccc(F)cc1
Product: O=C(O)CCc1ccc(OCc2c(C(F)(F)F)ccn2-c2ccc(F)cc2)cc1C(F)(F)F

Procedure:
4-Fluoroaniline was reacted with ethyl bromoacetate according to the procedure of Example 73, Step A. The resulting product was then reacted according to the procedures of Example 73, Steps B and C and Example 1, Step D, in sequence. The resulting product was then reacted with ethyl 3-(4-hydroxy-2-trifluoromethylphenyl)propanoate according to the procedures of Example 1, Step E and Step F, in sequence, to yield the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.O.[C:14]([OH:18])(=[O:17])[CH:15]=O.[CH2:19]([NH:22][CH2:23][CH:24]=[CH2:25])[CH:20]=[CH2:21]>C(#N)C>[CH2:19]([N:22]([CH2:23][CH:24]=[CH2:25])[CH:15]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][O:2][CH3:1])=[CH:5][CH:6]=1)[C:14]([OH:18])=[O:17])[CH:20]=[CH2:21]
Reactant: O=CC(=O)O
Reactant: COCc1ccc(B(O)O)cc1
Reactant: C=CCNCC=C
Solvent: CC#N
Solvent: O
Product: C=CCN(CC=C)C(C(=O)O)c1ccc(COC)cc1
Yield: 12.1 %

Procedure:
A solution of (4-(methoxymethyl)phenyl)boronic acid (999 mg, 6.02 mmol), glyoxylic acid monohydrate (554 mg, 6.02 mmol) and diallylamine (0.741 mL, 6.02 mmol) in acetonitrile (12 mL) was stirred at 60° C. for 5 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Diol, solvent; ethyl acetate), and crystallized from ethyl acetate/hexane to give 2-(diallylamino)-2-(4-(methoxymethyl)phenyl)acetic acid (200 mg, 0.726 mmol, 12.07%) as crystals.
Reaction SMILES: C(N(CC)CC)C.[N-:8]=[N+:9]=[N-:10].[Na+].[N+]([C:15]1[CH:33]=[CH:32][CH:31]=[C:17]2[C:18]([N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:21](=[O:22])[C:16]=12)=[O:19])([O-])=O>CS(C)=O>[N:8]([C:31]1[CH:32]=[CH:33][CH:15]=[C:16]2[C:21]([N:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:18](=[O:19])[C:17]=12)=[O:22])=[N+:9]=[N-:10]
Reactant: O=C(O)CCCCCN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(CCCCCC(=O)O)C2=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
2.58 ml (0.018 mol) of triethylamine, followed by 1.3 g (0.0198 mol) of sodium azide, are added to a mixture of 5.7 g (0.018 mol) of 6-(3-nitrophthalimidyl)-caproic acid in 35 ml of dimethylsulphoxide. The reaction mixture is heated for 6 hours at 50° C. and is then concentrated in vacuo, diluted with 100 ml of water and acidified with 4 ml of concentrated hydrochloric acid. The resulting suspension of the reaction product is stirred for 18 hours and filtered with suction, and the filter residue is washed with 20 ml of water and dried for 24 hours at 60° C./0.100. mm Hg, over phosphorus pentoxide. 5.1 g (94% of theory) of 6-(3-azidophthalimidyl)-caproic acid are obtained; melting point 87°-90° C. (with decomposition). IR spectrum (CH2Cl2): 1780 and 1725 cm-1 (CO--N--CO); 2130 cm-1 (N3).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=2)[N:11]=[C:10]([NH:24][CH:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[N:9]=1>C1C=CC=CC=1>[Cl:23][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[C:10]([NH:24][CH:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:9]=[C:8]([O:4][CH:1]([CH3:3])[CH3:2])[N:13]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CC(C)O
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(OC(C)C)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of isopropanol (2 mL) and sodium hydroxide (95 mg, 2.27 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.3 g, 0.78 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1–2% MeOH—CHCl3) to afford the title compound E21 as an off-white solid (0.30 g, 94%). mp 136–138° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 30.06 min, 98.78% purity; MS (CI): m/z 406 (M+H, 100).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][CH:22]([CH3:46])[CH2:23][NH:24][C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>C(#N)C>[CH3:21][CH:22]([CH3:46])[CH2:23][N:24]([C:18]([C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:20])[C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:26]1
Reactant: O=C(O)c1nc2ccccn2c1CCc1ccccc1
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)CN(C(=O)c1nc2ccccn2c1CCc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.4 %

Procedure:
Ethyl 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylate (883 mg) was dissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, neutralized with 1N hydrochloric acid, subjected to DIAION HP-20 (manufactured by Mitsubishi Chemical), and washed with water. The fraction eluted with acetone was concentrated under reduced pressure to give 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (1.03 g). The obtained 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (341 mg), tert-butyl(3S, 5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (370 mg) and N,N-diisopropylethylamine (862 μl) were dissolved in acetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (561 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object product (522 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][CH2:13]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH2:10][NH:11][C:18]([CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)=[O:19])=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCOCC1
Reactant: NCCSc1ccc(Cl)cc1
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCCSc1ccc(Cl)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8203.6 %

Procedure:
To a solution of 2-[(4-chlorophenyl)sulfanyl]ethanamine (15.32 g, 82 mmol, prepared from 4-chlorothiophenol and 2-chloroethylamine as described before) in DMF (247 ml) was added sequentially tetrahydro-2H-pyran-4-carboxylic acid (9.66 g, 74.2 mmol), EDC (15.65 g, 82 mmol) and HOAt (2.021 g, 14.85 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with EtOAc, washed with 1N HCl, aq NaHCO3, 3M LiCl, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica 1 kg, 50 to 100% EtOAc in hexane), to give N-{2-[(4-chlorophenyl)sulfanyl]ethyl}tetrahydro-2H-pyran-4-carboxamide (1825 g). MS: M+H=300. H1NMR (400 MHz, CDCl3) δ: 7.31 (d, J=9.9 Hz, 2H), 7.26 (d, J=9.9 Hz, 2H), 5.82 (br s, 1 H), 4.40-3.96 (m, 2H), 3.46 (dt, J=7.0, 7.0 Hz, 2H), 3.45-3.36 (m, 2H), 3.05 (t, J=7.0 Hz, 2 H), 2.34-2.26 (m, 1H), 1.82-1.65 (m, 4H).