Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Li+].N.[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]([O:13][CH3:14])[CH2:10][C:11]#[CH:12].Br[CH2:16][CH2:17][CH2:18][Cl:19]>O1CCCC1>[Cl:19][CH2:18][CH2:17][CH2:16][C:12]#[C:11][CH2:10][CH:9]([C:5]1[O:4][CH:8]=[CH:7][CH:6]=1)[O:13][CH3:14]
Reactant: C#CCC(OC)c1ccco1
Reactant: ClCCCBr
Agent: N
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: COC(CC#CCCCCl)c1ccco1
Yield: 67.8 %

Procedure:
To a stirred mixture of 0.51 g of lithium amide and 25 ml of liquid ammonia was added a solution of 3.0 g of 4-(2-furyl)-4-methoxy-1-butyne in 2.5 ml of tetrahydrofuran. The mixture was stirred under reflux for 30 minutes and then treated with a solution of 3.94 g of 1-bromo-3-chloropropane in 5 ml of tetrahydrofuran. This mixture was stirred under reflux for one hour, then the ammonia was allowed to evaporate and the residue partitioned with ether and water. The ether layer was separated and evaporated. The residue was distilled at 0.06 mm on a Kugelrohr, giving 3.07 g of the desired compound as an oil, bp 110°-120° C.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].N1CC[CH2:16][CH2:15]1>C1(C)C(C)=CC=CC=1>[N:2]1([CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH2:1][CH2:16][CH2:15][CH2:13]1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: C1CCNC1
Solvent: Cc1ccccc1C
Product: O=C(C=CN1CCCC1)c1cccnc1

Procedure:
A mixture of 0.1 mole of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one and a 0.15 mole of pyrrolidine in 200 ml of xylene was refluxed with distillation of the xylene by passing a stream of argon through the solution. Additional xylene was added periodically. After 10 hours the solvent was removed to give crude 3-(1-pyrrolidinyl)-1-(3-pyridinyl)-2-propen-1-one. This crude compound and 0.1 mole of (3-amino-1H-pyrazol-4-yl)-2-furanyl-methanone in 100 ml of glacial acetic acid was refluxed for 8 hours. The solvent was removed in vacuo and the product isolated as described in Example 1, giving the desired product as crystals, mp 228°-229° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18](=[O:32])[C@@H:19]([NH2:31])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:16][O:17][C:18](=[O:32])[C@@H:19]([NH:31][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH:14]=[CH2:15])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)OC
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of 2-(S)-tert-butoxycarbonylamino-pent-4-enoic acid (3.8 g, 18.0 mmol) and 2-(S)-amino-3-naphthalen-2-yl-propionic acid methyl ester (4.1 g, 18.0 mmol) in DMF (40 mL) are added 1-hydroxybenzotriazole (3.1 g, 23.4 mmol), N-methylmorpholine (9.1 g, 90.0 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (4.5 g, 23.4 mmol) consecutively and the reaction mixture is stirred for 3 hours. The reaction is quenched with aqueous NH4Cl and extracted with ethyl acetate. The extract is dried over Na2SO4, filtered and concentrated in vacuo and the residue purified over silica gel (hexanes/ethyl acetate, 1:1) to afford 6.4 g (84% yield) of the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]4=[O:38])=[CH:24][C:23]=3[F:39])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:39][C:23]1[CH:24]=[C:25]([N:28]2[CH2:32][C@H:31]([CH2:33][NH:34][C:35](=[O:37])[CH3:36])[O:30][C:29]2=[O:38])[CH:26]=[CH:27][C:22]=1[N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:17][CH2:18]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(CCN4CCN(C(=O)OC(C)(C)C)CC4)CC3)c(F)c2)C(=O)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(CCN4CCNCC4)CC3)c(F)c2)C(=O)O1

Procedure:
A solution of 200 mg of 4-[2-(4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazine-1-yl)ethyl]piperazine-1-carboxylic acid tert butyl ester (0.36 mmol) in 2 ml dichloromethane and 2 ml trifluoracetic acid was stirred for 10 min. The solvents were evaporated, the residue was digested in ether and the solid filtered. The solid was dissolved in water and neutralized with a saturated solution of sodium bicarbonate. The water was evaporated and the product dried as a mixture with the salts.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[I-].[K+]>P(Cl)(Cl)(Cl)=O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[CH:10]([CH3:11])[N:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:13][CH2:14]2
Reactant: COc1ccc(N(CCc2cccc(OC)c2)C(C)=O)cc1
Agent: [I-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(N2CCc3cc(OC)ccc3C2C)cc1
Reaction time: 0.5 h

Procedure:
N-(4-Methoxy-phenyl)-N-[2-(3-methoxyphenyl)-ethyl]-acetamide (0.60 g) was heated to 80° C. in phosphorus oxychloride (8.4 mL) for 24 h. The reaction was cooled then poured slowly onto ice (150 mL). Potassium iodide (0.65 g) was added. After 30 min, the mixture was extracted with methylene chloride (2×50 mL). The organic extracts were dried over sodium sulfate, filtered through celite and concentrated. The resulting residue was dissolved in methanol (21 mL) and sodium borohydride (0.23 g) was added slowly in small portions. After 18 h the solvent was removed under reduced pressure. The residue was partitioned between water (100 mL) and ethyl acetate (50 mL) and the aqueous layer was extracted with ethyl acetate (25 mL). The combined organic extracts were dried over sodium sulfate, filtered through celite and concentrated giving the title compound MS: 284.3 (MH+); HPLC tR; 2.11 min (method D).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[NH:14][C:15]4[N:16]([N:20]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)[N:22]=4)[C:17](=[O:19])[CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[NH:14][C:15]4[N:16]([N:20]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)[N:22]=4)[C:17](=[O:19])[CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: CC(=O)n1ncc2cc(-c3cc(=O)n4nc(-c5ccccn5)nc4[nH]3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=c1cc(-c2ccc3[nH]ncc3c2)[nH]c2nc(-c3ccccn3)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1-acetyl-1H-indazol-5-yl)-2-(pyridin-2-yl)-4H,7H-[1,2,4]triazolo[1,5-α]pyrimidin-7-one (120 mg, crude) in methanol (10 ml) was added a solution of potassium carbonate (48 mg, 0.35 mmol) in water (1 ml), and the reaction was stirred overnight at room temperature. The resulting solution was concentrated and diluted with water (5 ml). The solids were collected by filtration to give a crude product, which was purified by Flash-Prep-HPLC to afford 5-(1H-indazol-5-yl)-2-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a brown solid (36.9 mg, 12% 2 steps).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:20]([CH3:29])([CH3:28])[O:19][C:18]3=[O:30])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[C@@H:21]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:20]([CH3:28])([CH3:29])[O:19][C:18]4=[O:30])=[CH:15][CH:16]=3)=[N:9][N:8]=2)[N:7]=1
Reactant: CC1(C)OC(=O)N(c2ccc(C(=O)NNc3ccc(Cl)nn3)cc2)[C@H]1c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(-c3nnc4ccc(Cl)nn34)cc2)[C@H]1c1ccccc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
(S)—N′-(6-Chloropyridazin-3-yl)-4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzohydrazide (100 mg, 0.228 mmol) was dissolved in MeOH (2.284 mL). To the reaction mixture was added 4-methylbenzenesulfonic acid hydrate (43.4 mg, 0.228 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.). The mixture was heated at 55° C. and was stirred overnight. LC-MS indicated incomplete conversion. The mixture was then heated at 100° C. in a microwave for 1 hour. LC-MS indicated complete and clean conversion to the desired product. The reaction mixture was then concentrated under reduced pressure and providing a yellow residue. The residue was dissolved in 2 mL of MeOH and 1 mL of NH4OH, and the mixture was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 20% to 90% over 20 minutes. The pure fractions were combined and diluted with 30% ammonium hydroxide, and the aqueous layer was extracted with DCM (3×20 mL) to provide (S)-3-(4-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (30 mg, 0.071 mmol, 31.3% yield) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.50 (d, J=9.40 Hz, 1H), 8.20 (d, J=8.33 Hz, 2H), 7.74 (d, J=9.19 Hz, 2H), 7.52 (d, J=9.62 Hz, 1H), 7.36-7.42 (m, 2H), 7.26-7.35 (m, 3H), 5.55 (s, 1H), 1.67 (s, 3H), 0.94 (s, 3H). m/z (ESI) 420.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][O:24][CH2:25][CH2:26]Br.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(#N)C.C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:23][O:24][CH2:25][CH2:26][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: COCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: COCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.75 g, 17 mmol), K2CO3 (3 g, 21.7 mmol), bromoethyl methyl ether (2.84 g, 20.4 mmol) in acetonitrile (150 ml) was heated at reflux for 3.5 hours. The reaction was cooled. The inorganics were filtered and rinsed with DCM. The organic solution was concentrated down to an oil (7 g). Purification on a flash chromatography column (SiO2, 45 g; eluted with methanol/DCM) gave a light yellow oil as product (4 g, 87%). This oil was dissolved into ethanol and treated with a solution of fumaric acid (1.67 g) in ethanol (20 ml). White crystals (5.15 g) were collected, m.p.=157°-158° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@H:14](C4C=C(Br)C=CC=4S([O-])(=O)=O)[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[NH2:30][C@@H:31]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:32]([NH2:34])=[O:33]>C(#N)C>[F:28][C:2]([F:29])([F:1])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH:30][C@H:31]([C:32]([NH2:34])=[O:33])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=S(=O)([O-])c1ccc(Br)cc1[C@@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Solvent: CC#N
Product: CC(C)C[C@H](N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)C(N)=O
Temperature: 85 °C

Procedure:
The title compound was prepared by combining (3aR,4R,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-yl-4-bromobenzenesulfonate from Step 4 (150 mg, 0.305 mmol) and (S)-2-amino-4-methylpentanamide (119 mg, 0.916 mmol) in acetonitrile (0.2 mL). The reaction mixture was heated at 85° C. for 3 days, and the acetonitrile was evaporated. This material was purified using a 12 g silica gel cartridge eluted with a gradient of 0-3% methanol (2 N ammonia)/dichloromethane over 20 minutes to give crude product. It was further purified on 2×0.25 mm thin-layer chromatography plate eluted with 45% methanol (2 N ammonia)/dichloromethane to give N2-{(3aR,4S,6aS)-2-[6-(trifluoromethyl)pyridin-2-yl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.25 (s, 1H), 7.99 (s, 1H), 7.52 (t, J=7.9, 1H), 6.98 (d, J=7.2, 1H), 6.49 (d, J=8.6, 1H), 3.60 (dd, J=10.6, 9.0, 1H), 3.55-3.40 (m, 3H), 3.24 (dd, J=10.8, 3.7, 1H), 3.17 (dd, J=10.2, 5.7, 1H), 2.83-2.71 (m, 1H), 2.64-2.55 (m, 1H), 2.30-2.10 (bs, 1H) 2.08-1.93 (m, 3H), 1.76 (ddd, J=13.5, 8.1, 5.5, 1H), 1.71-1.64 (m, 1H), 1.58 (dd, J=12.7, 5.8, 1H), 1.31 (dd, J=12.7, 5.9, 1H), 0.96 (d, J=6.6, 3H), 0.93 (d, J=6.6, 3H); MS (ESI+) m/z 385 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]([OH:33])([CH2:31][CH3:32])[C:4]#[C:5]/[CH:6]=[C:7](/[C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[O:12][CH2:13][C:14]1[CH:15]=[C:16]([C:24](OC)=[O:25])[C:17](=[CH:22][CH:23]=1)[C:18](OC)=[O:19])\[CH3:8])[CH3:2].[BH4-].[Li+]>>[OH:25][CH2:24][C:16]1[CH:15]=[C:14]([CH:23]=[CH:22][C:17]=1[CH2:18][OH:19])[CH2:13][O:12][C:11]1[CH:10]=[C:9](/[C:7](/[CH3:8])=[CH:6]/[C:5]#[C:4][C:3]([CH2:31][CH3:32])([OH:33])[CH2:1][CH3:2])[CH:30]=[CH:29][CH:28]=1
Reactant: CCC(O)(C#C/C=C(\C)c1cccc(OCc2ccc(C(=O)OC)c(C(=O)OC)c2)c1)CC
Agent: [BH4-]
Agent: [Li+]
Product: CCC(O)(C#C/C=C(\C)c1cccc(OCc2ccc(CO)c(CO)c2)c1)CC

Procedure:
In a manner similar to Example 53(e), by reacting 390 mg (0.87 mmol) of dimethyl 4-[3-((E)-5-ethyl-5-hydroxy-1-methylhept-1-en-3-ynyl)phenoxymethyl]phthalate (prepared from the previous product in a manner similar to Example 64(d)) with 56 mg (2.6 mmol) of lithium borohydride, a colourless oil is obtained (m=248 mg; Y=72%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C.[Cl-]>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A solution of acryloyl chloride (0.092 mL, 1.14 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 63, 480 mg, 1.03 mmol) and DIPEA (0.214 mL, 1.24 mmol) in CH2Cl2 (18 mL) at r.t. After 0.25 h, additional acrolyl chloride (15 mg in 0.15 mL CH2Cl2) was added. The mixture was stirred for 0.5 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (390 mg, 73%) as a yellow solid, after trituration with CH3OH; 1H NMR: 2.27 (3H, s), 2.53-2.61 (4H, m), 2.84-2.97 (4H, m), 3.77 (3H, s), 5.70 (1H, d), 6.17 (1H, d), 6.61 (1H, dd), 6.89 (1H, s), 7.11 (1H, t), 7.3-7.42 (1H, m), 8.10 (1H, s), 8.26-8.47 (2H, m), 8.70 (1H, s), 8.83 (1H, d), 8.96 (1H, s), 9.02 (1H, s); m/z: ES+ MH+ 519.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([B:10]([OH:15])[OH:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cccc(Br)c1
Product: COc1cccc(B(O)O)c1
Yield: 82 %

Procedure:
3-Methoxyphenylboronic acid was prepared in the same manner as described in Example 33B from 3-bromoanisole and triisopropyl borate in 82% yield. This was used in the next step without any further purification.
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[N:48]1[CH:49]=[CH:50][N:51]2[CH:56]=[CH:55][C:54]([CH2:57][NH2:58])=[CH:53][C:52]=12.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:48]1[CH:49]=[CH:50][N:51]2[CH:56]=[CH:55][C:54]([CH2:57][NH:58][C:21]([C:10]3[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=4)[CH:13]=[C:8]([C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH3:24])=[O:7])[CH:9]=3)=[O:22])=[CH:53][C:52]=12
Reactant: NCc1ccn2ccnc2c1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NCc3ccn4ccnc4c3)cc(C(=O)N(C)CC(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (15 mg, 0.046 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (18 mg, 0.092 mmol), 1-hydroxybenzotriazole hydrate (7.0 mg, 0.046 mmol), and CH2Cl2 (2 mL) were added imidazo[1,2-a]pyridin-7-ylmethanamine (10 mg, 0.069 mmol) and N,N-diisopropylethylamine (12 μL, 0.069 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 40-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].O[C:18]1C(C(C)(C)C)=CC(C)=CC=1N1N=C2C=CC(Cl)=CC2=N1.OC1C(C(C)(C)C)=CC(C(C)(C)C)=CC=1N1N=C2C=CC(Cl)=CC2=N1.OC1C=CC(C)=CC=1N1N=C2C=CC=CC2=N1.OC1C(C(CC)(C)C)=CC(C(CC)(C)C)=CC=1N1N=C2C=CC=CC2=N1.C(OC1C=CC=CC=1)(=O)C1C(=CC=CC=1)O.C(C1C=C(C(C)(C)C)C=CC=1C1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1C([O-])=O)(C)(C)C>>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:18])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: Cc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C)c1ccc(-c2c(C(=O)[O-])cc(C(C)(C)C)c(O)c2C(C)(C)C)c(C(C)(C)C)c1
Agent: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1

Procedure:
2-hydroxy-4-octoxybenzopnenone; 2,4-dihydroxybenzophenone; 2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5-chlorobenzotriazole; 2-(2'-hydroxy-3',5'-di-t-butyl-phenyl)-5-chlorobenzotriazole; 2-(2'-hydroxy-5'-methylphenyl)benzotriazole; 2-(2'-hydroxy-3',5'-di-t-amylphenyl) benzotriazole; phenyl salicylate; 2,4-di-t-butylphenyl-3,5-di-t-butyl-4-hydroxybenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:11]=2[N+:30]([O-])=O)=[N:6][CH:7]=1.O.O.[Sn](Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:33])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]3)[C:11]=2[NH2:30])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc(C(=O)Nc3ccc(Cl)cn3)c2[N+](=O)[O-])CC1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc(C(=O)Nc3ccc(Cl)cn3)c2N)CC1
Yield: 58.6 %

Procedure:
In a manner similar to that described in Paragraph A above, N-(5-chloropyridin-2-yl)-2-nitro-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide (13 g, 26 mmol) was reacted with tin(II) chloride dihydrate (29 g, 130 mmol) in pyridine (100 mL) to afford 7.1 g (60% yield) of N-(5-chloropyridin-2-yl)-2-amino-3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-chlorobenzamide, as a yellow solid; NMR (DMSO-d6) 10.8 (s, 1), 8.4 (d, 1), 8.1 (d, 1), 7.9 (dd, 1), 7.6 (d, 1), 7.1 (d, 1), 6.2 (d, 2), 3.3 (m, 4), 2.7 (br, 4), 1.4 (s, 9) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(O)=O.N1CCCCC1>CCO>[C:10](/[C:18](=[CH:7]/[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[CH:9]=1)/[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cncc(C=O)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)/C(=C\c1cncc(C)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.1 %

Procedure:
A mixture of 5-methylnicotinaldehyde (400 mg), ethyl benzoylacetate (635 mg), AcOH (0.15 ml), piperidine (0.15 ml) in EtOH (5 ml) was stirred at room temperature for 24 hours. After evaporation, the residue was diluted with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo to give ethyl (2Z)-2-benzoyl-3-(5-methyl-3-pyridyl)acrylate (986 mg) as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([C:20]([F:23])([F:21])[F:22])=[CH:10][C:9]2[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=4)[CH:30]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-(isobutyl-methyl-amino)-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M275) (0.44 g, 0.73 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (186 mg, 53%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)[CH3:23].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:16]([C:13]([CH3:14])([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([OH:2])=[O:21])[CH:11]=[CH:10][CH:9]=2)[CH3:15])=[O:18])=[CH:26][CH:25]=1)[CH3:23]
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Reactant: CCc1ccc(CCN)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCc1ccc(CCNC(=O)C(C)(C)Oc2cccc(C[C@H](OC)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and 2-(4-ethyl-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H31NO5 [M−H]−: 412.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[CH:18](OC(C)(C)C)=O>>[N+:1]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1)#[C-:18]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Reactant: CC(C)(C)OC=O
Product: [C-]#[N+]c1ccc2cnn(C(=O)OC(C)(C)C)c2c1

Procedure:
Intermediate 8 was prepared in a similar manner as Intermediate 6 from tert-butyl 6-amino-1H-indazole-1-carboxylate. 1H NMR (400 MHz, CDCl3) δ 8.28 (1H, s), 8.20 (1H, s), 7.76 (1H, d, J=8.34 Hz), 7.28-7.40 (1H, m), 1.74 (9H, s) ppm. MS (ESI) m/z: 144 (M+H-Boc)+.