Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[C:6]([C:8]1[S:9][C:10]2[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7].Cl.N1C=CC=CC=1>C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[C:6]([C:8]1[S:9][C:10]2[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:7]
Reactant: COc1cccc(C(=O)c2sc3cc(OC)ccc3c2-c2ccccc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(c1cccc(O)c1)c1sc2cc(O)ccc2c1-c1ccccc1
Yield: 91 %

Procedure:
Employing the procedure of Example 7, 5.0 g. (0.0134 mole) of the product from Example 11 was demethylated by treatment with 25 g. of pyridine hydrochloride for three hours in a 220° C. oil bath. Yellow crystals, obtained from ethyl acetate, were recrystallized from a mixture of 20 ml. of methanol and about 12 ml. of water to give 4.184 g. (91 percent) of the title compound as yellowish-brown crystals. Melting point 202.0°-202.5° C.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[I-].[C:17]([CH2:19][CH2:20][N:21]([C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[N:18]>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:31]1[CH2:32][CH2:33][C@H:29]([N:21]([CH2:20][CH2:19][C:17]#[N:18])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:30]1)#[N:2]
Reactant: N#CCCN(Cc1ccccc1)[C@H]1CCNC1
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Agent: [I-]
Product: CC(C)C(C#N)(CCCN1CC[C@H](N(CCC#N)Cc2ccccc2)C1)c1cccs1

Procedure:
Optically active body, 4-cyano-4-(2-thienyl)-5-methylhexyl iodide (iodide D (optically active body)) was synthesized from the alcohol A in accordance with Example 77 (1). The title compound was synthesized in accordance with Example 75 from the iodide D and (3S)-3-[N-(2-cyanoethyl)-N-benzylamino]pyrrolidine of “Synthetic method A” (1) (1) of Example 175. The physico-chemical data of the title compound was as below.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][NH2:7].CN(C=O)C.[Br:13][C:14]1[C:15](=[O:36])[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:17]([C:24](OC)=[O:25])[N:18]([CH2:20][CH:21](O)O)[CH:19]=1.[Br-]>C(#N)C.C(O)(=O)C>[Br:13][C:14]1[C:15](=[O:36])[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:17]2[C:24](=[O:25])[N:7]3[CH2:6][C@H:2]4[CH2:3][CH2:4][CH2:5][N:1]4[C@@H:21]3[CH2:20][N:18]2[CH:19]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(O)O
Reactant: NC[C@H]1CCCN1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C1c2c(OCc3ccccc3)c(=O)c(Br)cn2C[C@@H]2N1C[C@H]1CCCN12
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
A reactor was charged with [(2R)-2-pyrrolidinylmethyl]amine (0.75 kg) and 4.6 L of DMF was added followed by 0.45 kg of glacial acetic acid. Acetonitrile (41.4 L) was then added and the mixture was agitated for 15 minutes. To the reaction mixture was added methyl 5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate (2.30 kg). After stirring for 20 minutes at ambient temperature, the mixture was heated at 75-85° C. until the bromide starting material was consumed by HPLC analysis (about 6 hrs). Upon completion, the mixture was cooled until the refluz subsided and then charged with 6.9 L of methanol and the mixture was heated at reflux for about 45 minutes then cooled to 15° C. and filtered and dried to provide (4aS,13aR)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-9,11-dione (1.93 kg, 78%) as a white solid.). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.65 (m, 1H), 7.54 (m, 2H), 7.33 (m, 3H), 5.15 (d, 1H), 4.99 (d, 1H), 4.60 (m, 1H), 4.36 (m, 1H), 4.03 (m, 1H), 3.90 (m, 1H), 3.65 (m, 1H), 3.06-2.84 (m, 3H), 1.92-1.60 (m, 4H).
Reaction SMILES: [CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18][NH2:19])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[CH3:28][O:29][CH2:30][CH2:31][O:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[CH:38][C:39]([CH:43]=O)=[N:40]2)=[CH:35][CH:34]=1.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>CCO>[CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:43]([C:39]4[CH:38]=[CH:37][C:36]5[C:41](=[CH:42][C:33]([O:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:34][CH:35]=5)[N:40]=4)=[N:19][N:18]=3)[CH:13]=2)[C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN([C@@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COCCOc1ccc2ccc(C=O)nc2c1
Agent: O=Ic1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: COCCOc1ccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (53 mg, 0.14 mmol), 7-(2-methoxyethoxy)quinoline-2-carbaldehyde (30 mg, 0.13 mmol) and EtOH (1.4 mL) was stirred at ambient temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in DCM (1.4 mL) and iodosobenzene diacetate (54 mg, 0.17 mmol) was added. The reaction mixture was stirred at ambient temperature overnight and then loaded to a silica gel column eluting with 1:2 to 3:1 EtOAc/hexanes to give tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (72 mg, 92%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH2:16][O:17][CH3:18])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH2:29])=[CH:24][CH:23]=2>>[CH3:18][O:17][CH2:16][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[NH:29][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20]([CH3:19])=[CH:28]3)[CH:8]=1
Reactant: COCn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: COCn1ccnc1-c1cc2nccc(Nc3ccc4[nH]c(C)cc4c3)c2s1

Procedure:
The title compound was prepared from 7-chloro-2-(1-methoxymethyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridine and 2-methyl-5-aminoindole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.15 (d, 1H), 7.85 (s, 1H), 7.53 (s, 1H), 7.37 (m, 2H), 7.11 (s, 1H), 7.02 (d, 1H), 6.81 (d, 1H), 6.19 (s, 1H), 5.46 (s, 2H), 3.38 (s, 1H), 2.44 (s, 1H); RP18-HPLC RT: 4.38 minutes; API MS: 390 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:18][C:19]([OH:21])=O)[N:11]=[C:12]([C:13]3[NH:14][CH:15]=[CH:16][N:17]=3)[C:5]=12.Cl.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][C:26]=1[O:37][CH3:38].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:18][C:19]([N:34]3[CH2:33][CH2:32][N:31]([C:28]4[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([O:37][CH3:38])[CH:27]=4)[CH2:36][CH2:35]3)=[O:21])[N:11]=[C:12]([C:13]3[NH:17][CH:16]=[CH:15][N:14]=3)[C:5]=12
Reactant: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Reactant: COc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4c(N)ncnc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
[4-Amino-3-(1H-imidazol-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid dihydrochloride (79 g, 0.238 mol) and 1-(4-chloro-3-methoxyphenyl)piperazine dihydrochloride (71.3 g, 0.238 mol) were suspended in anhydrous DMF (793 mL) and cooled in an ice bath. N,N-diisopropylethylamine (290 mL, 1.67 mol) was added and the mixture was stirred at room temperature until all solids dissolved to form a brown solution. HCTU (113.23 g, 0.273 mol) was added in portions over 10 min while maintaining the internal temperature below 20° C. After 3 h, the reaction mixture was poured slowly into a flask of vigorously stirred ice water (6 L) to give a suspension, which was stirred for 1 h, filtered, and washed with saturated NaHCO3 (500 mL×2) and water (500 mL×2). The solid was purified by trituration in refluxing MeCN (2×500 mL) to provide 2-[4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]ethanone (90.5 g, 81% yield, >98% pure by LC-MS). 1H NMR (400 MHz, d6-DMSO) δ 13.0 (s, 1H), 10.14 (d, 1H, J=3.7 Hz), 8.16 (s, 1H), 7.95 (d, 1H, d, J=3.7 Hz), 7.25 (dd, 1H, J=1.03 and 1.36 Hz), 7.20 (d, 1H, J=8.8 Hz), 7.16 (s, 1H), 6.70 (d, 1H, J=2.4 Hz), 6.52 (dd, 1H, J=2.4 and 8.8 Hz), 5.37 (s, 2H), 3.83 (s, 3H), 3.74 (t, 2H, J=4.8 Hz), 3.58 (t, 2H, J=4.8 Hz), 3.28 (t, 2H, J=4.8 Hz), 3.17 (t, 2H, J=4.8 Hz). 13C NMR (100.6 MHz, d6-DMSO) δ 165.3, 159.0, 157.3, 155.7, 155.5, 151.6, 141.2, 136.6, 130.3, 128.7, 119.0, 111.9, 109.0, 101.9, 98.0, 56.7, 49.4, 48.9, 48.8, 44.7, 42.1; IR (KBr) 3219, 2937, 1682, 1638, 1594, 1567 cm−1; MS (ES) m/z 468.1 (M+H+). Anal. Calcd for C21H22N9O2Cl-0.85 H2O: C, 52.20; H, 4.94; N, 26.09; Cl, 7.34. Found: C, 51.92; H, 4.68; N, 26.44; Cl, 7.18.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([S:22][C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
2,4-Dichloropyrdine (4.44 g, 30.0 mmol) and potassium carbonate (8.28 g, 60.0 mmol) in dimethylformamide (60 mL) was purged with nitrogen for 10 min. 4-Aminothiophenol (3.76 g, 30.0 mmol) was added and the mixture stirred under nitrogen at room temperature for 18 h. Water (300 mL) was added and the slurry stirred for 30 min. The resulting solid was filtered, washed with water and vacuum dried at room temperature. Recrystallization from ethyl acetate (35 mL), filtered hot, then cooled gave 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine (3.946 g, 56% yield).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[Cl:23][C:24]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][CH2:28][O:29]2>>[Cl:23][C:24]1[C:33]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:3]=2)=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][CH2:28][O:29]2
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: CC1(C)OB(c2ccc3c(c2Cl)CCCO3)OC1(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc2c(c1Cl)CCCO2

Procedure:
This compound is prepared according to general method E starting from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate and 2-(5-chlorochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: O.[CH2:2]=[CH:3][CH3:4].CCC.[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH:3]([CH3:4])[CH3:2])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccccc1
Reactant: C=CC
Solvent: CCC
Solvent: O
Product: CC(C)c1ccccc1

Procedure:
The first alkylation reactor effluent stream enters a heat exchanger 22, where the first alkylation reactor effluent stream is cooled by exchanging heat indirectly with another stream in the process or with boiler feed water to produce low pressure steam. The cooled first alkylation reactor effluent stream passes through a line 24 and is admixed with another stream containing propylene and propane that enters the process in a line 28. This produces a second alkylation reactor feed stream carried by a line 26. The second alkylation reactor feed stream may be heated in a heat exchanger or a heater, which is not shown, and enters a second alkylation reactor 30. The second alkylation reactor feed stream contacts a beta zeolite catalyst maintained at alkylation conditions to alkylate benzene with propylene to produce cumene. The second alkylation reactor effluent stream, which contains benzene, cumene, DIPB, heavier alkylated hydrocarbons, and water, exits the second alkylation reactor 30 in a line 32. The second alkylation reactor effluent stream may be depressured by passing through a pressure control valve which is not shown, may be heated in a heater or heat exchanger which is also not shown, or both. The second alkylation reactor effluent stream then enters a stripping column 40 at a feed point above the top tray of the stripping column 40.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([O:28][CH3:29])[C:23]([O:26][CH3:27])=[CH:24][CH:25]=1.O>CN1CCCC1=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1OC
Reactant: Oc1ccc2nc(Cl)n(Cc3ccccc3)c2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(Nc2nc3ccc(O)cc3n2Cc2ccccc2)cc1OC
Temperature: 150 °C
Yield: 38.9 %

Procedure:
A mixture of 3-benzyl-2-chloro-3H-benzoimidazol-5-ol (250 mg) and 4-amino veratrole (296 mg) in N-methylpyrrolidinone (3 ml) was heated at 150° C. in a sealed tube for 4 hours then allowed to cool. The reaction mixture was then poured into water (30 ml) and extracted three times with ethyl acetate (30 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5, v/v) to give 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-ol (141 mg) as a yellow solid. Mass spectrum: 376 [M+H]+ retention time: 3.44 minutes.
Reaction SMILES: [NH3:1].[CH2:2]([OH:4])[CH3:3].[CH2:5]1[CH2:9]O[CH2:7][CH2:6]1>>[NH2:1][CH2:3][CH:2]([C:5]1[CH:9]=[CH:9][C:5]([C:6]2[CH:7]=[CH:6][CH:5]=[CH:9][CH:7]=2)=[CH:7][CH:6]=1)[OH:4]
Reactant: CCO
Reactant: C1CCOC1
Reactant: N
Product: NCC(O)c1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
The product mixture obtained in a) above was dissolved in THF (ca 100 mL) and a large excess of concentrated ammonia and ethanol was added to give a homogeneous system. TLC analysis after 4 hours showed only starting materials. A slight increase in temperature gave scarce improvement and the mixture was finally heated to 70° C. in a sealed vessel for 20 hours. TLC analysis showed absence of starting materials and NMR analysis showed a complex mixture of products. The solvents were evaporated and dichloromethane (150 mL) was added to give a precipitate. The mixture was filtered and the solid, about 3.8 g, and filtrate was analysed with TLC and NMR. Analyses showed mixtures of products but with, possibly, expected product in the solid phase. A sample of the solid (1.04 g) was purified by silica gel chromatography (200 mL) using dichloromethane/methanol/concentrated ammonia (90+10+1) as eluant. Evaporation of pure fractions gave 0.62 g of the sub-titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH2:19]OS(C1C(C)=CC(C)=CC=1C)(=O)=O.[C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:36])[C:34]#[CH:35].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:4]([N:19]=[CH:35][C:34]=2[C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COC(=O)c1cc(Cl)cnc1-c1cccc(F)c1
Reactant: C#CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c2c(C(=O)OC(C)(C)C)cnn2c1-c1cccc(F)c1
Reaction time: 24 h
Yield: 30.2 %

Procedure:
The methyl 5-chloro-2-(3-fluorophenyl)nicotinate (1.00 g, 3.76 mmol) was combined with freshly prepared 2-[(aminooxy)sulfonyl]-1,3,5-trimethylbenzene (0.972 g, 4.52 mmol) ether solution in acetonitrile (20.0 mL) at room temperature. The reaction was stirred for 24 hours and became a tan colored slurry. The slurry was added portion wise to a vigorously stirring suspension of tert-butyl propiolate (1.55 mL, 11.3 mmol), N,N-dimethylformamide (20.0 mL, 258 mmol) and potassium carbonate (2.60 g, 18.8 mmol) open to the air. After stirring for 15 minutes, the reaction was a dark red brown suspension. This was allowed to stir for 5 hours at room temperature. The reaction was taken up in ethyl acetate and decanted from the solids. The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as a reddish brown oil. The product was purified on silica gel eluting hexane:ethyl acetate gradient to give 3-tert-butyl 6-methyl 4-chloro-7-(3-fluorophenyl)pyrazolo[1,5-a]pyridine-3,6-dicarboxylate (0.46 g, 30%) as a semi-solid residue. LCMS calculated for C20H19ClFN2O4 (M+H)+: m/z=405.1. found: 404.9.
Reaction SMILES: CC1(C)CCCC(C)(C)N1[Mg]Cl.[Cl-].[Li+].[N:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH:41]=[O:42]>C1COCC1.ClCCl>[OH:42][CH:41]([C:32]1[CH:33]=[CH:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=1)[C:23]1[CH:22]=[C:21]([C:18]2[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=2)[S:25][C:24]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1ccc(-c2ccncc2)s1
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1sc(-c2ccncc2)cc1C(O)c1ccc2ccccc2c1
Temperature: -25 °C
Yield: 49 %

Procedure:
A dry, nitrogen flushed flask, equipped with a stirbar and septum, was charged with 2,2,6,6-tetramethylpiperidinylmagnesium chloride.lithium chloride in tetrahydrofuran (1.0M, 1.21 mL, 1.21 mmol). The flask was cooled to −25° C. and a solution of ethyl 5-pyridin-4-ylthiophene-2-carboxylate (0.257 g, 1.10 mmol) in tetrahydrofuran (1.0 mL, 12 mmol) was added dropwise with stirring. The resulting dark reddish orange solution was stirred at −25° C. for 30 minutes. 2-Naphthalenecarboxaldehyde (0.172 g, 1.10 mmol) was then added dropwise (as a solution in 1.5 ml THF)— the reaction mixture became purple. The reaction was stirred at −25° for 5 minutes, then the cooling bath was removed and the reaction was allowed to warm to room temperature with stirring. An aliquot was removed from the reaction and quenched into sat. NH4Cl solution, then extracted with ethyl acetate. A LCMS of this extract indicated that all starting material had been consumed and that the major peak had correct mass for the desired product. The reaction was quenched by the slow dropwise addition of a saturated ammonium chloride solution (5 ml). The resulting yellow-orange mixture was transferred to a reparatory funnel and diluted further with water and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The extracts were combined, washed with saline, dried, and evaporated to leave crude product as an orange oil which was dissolved in minimal dichloromethane then was purified by column chromatography on silica gel (gradient 100% DCM to 5% MeOH in ethyl acetate) to afford product 210 mg (49% yield) as a white foam. LC/MS (FA) ES+ 390. 1H NMR (400 MHz, DMSO) δ 8.63-8.58 (dd, J=4.6, 1.6 Hz, 2H), 8.04-8.00 (s, 1H), 8.00-7.96 (s, 1H), 7.87-7.81 (d, J=8.7 Hz, 3H), 7.76-7.71 (dd, J=4.6, 1.7 Hz, 2H), 7.62-7.58 (d, J=1.6 Hz, 1H), 7.50-7.45 (t, J=3.0 Hz, 2H), 6.74-6.69 (d, J=4.2 Hz, 1H), 6.33-6.28 (d, J=4.2 Hz, 1H), 4.37-4.31 (dd, J=7.1, 4.3 Hz, 2H), 1.35-1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][C:30]=2[C:36]([F:39])([F:38])[F:37])[CH2:24][CH2:23]1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]2)=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)=[O:20]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 16.1) and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 542.9 [M+H]+; single peak at tR=3.31 min (System 1); Rf=0.16 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([CH3:26])[N:20]=1>>[Cl:25][C:24]1[C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)=[N:20][C:21]([CH3:26])=[N:22][CH:23]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ncc(Cl)c(N)n1
Product: Cc1ncc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 4-amino-5-chloro-2-methylpyrimidine (42 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.58 (d, J=1.5 Hz, 1H), 8.72-8.65 (m, 2H), 7.42 (dd, J=6, 5.1 Hz, 1H), 6.70 (s, 1H), 5.32 (s, 2H), 1.70 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C1CC(NCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, dissolved in DCM and cooled to 0 centigrade is added a corresponding benzaldehyde, then NaBH(OAc)3 and 5 drops of HOAc. The mixture is warmed to room temperature and stirred overnight. The mixture is diluted with DCM, washed with brine, and dried. After removal of solvent, the crude 4-(benzylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester is obtained (33) and used for the next step without further purification.