Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:18]=[C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:16]3=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCn1nc2cccc(C)c2n1
Reactant: FCc1cccc(Br)n1
Product: Cc1cccc2nn(CCC#Cc3cccc(CF)n3)nc12
Yield: 62.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (73 mg, 0.39 mmol) and 2-but-3-ynyl-4-methyl-2H-benzo[d][1,2,3]triazole (65 mg, 0.35 mmol, 163(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 65 mg (0.22 mmol, 63%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-4-methyl-2H-benzo[d][1,2,3]triazole as a yellow semi-solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([O:21][CH2:22][C:23]([NH:25][NH2:26])=[O:24])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)[CH:29]=[O:30].C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([O:21][CH2:22][C:23]3[O:24][C:29](=[O:30])[NH:26][N:25]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc3ncccc3c(OCC(=O)NN)n2)cc1OC
Reactant: CN(C)C=O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3ncccc3c(OCc3n[nH]c(=O)o3)n2)cc1OC
Temperature: 70 °C

Procedure:
54 mg [7-(3,4-Dimethoxy-phenyl)-[1,6]-naphthyridine-5-yloxy]-acetic acid hydrazide (I.34) was placed in tetrahydrofuran (10 mL) and N,N-dimethyl formamide (1 mL) at ambient temperature before 37 mg carbonyl diimidazole and 43 μl triethylamine were added. The reaction mixture was heated to 70° C. where it was maintained for 16 h. After this time additional carbonyl diimidazole and triethylamine were added and the reaction was maintained at 70° C. for a further 5 h. After this time additional carbonyl diimidazole and triethylamine were added and the reaction was maintained at 70° C. for a further 19 h. The solvent was then removed under reduced pressure and the crude product that remained was partitioned between dichloromethane and water. The dichloromethane layer was separated and the aqueous phase was extracted with additional dichloromethane (×2). The combined organic fractions were washed with water, saturated sodium chloride solution and then dried over sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification twice by chromatography on silica gel (methanol/ethyl acetate: 0%-5% and then methanol/ethyl acetate: 0%-2%) followed by trituration with dichloromethane provided the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Li]CCCC.C(OC([N:21]1[CH2:26][CH2:25][C:24]2([CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH2:23][CH2:22]1)=O)(C)(C)C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH2:30][CH2:31][C:24]3([CH2:25][CH2:26][NH:21][CH2:22][CH2:23]3)[CH2:27][CH:28]=2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ccc(C2=CCC3(CCNCC3)CC2)cc1
Reaction time: 0.5 h

Procedure:
Was prepared according to method A with the following variation: A solution of 4-bromochlorobenzene (1.15 g, 5.98 mmol) in THF (5 mL) was added drop-wise to a solution of n-BuLi (1.6 M in hexanes (4 mL, 6.4 mmol)) at −78° C. and stirred for 30 min. A solution of 9-oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (500 mg, 1.87 mmol) in THF (5 mL) was added. The mixture was stirred for 1 h. White solid Mp. 104.2-107.1° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[CH3:25][N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH2:36])[CH:34]=2)[CH2:29][CH2:28][CH2:27]1>CS(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:36][C:33]3[CH:34]=[C:35]4[C:30]([CH2:29][CH2:28][CH2:27][N:26]4[CH3:25])=[CH:31][CH:32]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: CN1CCCc2ccc(N)cc21
Solvent: CS(C)=O
Solvent: CO
Product: CN1CCCc2ccc(Nc3ncc4c(=O)n(-c5ccccc5Cl)c5nccn5c4n3)cc21

Procedure:
A mixture of Example 1E (60.0 mg, 0.167 mmol) and 1-methyl-1,2,3,4-tetrahydroquinolin-7-amine (48.7 mg, 0.300 mmol) was heated in a capped vial at 90° C. for 1 hour. After cooling, the residue was treated with dimethylsulfoxide/methanol (2 mL). The precipitate was filtered, washed with methanol and water, and oven-dried to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77-1.99 (m, 2H), 2.69 (t, J=6.26 Hz, 2H), 2.90 (s, 3H), 3.11-3.28 (m, 2H), 6.92 (d, J=7.93 Hz, 1H), 7.02 (d, J=7.32 Hz, 1H), 7.07 (s, 1H), 7.18 (s, 1H), 7.50-7.65 (m, 3H), 7.69-7.74 (m, 2H), 9.09 (s, 1H), 10.53 (s, 1H). MS (ESI+) m/z 458.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:38]1[CH:52]=[CH:51][C:41]([CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])=[CH:40][C:39]=1[F:53]>>[CH2:1]([O:8][C:9]1[C:10]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:38]4[CH:52]=[CH:51][C:41]([CH2:42][O:43][Si:44]([C:47]([CH3:49])([CH3:48])[CH3:50])([CH3:45])[CH3:46])=[CH:40][C:39]=4[F:53])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(CC2CCN(c3ccc(Br)cc3)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(Br)c(F)c1
Product: Cc1nc(CC2CCN(c3ccc(-c4ccc(CO[Si](C)(C)C(C)(C)C)cc4F)cc3)CC2)nc(C(=O)OC(C)(C)C)c1OCc1ccccc1
Yield: 16 %

Procedure:
In accordance with Example 19-(2), but using tert-butyl 5-(benzyloxy)-2-{[1-(4-bromophenyl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate instead of tert-butyl 5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate, and [(4-bromo-3-fluorobenzyl)oxy](tert-butyl)dimethylsilane instead of tert-butyl[(4-iodobenzyl)oxy]dimethylsilane, the title compound (yield 16%) was afforded as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[OH:33])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)([OH:33])[CH:34]2[CH2:35][CH2:36][N:37]([C:14](=[O:15])[CH2:13][N:10]3[CH2:11][CH2:12][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[C:9]3=[O:17])[CH2:38][CH2:39]2)=[CH:28][CH:27]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
A mixture of the product of Example 58D (171 mg, 0.518 mmol), the product of Example 32A (157 mg, 0.518 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (197 mg, 0.518 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.361 mL, 2.07 mmol) in CH2Cl2 (5 mL) was stirred at ambient temperature for 36 hours. The reaction mixture was diluted by CH2Cl2, and the organic mixture was washed with 1 N aqueous HCl and saturated NaHCO3 solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 50% ethyl acetate/hexanes) to afford purified material that was taken up in a minimal amount of ether. Addition of hexanes caused formation of a solid that was collected by vacuum filtration and air-dried to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.59-7.47 (m, 4H), 7.40-7.29 (m, 4H), 7.18-7.04 (m, 8H), 5.48 (s, 1H), 4.41-4.29 (m, 1H), 4.19 (d, J=16.5, 1H), 4.09 (d, J=16.6, 1H), 3.86-3.75 (m, 1H), 3.38-3.30 (m, 2H), 3.05-2.89 (m, 1H), 2.85-2.63 (m, 3H), 2.63-2.51 (m, 1H), 1.40-1.17 (m, 4H); MS (DCI+) m/z 617 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:19][NH:20][CH3:21].C1COCC1>CN(C=O)C.CCOC(C)=O>[CH3:19][N:20]([CH3:21])[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)nc2)c2ccccc12
Reactant: CNC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)c1ccc(-c2n[nH]c(=O)c3ccccc23)cn1

Procedure:
A mixture of the product from Example 4A (0.296 g, 1.15 mmol) and a solution of dimethylamine in THF (2 M, 2.3 mL, 4.6 mmol) in DMF (2 mL) was microwaved at 200° C. for 30 minutes, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, and concentrated to give 0.25 g of crude 4-(6-(dimethylamino)pyridin-3-yl)phthalazin-1(2H)-one, which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH:24]=O.C(O)(=O)C(O)=O.[CH2:33]([O:35][P:36]([CH2:41][CH2:42][NH2:43])(=[O:40])[O:37][CH2:38][CH3:39])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C>[CH2:38]([O:37][P:36]([CH2:41][CH2:42][NH:43][CH2:24][C:23]([CH3:26])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1])[CH2:9][O:8][C:7]2=[O:13])(=[O:40])[O:35][CH2:33][CH3:34])[CH3:39]
Reactant: CCOP(=O)(CCN)OCC
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Reaction time: 48 h
Yield: 96.5 %

Procedure:
To a solution of 4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal (84 mg, 0.22 mmol), (2-amino-ethyl)-phosphonic acid diethyl ester oxalate (91 mg, 0.33 mmol), and sodium triacetoxyborohydride (93 mg, 0.44 mmol) in DMF (1.5 mL) was added acetic acid (60 μL, 1.0 mmol) at room temperature. The solution was stirred for 2 days when it was quenched by addition of saturated aqueous sodium bicarbonate solution and EtOAc. The organic layer was separated and concentrated under reduced pressure. The residue was purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 115 mg (96%) of the product as an oil. 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 1.16-1.27 (m, 2H), 1.34 (t, 6H, J=7 Hz), 1.94 (s, 3H), 2.18 (s, 3H), 2.20-2.31 (m, 2H), 3.13-3.31 (m, 2H), 3.48 (d, 2H, J=7 Hz), 3.54 (s, 2H), 3.78 (s, 3H), 4.14 (pent, 4H, J=7 Hz), 4.30-4.37 (m, 2H), 5.13 (s, 2H), 5.65 (t, 1H, J=7 Hz), 6.23 (br s, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 27.8 ppm; MS (m/z) 542.3 [M+H]+, 564.2 [M+Na]+.
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]=2[F:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.CN(C)C=O>O>[C:1]([C:5]1[CH:32]=[CH:31][C:8]([NH:9][C:10]2[CH:29]=[CH:28][C:13]([O:14][C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:41][CH2:42][N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[CH:12][C:11]=2[F:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCN1CCOCC1
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)c(F)c3)ccnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)c(F)c3)ccnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
4-{4-[4-(Tert-butyl)anilino]-3-fluorophenoxy}-6-methoxy-7-quinolinol (starting compound 6) (1.75 g), potassium carbonate (2.80 g), and 4-(2-chloroethyl)morpholine hydrochloride (1.13 g) were added to N,N-dimethylformamide (20 ml), and the mixture was stirred at 80° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and was dried over sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude thus obtained was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (1.44 g, yield 64%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]2[N:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]([C@@H:12]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)[CH3:13])=[N:11][C:7]=2[CH:6]=[CH:5][C:4]=1[F:36]>O1CCOCC1.CO>[Cl:2][C:3]1[C:8]2[N:9]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:10]([CH:12]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][NH:19]4)[CH3:13])=[N:11][C:7]=2[CH:6]=[CH:5][C:4]=1[F:36]
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Cl)c2n1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Cl)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
4N HCl in dioxane (0.5 mL) was added to a solution of [(S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (166 mg, 0.34 mmol) in MeOH (5 mL) and the mixture was stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting residue was purified by HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 10-90%, 0.1% HCO2H in acetonitrile/water) to afford 179 (96 mg, 69%). LCMS (Method K): RT 3.80 min [M+H]+ 408.0/409.9/411.08. 1H NMR (DMSO-d6, 400 MHz): δ 8.22-7.83 (3H, m), 7.69-7.34 (6H, m), 7.33-7.24 (1H, t, J=9.50 Hz), 5.25 (1H, s), 1.56 (3H, d, J=6.88 Hz)
Reaction SMILES: Cl.[CH:2]1([C@H:8]2[CH2:13][NH:12][CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[CH:23]=[C:22]([CH3:32])[N:21]=1.ClC1N=C(NC2NN=CC=2)C=C(C)N=1>>[CH:2]1([C@H:8]2[CH2:13][N:12]([C:20]3[N:21]=[C:22]([CH3:32])[CH:23]=[C:24]([NH:26][C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[N:25]=3)[CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)C[C@@H]1CNC[C@H](C2CCCCC2)C1
Reactant: Cc1cc(Nc2nccs2)nc(Cl)n1
Agent: Cc1cc(Nc2ccn[nH]2)nc(Cl)n1
Agent: Cl
Product: COC(=O)C[C@H]1C[C@@H](C2CCCCC2)CN(c2nc(C)cc(Nc3nccs3)n2)C1

Procedure:
The title compound was prepared by the similar manner described in Example 1 using methyl (cis-5-cyclohexylpiperidine-3-yl)acetate hydrochloride prepared in Step 3 of Example 22 instead of (S)-3-(tert-butoxycarbonylamino)piperidine, and 2-chloro-6-methyl-N-(1,3-thiazol-2-yl)pyrimidin-4-amine prepared in Referential Example 3 instead of 2-chloro-6-methyl-N-(1H-pyrazol-5-yl)pyrimidin-4-amine.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([NH:11][C:12](=[O:24])[NH:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][C:15]=2[O:22][CH3:23])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(N=C=O)C=CC=CC=1.CCCCCCC>ClCCl>[C:5]1([NH:11][C:12](=[O:24])[NH:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][Cl:3])=[CH:16][C:15]=2[O:22][CH3:23])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1cc(CO)ccc1NC(=O)Nc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: O=C=Nc1ccccc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: COc1cc(CCl)ccc1NC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.55 mL (103.4 mmol) of thionyl chloride were added dropwise to a suspension of 14.07 g (51.7 mmol) of 4-(3-phenylureido)-3-methoxybenzyl alcohol (prepared as described in Example 1, phenyl isocyanate being employed instead of 2-methylphenyl isocyanate) in 200 mL of dichloromethane. The mixture then was stirred at room temperature for 2 hours, allowed to stand overnight and poured onto 800 mL of heptane. The heptane was decanted off from the separated oil, the residue was suspended several times in heptane and in each case the heptane was decanted off. The residue was dissolved in 100 mL of dichloromethane and added dropwise to 800 mL of diisopropyl ether. The mixture was stirred for 1 hour with ice cooling, and the product was filtered off with suction, washed with diisopropyl ether and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[C:13]([NH:29][C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1cnccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (165 mg, 0.48 mmol) in methylene chloride (12 mL) and N,N-dimethylformamide (1 drop) cooled to 0° C. was treated dropwise with a 2.OM solution of oxalyl chloride in methylene chloride (0.27 mL, 0.55 mmol). The reaction was stirred at 0° C. for 30 min. At this time, the reaction was concentrated in vacuo to yield a light yellow oil. This oil was dissolved in tetrahydrofuran (5 mL) and then treated with a solution of 2-aminopyrazine (91 mg, 0.95 mmol) dissolved in tetrahydrofuran (10 mL) and pyridine (0.19 mL, 2.4 mmol). The reaction was then stirred at 25° C. for 16 h. At this time, the reaction was diluted with water (15 mL) and extracted with methylene chloride 3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 25/75 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-pyrazin-2-yl-3-(tetrahydro-pyran-4-yl)-propionamide (100 mg, 50%) as a white foam: (ES)+-HRMS m/e calcd for C19H22ClN3O4S (M+H)+ 424.1093. found 424.1095.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:21][C:20]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)=[O:23])=[C:19]([CH3:33])[CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:21][C:20]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[O:23])=[C:19]([CH3:33])[CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1cc(Br)sc1C(=O)NCc1cccc(F)c1
Product: Cc1cc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cccc(F)c1
Yield: 45 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 5-bromo-N-(3-fluorobenzyl)-3-methylthiophene-2-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 45% yield: mp 140-141° C.; 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=7.8 Hz, 1H), 7.43-7.27 (m, 6H), 7.11 (d, J=7.8 Hz, 1H), 7.04 (d, J=9.6 Hz, 1H), 7.00-6.92 (m, 1H), 6.84 (s, 1H), 6.29 (t, J=5.7 Hz, 1H), 6.14 (dd, J=7.8, 2.7 Hz, 1H), 6.05 (d, J=2.7 Hz, 1H), 5.02 (s, 2H), 4.58 (d, J=5.7 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 164.6, 163.0, 163.0 (d, JC-F=246.6 Hz), 162.2, 161.3, 140.7 (d, JC-F=7.0 Hz), 139.9, 139.7, 134.7, 134.4, 130.2 (d, JC-F=8.2 Hz), 128.8, 128.7, 127.8, 126.7, 123.2 (d, JC-F=2.9 Hz), 121.9, 114.6 (d, JC-F=15.2 Hz), 114.3 (d, JC-F=14.4 Hz), 103.4, 98.1, 70.6, 43.3, 15.9; MS (ES+) m/z 449.3 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:3]1=[O:17].C(N(CC)CC)C.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.ClCCl>[F:38][C:26]([F:25])([F:37])[C:27]1[CH:28]=[CH:29][C:30]([S:33]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=3)[C:3]2=[O:17])(=[O:35])=[O:34])=[CH:31][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C1[C@@H](O)CCN1c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1[C@@H](OS(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1c1ccc(C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
To a dichloromethane (10 mL) solution of (3S)-3-hydroxy-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one (691 mg, 2.82 mmol), triethylamine (589 μL, 4.23 mmol), and 4-(dimethylamino)pyridine (69 mg, 0.56 mmol) at 0° C. was added a dichloromethane (10 mL) solution of 4-(trifluoromethyl)benzenesulfonyl chloride (827 mg, 3.38 mmol) dropwise. After stirring for 3 hours, the mixture was partitioned between diethyl ether (100 mL) and water (100 mL). The organic layer was washed with brine (2×100 mL), dried (magnesium sulfate) and concentrated to give the title compound, which was subjected to the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=7.9 Hz, 2H), 7.85 (d, J=7.4 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 5.25 (t, J=8.0 Hz, 1H), 3.98-3.93 (m, 1H), 3.85-3.81 (m, 1H), 2.81-2.75 (m, 1H), 2.49-2.43 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][C:7](=[O:20])[C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16](N)=[O:17])[CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[OH-:23].[K+].O.Cl>CCCCCC.CO.O1CCCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][C:7](=[O:20])[C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([OH:23])=[O:17])[CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1ccc(Cl)cc1S2
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1ccc(Cl)cc1S2
Temperature: 0 °C
Yield: 45.4 %

Procedure:
A mixture of 0.2 g of 2-(7-chloro-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 10 g of potassium hydroxide, 60 ml of water, 20 ml of tetrahydrofuran and 200 ml of methanol was refluxed for 5 hours. The solvent was removed by distillation to obtain a residue, to which was added ice water, and the mixture was acidified with hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, which was chromatographed over silica gel and eluted with chloroform/benzene (3/1), thereby obtaining a solid substance. This was recrystallized from benzene--n-hexane to give 91 mg (yield: 45%) of 2-(7-chloro-10,11-dihydro-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as light yellow granular crystals having a melting point of 142°-143° C.