Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]1([CH3:35])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[C:18]1[C:19]([CH3:34])=[N:20][N:21]2[C:26](=O)[C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:24]([CH3:33])[NH:23][C:22]=12.P(Cl)(Cl)([Cl:38])=O>>[Cl:38][C:26]1[N:21]2[N:20]=[C:19]([CH3:34])[C:18]([C:11]3[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=3[CH3:35])=[C:22]2[N:23]=[C:24]([CH3:33])[C:25]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Yield: 61.4 %

Procedure:
Five droplets of N,N-dimethylaniline was added to a solution of ethyl 3-mesityl-2,5-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-carboxylate (3 g, 8.49 mmol) in phosphorus oxychloride (80 g), followed by heating under reflux for four hours. The reaction mixture was added to ice and stirred for a while. Then, the mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous saturated solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (15-30% ethyl acetate/hexane), to give the title compound (1.94 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][C:5]([F:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[Cu]I.[Cu]>[Cl:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:28][C:2]1[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][C:5]([F:20])=[CH:4][N:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=C(c1cc(F)cnc1Cl)N1CCCc2ccccc21
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: O=C(c1cc(F)cnc1Oc1cccc(Cl)c1)N1CCCc2ccccc21
Temperature: 200 °C
Yield: 6.2 %

Procedure:
To a solution of (2-chloro-5-fluoro-pyridin-3-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone (53.2 mg, 0.18 mmol, 1.0 equiv) and 3-chloro-phenol (23.5 mg, 0.18 mmol, 1.0 equiv; [CAS RN 108-43-0]) in acetonitrile (1 mL) was added potassium carbonate (50.7 mg, 0.37 mmol, 2.0 equiv; [CAS RN 584-08-7]), copper(I) iodide (3.5 mg, 0.018 mmol, 0.1 equiv; [CAS RN 7681-65-4]) and copper(0) nanopowder with an averaged particle size of 100 nm (3.5 mg, 0.055 mmol, 0.3 equiv; [CAS RN 7440-50-8]). The reaction mixture was heated by microwave irradiation to 200° C. for 90 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 4.3 mg (6%) of the title compound. MS (ISP): 383.2 [M+H]+.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][C:35]3[N:40]=[C:39]([NH2:41])[C:38](N)=[CH:37][CH:36]=3)[CH2:28][CH2:27]2)=[CH:11][CH:10]=1>C(O)(=O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][NH:34][C:35]3[N:40]=[C:39]4[N:41]=[C:2]([CH3:3])[NH:7][C:38]4=[CH:37][CH:36]=3)[CH2:28][CH2:27]2)=[CH:13][CH:14]=1
Reactant: Nc1ccc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)nc1N
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc2nc(NCCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
A mixture of 5 parts of ethyl ethanimidate hydrochloride, 9 parts of N6 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]-amino]-1-piperidinyl]ethyl]-2,3,6-pyridinetriamine and 100 parts of acetic acid was stirred overnight at room temperature. The reaction mixture was evaporated. The residue was dissolved in trichloromethane. Water was added and sodium hydrogen carbonate was added till foaming had ceased. The layers were separated. The organic layer was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 4.8 parts (48.5%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-methyl-1H-imidazo[4,5-b]pyridin-5-amine; mp. 202.0° C. (compound 146).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:35][CH2:2][CH2:3][CH2:4][CH:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6]
Reactant: BrC(Br)(Br)Br
Reactant: CC(CCCO)NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(CCCBr)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
To an ice-cold solution of tert-butyl (5-hydroxypentan-2-yl)carbamate (3.6 g, 17.71 mmol) in dichloromethane (150 mL) was added triphenylphosphine (6.97 g, 26.6 mmol) followed by carbon tetrabromide (8.81 g, 26.6 mmol). The reaction mixture was stirred at room temperature for 18 h while monitoring by TLC. The solvent was removed under reduced pressure and the residue was purified by column chromatography (60-120 mesh silica) using 2-5% ethyl acetate in pet-ether to give tert-butyl (5-bromopentan-2-yl)carbamate (2.5 g, 53%) as a light brown liquid. 1H NMR: (400 MHz, CDCl3) δ ppm 4.29 (1H, br s), 3.68 (1H, br s), 3.42 (2H, t, J=6.8 Hz), 1.94-1.86 (2H, m), 1.59-1.46 (2H, m), 1.44 (9H, s), 1.13 (3H, d, J=6.4 Hz).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH2:12][CH3:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][C:18]2[NH:19][C:20](=[O:22])[S:21][C:17]=2[CH:16]=1>>[CH2:12]([C:9]1[NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:14][C:15]3[C:24]([O:25][CH3:26])=[CH:23][C:18]4[NH:19][C:20](=[O:22])[S:21][C:17]=4[CH:16]=3)[C:3]=2[C:10]=1[CH3:11])[CH3:13]
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Reactant: CCc1[nH]c2ncnc(Cl)c2c1C
Product: CCc1[nH]c2ncnc(Nc3cc4sc(=O)[nH]c4cc3OC)c2c1C

Procedure:
25 mg (128 μmol) 4-Chloro-6-ethyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (prepared according to intermediate example 1a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 22.3 mg (47%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:29][C:30]1[CH:35]=[C:34]([C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[C:5]([NH:11][C:12]3[CH:27]=[CH:26][C:15]([C:16]([NH:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[O:17])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)[CH:33]=[CH:32][N:31]=1
Reactant: COc1cc(B(O)O)ccn1
Reactant: O=C(NCc1cccnc1)c1ccc(Nc2ccc(Cl)n3ncnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2ccc(Nc3ccc(C(=O)NCc4cccnc4)cc3)c3ncnn23)ccn1
Temperature: 110 °C
Yield: 77.2 %

Procedure:
A suspension of 4-(5-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-N-pyridin-3-ylmethyl-benzamide (50 mg, 132 μmol), 2-methoxypyridin-4-boronic acid (40 mg, 260 μmol), Pd(PPh3)4 (46 mg, 40 μmol) and NaOtBu (51 mg, 530 μmol) in 1.2 mL of DMF/water (5:1, degassed) is degassed for 1 min in a sealed tube. The tube is sealed and the reaction mixture heated at 110° C. for five hours. After evaporation of the solvents, the residue is purified by flash chromatography (silica gel, dichloromethane/7N NH3 in methanol 97:3) affording the title compound (46 mg), which is isolated as a mixture containing 50% of product.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH:37]2[CH2:43]Cl)=[CH:32][CH:31]=1>C(O)(C)C.CO>[CH3:42][N:39]1[CH2:38][C@@H:37]([CH2:43][O:10][C:7]2[CH:8]=[CH:9][C:3]3[O:2][CH2:1][O:5][C:4]=3[CH:6]=2)[C@H:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CN1CCC(c2ccc(F)cc2)C(CCl)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: CN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc3c(c2)OCO3)C1
Yield: 75.6 %

Procedure:
Sesamol (4.32 g, 31.2 mmol) was added to a solution of tetrabutylammonium hydroxide in isopropanol/methanol (0.1N, 342 mL), and the solvents were evaporated under vacuum to dryness. The residual tetrabutylammonium salt of sesamol was dissolved in acetonitrile (40 mL) and 4-(4-fluorophenyl)-3-chloromethyl-N-methyl-piperidine (CIPMA) (7.5 g, 31.2 mmol) was added. The reaction mixture was stirred with heating at reflux for 4 hours. After cooling, the reaction mixture was evaporated to dryness in vacuum and the residue was dissolved in toluene. The toluene solution was washed with 5% aq. sodium hydroxide and then with water. After drying with sodium sulfate and evaporation of the solvent in vacuum, N-methylparoxetine (8.1 grams) was obtained with yield 76%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[O:14][C@@H:13]([CH2:15][OH:16])[C:12]([CH3:18])([CH3:17])[CH2:11][O:10]2)=[CH:5][CH:4]=1.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>C(Cl)Cl>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:16][CH2:15][C@H:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][O:10][C@@H:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[O:14]2)=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: COc1ccc([C@@H]2OCC(C)(C)[C@H](CO)O2)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: COc1ccc([C@@H]2OCC(C)(C)[C@H](COC(=O)c3ccc([N+](=O)[O-])cc3)O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of compound obtained in Step B (3.59 g, 14.24 mmol) and TEA (1.98 ml, 14.24 mmol) in DCM (50 ml), 4-Nitrobenzoyl chloride (2.64 g, 14.24 mmol) was added and the reaction was stirred overnight at r.t. The organic phase was washed with a solution of NaH2PO4 5% and brine, dried (MgSO4) and evaporated under reduced pressure. The crude was crystallized from EtOAc at 0° C. adding n-hexane. The product was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.Cl.[NH2:20][CH2:21][C:22]([NH2:24])=[O:23].[OH-].[Na+].Cl.C(=O)(O)[O-].[K+]>O.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:20]=[CH:21][C:22]([OH:23])=[N:24][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2ncc(O)nc2-c2ccc(C)cc2)cc1

Procedure:
First, 5.5 g (23 mmol) of 4,4′-dimethylbenzil, 3.1 g (28 mmol) of glycinamide hydrochloride, 2.2 g (55 mmol) of sodium hydroxide, and 120 mL of methanol were put into a three-neck flask equipped with a reflux pipe, the air in the flask was replaced with nitrogen, and the mixture was refluxed for 8.5 hours. Then, stirring was performed until the temperature of the flask was returned to room temperature. After that, 3 mL of 12 M concentrated hydrochloric acid, 2.3 g of potassium bicarbonate, and 58 mL of water were added to this mixture, and filtration was performed.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:28][C@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([OH:29])[CH2:6]1)=[N+]=[N-].[H][H]>[Pd].O1CCCC1>[NH2:1][CH2:4][C@H:5]1[O:28][C@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:7]([OH:29])[CH2:6]1
Reactant: [H][H]
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CN=[N+]=[N-])C[C@H]1O)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CN)C[C@@H]1O)(c1ccccc1)c1ccccc1
Yield: 96 %

Procedure:
A slurry of 3.78 g of product from Example 276, 0.562 g of 10% palladium on carbon and 50 ml of tetrahydrofuran is hydrogenated under a balloon of hydrogen for 1 hour. The reaction mixture is filtered and the filtrate is concentrated in vacuo to give 3.4 g of the desired product.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=3[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[NH:57]1[CH:61]=[CH:60][CH:59]=[C:58]1[C:62]([OH:64])=O>>[NH:57]1[CH:61]=[CH:60][CH:59]=[C:58]1[C:62]([NH:18][C@H:19]([C:44]([NH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:64]
Reactant: O=C(O)c1ccc[nH]1
Reactant: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)c1
Product: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)c2ccc[nH]2)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-2,5-dimethoxyaniline (988 mg, 1.33 mmol, example 82, step A) as described for example 82 (step B) using pyrrole-2-carboxylic acid (222 mg, 2.0 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using successively 10%, 15% and 20% EtOAc/CH2Cl2. The title compound was obtained as white crystals (497 mg, 61%).
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:40])[C:22]=1[N:23]1[CH2:29][C:28]([F:31])([F:30])[CH2:27][CH:26]([NH:32]C(=O)OC(C)(C)C)[CH2:25][CH2:24]1)=[O:16])=O)(C)(C)C.[F:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46]([F:61])[C:47]=1[Sn](CCCC)(CCCC)CCCC>>[NH2:8][C:9]1[S:13][C:12]([C:47]2[C:46]([F:61])=[CH:45][N:44]=[CH:43][C:42]=2[F:41])=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:40])[C:22]=1[N:23]1[CH2:24][CH2:25][CH:26]([NH2:32])[CH2:27][C:28]([F:30])([F:31])[CH2:29]1)=[O:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cncc3F)sc2N)c1N1CCC(N)CC(F)(F)C1
Yield: 43 %

Procedure:
Following the procedure for Example 422 starting from tert-butyl 1-(4-(5-(tert-butoxycarbonyl-amino)-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6,6-difluoroazepan-4-ylcarbamate and 3,5-difluoro-4-(tributylstannyl)pyridine gave 438 as a white solid (68 mg, 43% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.83 (s, 1H), 8.67 (s, 2H), 7.78 (s, 2H), 7.61-7.56 (m, 1H), 3.79-3.56 (m, 4H), 3.46-3.33 (m, 1H), 3.37-3.16 (m, 2H), 3.16-3.06 (m, 1H), 2.35-2.08 (m, 2H), 1.91-1.78 (m, 1H), 1.81-1.60 (m, 3H). LCMS (ES+) m/z 485 (M+1)
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([CH3:23])=[CH:8]2)=[O:4].[NH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:24])[C:5]([C:3]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([CH3:23])[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cc1cc2c(O)c(C(=O)NCCC(=O)O)ncc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Yield: 33.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (36 mg, 0.11 mmol), β-alanine (990 mg, 11 mmol) and NaOMe solution (16.6 mL, 8.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 1 with 1 M HCl, and the resulting precipitate was isolated by filtration and dried to give 14 mg of the title compound as a pale yellow solid. MS: (+) m/z 382.22 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]([C:9]2[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>O>[C:22]([O:15][C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:8])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccccc1C(=O)c1ccccc1

Procedure:
1 g. (0.005 mole) of O-hydroxybenzophenone was warmed in 25 mls of dry pyridine containing 1 g (0.01 mole) of pivaloyl chloride for 3 hrs. at 50° C. Poured into H2O containing 2 g of Na2CO3 and extracted with EtOAc+Et2O and washed with H2O. After drying over Na2SO4 and filtration, the product was isolated by evaporation of the solvent. Oily material. 1.2 g. (85%) yield.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[OH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[OH:31][C:32]1[CH:37]=[C:36]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OB(O)c1cccc(O)c1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cccc(O)c1
Yield: 35 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 3-hydroxyphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as an off-white solid (35% yield); 1H-NMR (d6-DMSO) 1.08 (9H, s), 3.65 (2H, t), 4.07 (2H, t), 6.34 (1H, s), 6.58-6.63 (3H, m), 7.06 (1H, m), 9.23 (1H, s); MS ES(+) 222.1 (M+-tBu); Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C, 64.77; H, 7.08; N, 4.85. IR λmax=3365, 1666 cm−1.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[C:14]([O-])(O)=O.[Na+]>CO>[CH3:14][O:5][C:4](=[O:6])[CH:3]([OH:2])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])O
Reactant: O=C(O)C(O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Hydrogen chloride was bubbled for 15 minutes into a solution of 2-hydroxy-3-phenyl-propionic acid (10.0 g, 60 mmol) in 100 mL of methanol at room temperature. The vessel was sealed and then stirred overnight at room temperature. The reaction was made basic by the addition of 5% NaHCO3 and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water and extracted with ethyl acetate. The organic layer was extracted with saturated NaCl, dried (MgSO4) and the solvent removed under reduced pressure to give 2-hydroxy-3-phenyl-propionic acid methyl ester (9.7 g, 90%) as a yellow oil, MS m/z 180 [M]+. Elemental Analysis for C10H12O3. Calc'd: C, 66.65; H, 6.71; N, 0.00. Found: C, 66.52; H, 6.86; N, 0.29
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=O)[CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:38]([F:41])([F:40])[F:39])([O-:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:51])=CC=1>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[S:51])[CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:38]([F:41])([F:40])[F:39])([O-:3])=[O:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Product: O=[N+]([O-])c1ccc(NC2CCN(C(=S)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F

Procedure:
1-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butan-1-one (20 mg; 0.034 mmol, prepared in accordance with Example 165) is reacted with Lawesson's reagent (7 mg; 0.017 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (11 mg; 0.018 mmol). The structure was confirmed using Protocol I-B. Calculated mass=604; observed mass=604; HPLC retention time=4.64 min.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=1[CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>C(O)C.C1(C)C=CC=CC=1>[CH2:29]([O:28][P:24]([CH2:23][C:22]1[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=1[CH2:20][CH2:19][CH2:18][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O:25][CH2:26][CH3:27])=[O:31])[CH3:30]
Reactant: CCOP(=O)(Cc1ccccc1CCCBr)OCC
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCCc1ccccc1CP(=O)(OCC)OCC)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Yield: 42 %

Procedure:
To 0.48 g (21 mmol) of sodium in 50 mL of dry ethanol was added 4.56 g (21 mmol) of solid diethyl acetamidomalonate portionwise. This solution was stirred at reflux under nitrogen for 2 h. After cooling to room temperature the solvent was removed under reduced pressure yielding a tan solid. This solid was dried under vacuum about 2 h. The sodium salt of diethyl acetamidomalonate was then suspended in 50 mL of dry toluene and 9.0 g (21 mmol) of diethyl 2-(3-bromopropyl)benzylphosphonate in 25 mL of dry toluene was added dropwise. This solution was stirred at reflux under nitrogen for 20 h. After cooling to room temperature the solid which precipitated was removed by filtration and washed with toluene. The combined toluene solutions were concentrated under reduced pressure to yield a dark oil. This oil was chromatographed on a column of silica gel with ethyl acetate as eluant. The combined fractions were concentrated under reduced pressure yielding 4.2 g (42%) of the product as a yellow viscous oil which solidified upon standing, mp 76°-79° C. IR(neat) 1745.9, 1680 cm-1 (C=O). 1H NMR(CDCl3) δ 1.0-1.4 (m, 12H); 2.0 (s, 3H); 2.2-3.3 (m, 6H); 3.7-4.4 (m, 8H); 6.8 (5, 1H); 7.0-7.3 (m, 4H). Anal. Calcd. for C23H36NO8P: C, 56.90; H, 7.48; N, 2.89. Found: C, 56.27; H, 7.51; N, 2.86.