Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.080 mMol) benzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C[CH2:11][O:12]CC>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:8][CH3:9])[CH:11]=[O:12]
Reactant: COc1ccccc1F
Reactant: CCOCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C=O)cc1F
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a solution of o-fluoroanisole, 101 g (0.80 mol) in 500 ml dry methylene chloride is added dropwise over 30 minutes a solution of titanium tetrachloride, 182 g (0.96 mol, 1.2 equiv.) and α,α-dichloromethylmethyl ether, 110 g (0.96 mol) in an equal volume of methylene chloride. The temperature is maintained at 10-20° C. with an ice-bath. The mixture is stirred at room temperature for 1 hour longer and then poured over crushed ice-water with stirring. Ether (1) is added, and the mixture stirred under nitrogen until solution occurs. The organic layer is extracted with water (3×), sodium bicarbonate solution (3×) and dried (MgSO4). The solvent is evaporated off at 30° C. to give crude product as an oil. The oil is vacuum distilled through a jacketed Vigreoux column when it gives 3-fluoro-4-methoxybenzaldehyde, B.P. 120-121 ° C., at 10 mm Hg; Rf 0.6 on a silica-gel G plate with methylene chloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([Cl:25])[C:6]=1F)[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1.CS(C)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([Cl:25])[C:6]=1[NH:31][CH:28]1[CH2:30][CH2:29]1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1F
Reactant: NC1CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1NC1CC1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A solution of 4-[(S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-3-chloro-2,5-difluorobenzoic acid ethyl ester (Example 2c, 9.34 g, 23.1 mmol), cyclopropylamine (16 mL, 228 mmol), and dimethyl sulfoxide (30 mL) is heated in a sealed tube at 110° C. for 3 days. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford a brown residue. The residue is then purified via flash column chromatography (1:1 ethyl acetate/hexanes) to afford the title compound (4.41 g). MS CI: m/z 442 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1.Cl[S:32]([OH:35])(=[O:34])=[O:33]>S(Cl)(Cl)=O>[CH3:30][O:29][C:28]1[CH:27]=[C:26]([S:32]([OH:35])(=[O:34])=[O:33])[C:5](=[CH:4][C:3]=1[O:2][CH3:1])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH2:20][CH3:21])[C:12](=[O:22])[N:11]([CH2:23][CH2:24][CH3:25])[C:10]=2[N:9]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CCC)c1=O
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
(E)-8-(3,4-Dimethoxystyryl)-7-methyl-1,3-dipropylxanthine (WO92/06976) (2.41 g, 5.84 mmol) was dissolved in thionyl chloride (11 ml), and chlorosulfonic acid (1.17 ml, 17.53 mmol) was added dropwise thereto at 0° C. The resulting solution was stirred at room temperature for 30 minutes and then poured into ice-water cautiously. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give 2.77 g (yield 93%) of Compound 1 as a yellow powder.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[N:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:20](Cl)(=[O:22])[CH3:21].C(=O)([O-])O.[Na+]>O1CCCC1>[Br:3][C:4]1[N:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:20](=[O:22])[CH3:21])=[CH:6][CH:5]=1
Reactant: NCCOc1ccc(Br)nc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NCCOc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-((6-bromopyridin-3-yl)oxy)ethanamine dihydrochloride obtained in Reference Example 5 (1.00 g), pyridine (1.12 mL) and tetrahydrofuran (20 mL) was added dropwise acetyl chloride (0.368 mL) at 0° C. The reaction mixture was stirred at room temperature for 5 hr, aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration, and washed with diisopropyl ether to give the title compound (0.792 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:17]([OH:19])=O)[C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:26]C=2C=1.CN1CCOCC1.C(Cl)CCl.[OH-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1([C:17](=[O:19])[NH2:26])[C:12]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC12CCCC2
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC1(C(N)=O)CC12CCCC2
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of 1-(tert-butoxycarbonylaminomethyl)-spiro[2.4]heptane-1-carboxylic acid (12.5 g, 46.6 mmol) in THF (450 mL) was added HOBT (6.6 g, 48.9 mmol), 4-methylmorpholine (5.4 mL, 48.9 mmol) and EDC (9.83 g, 51.3 mmol). The reaction mixtured was stirred for 3 hours and then concentrated aqueous ammonium hydroxide (6.3 mL, 93.2 mmol) was added. The reaction mixture was stirred for 48 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (500 mL) and half saturated potassium hydrogen sulfate solution. The layers were separated. The organic layer was washed with half saturated potassium hydrogen sulfate, saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated to give 9.7 g (78%) of (1-carbamoyl-spiro[2.4]hept-1-ylmethyl)-carbamic acid tert-butyl ester as a white solid: 1H NMR (300 MHz, CDCl3) δ 0.74 (d, J=4.5 Hz, 1H), 1.38 (d, J=4.5 Hz, 1H), 1.44 (s, 9H), 1.6-1.8 (m, 7H), 1.83 (m, 1H), 3.15 (dd, J=5.1, 14.8 Hz, 1H), 3.65 (dd, J=5.1, 14.8 Hz, 1H), 5.0 (br s, 1H), 5.49 (br s, 1H), 6.45 (br s, 1H); MS (APCI) m/z 169 [M+H-100(Boc)]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].N[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.N1C=CN=C1>O1CCOCC1>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([N:6]2[C:5](=[O:15])[C:4]3[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH2:1])[CH:3]=3)[C:7]2=[O:14])[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: c1c[nH]cn1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)c3cc(N)c([N+](=O)[O-])cc3C2=O)CC1
Temperature: 140 °C
Yield: 53.5 %

Procedure:
A mixture of 5-amino-6-nitro-isoindole-1,3-dione (2.07 g, 10 mmol), tert-butyl 4-amino-piperidine-1-carboxylate (2.5 g, 12 mmol), imidazole (1.63 g, 24 mmol) in dioxane (100 mL) was sealed in a ChemGlass heavy wall pressure flask. After it was heated at 140° C. for 72 h, the reaction mixture was evaporated to dryness at 95° C. (the bath temperature) under reduced pressure. The chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (320:10:1) afforded the title compound (2.09 g, 54%). 1H NMR (CDCl3) δ 1.49 (s, 9H), 1.73 (m, 2H), 2.38 (m, 2H), 2.80 (m, 2H), 4.20-4.31 (3H), 7.03 (br s, 2H, NH), 7.34 (s, 1H), 8.61 (s, 1H); ESI-MS m/z 391.5 (MH+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18]>C1COCC1.C(OCC)(=O)C>[CH2:3]([N:2]([CH3:1])[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
To a solution of N-methyl benzylamine (600 mg, 5 mmol) and triethylamine (1.5 ml, 10 mmol) in anhydrous THF (15 ml), was slowly added 3-nitro benzoyl chloride (1 g, 5.4 mmol) and stirred overnight at room temperature. The solvent was evaporated to give a residue which was dissolved in ethyl acetate and washed thoroughly with water. The organic layer was dried and evaporated to give N-benzyl-N-methyl-3-nitro-benzamide (350 mg, 27%) as solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][OH:7])[NH2:5].C(O[CH2:14][C:15](O)=O)(C)(C)C.[Cl-:18]>>[Cl:18][CH2:14][C:15]1[O:7][CH:6]=[C:4]([C:3]([O:2][CH3:1])=[O:8])[N:5]=1
Reactant: CC(C)(C)OCC(=O)O
Reactant: [Cl-]
Reactant: COC(=O)[C@@H](N)CO
Product: COC(=O)c1coc(CCl)n1

Procedure:
Yokokawa (Synthetic Lett., 1992, 2, 153) has recently described the preparation and cyclization of N-acylserine ester derivatives to give 2-substituted-4,5-dihydrooxazole-4-carboxylate esters which, after oxidation, give the corresponding 2-substituted-oxazole-4-carboxylate esters. By inference, N-acylation of serine methyl ester with t-butoxyacetic acid, followed by cyclization, oxidation, deprotection and conversion to the chloride by standard methods should give methyl 2-(chloromethyl)oxazole-4-carboxylate, as outlined in Scheme XX below. Eliminiation of the oxidation step will give the corresponding oxazoline. ##STR52##
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16](=[O:33])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22](B2OCC(C)(C)CO2)=[CH:21][N:20]=1)([CH3:14])([CH3:13])[CH3:12].COC1C=CC2N=C(C3C=NC(N)=NC=3)SC=2C=1>>[C:11]([O:15][C:16](=[O:33])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:21][N:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1nc2ccccc2s1
Reactant: CC1(C)COB(c2ccc(CNC(=O)OC(C)(C)C)nc2)OC1
Agent: COc1ccc2nc(-c3cnc(N)nc3)sc2c1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccccc3s2)cn1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
2-Chlorobenzothiazole (31 μL, 0.25 mmol) and tert-butyl[5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)pyridin-2-yl]methylcarbamate (80 mg, 0.25 mmol) were reacted according to the procedure used for the preparation of 5-(6-methoxy-1,3-benzothiazol-2-yl)pyrimidin-2-amine. After 1 h at 80° C., the mixture was concentrated under reduced pressure and the residue was partitioned between DCM and H2O. The organic phase was concentrated. Flash chromatography (Heptane/EtOAc gradient) gave the product (53 mg) as a white solid. MS m/z (M+H) 342.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[C:49]([C:52]1[CH:53]=[C:54]([CH:59]=[CH:60][C:61]=1[OH:62])[O:55][CH2:56][CH2:57][NH-:58])(=[O:51])[NH2:50].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:49]([C:52]1[CH:53]=[C:54]([CH:59]=[CH:60][C:61]=1[OH:62])[O:55][CH2:56][CH2:57][NH-:58])(=[O:51])[NH2:50]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCOc1ccc(O)c(C(N)=O)c1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 132 mg of Z-Phe-His-OH, 95 mg of H-Leu-Val-2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl amide, 46 mg of HOBt and 72 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.21, Rf (B11)=0.56.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][CH:39]=[CH:38][C:4]=1[C:5]([N:7]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[C:8](=[O:30])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:11][CH:10]=1)=[O:6].[CH3:42][I:43]>>[I-:43].[CH3:1][O:2][C:3]1[CH:41]=[CH:40][CH:39]=[CH:38][C:4]=1[C:5]([N:7]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N+:33]=1[CH3:42])[C:8](=[O:30])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:14]=1)=[O:6]
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(=O)c2ccccc2OC)cc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2cccc[n+]2C)C(=O)c2ccccc2OC)cc1
Product: [I-]
Temperature: 105 °C

Procedure:
A mixture of 0.770 g of product from Example 6 and 4.29 ml methyl iodide is heated in a sealed tube at 105° C. for 15 hours. The cooled reaction is concentrated in vacuo to give 0.960 g of the desired product as a thick yellow oil which solidified on standing.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(COc2ccc(C(C)=O)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2′,4′-Dihydroxyacetophenone (11.71 g, 0.077 mol), 4-methoxybenzyl chloride (10.44 ml, 0.077 mol), anhydrous potassium carbonate (11.75 g, 0.085 mol) and potassium iodide (12.78 g, 0.077 mol) are heated together in refluxing dry acetone (80 ml) for 4 hours. The mixture is then cooled to room temperature, poured into water (250 ml) and extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts are combined, washed with saturated brine (100 ml), dried (MgSO4), filtered and concentrated, until crystallization commences. After standing at 4° C. for 16 h, the crystals are recovered by filtration, washed with cold ethyl acetate and then with n-hexane and dried.
Reaction SMILES: COC1C=CC(C(O[C:10]2[C:15]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[CH:14][C:13]([O:27]C)=[CH:12][C:11]=2[Br:29])=O)=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1C=CC(C)=CC=1>O>[Br:29][C:11]1[C:10]2[O:26][C:17]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[N:16][C:15]=2[CH:14]=[C:13]([OH:27])[CH:12]=1
Reactant: COc1ccc(C(=O)Nc2cc(OC)cc(Br)c2OC(=O)c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: Oc1ccc(-c2nc3cc(O)cc(Br)c3o2)cc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
A suspension of 2-bromo-4-methoxy-6-[(4-methoxybenzoyl)amino]phenyl 4-methoxybenzoate (42.0 g, 86.4 mmol), p-toluenesulfonic acid monohydrate (32.8 g, 172.8 mmol) and anhydrous p-xylene (800 mL) was refluxed for 1 h with continuous water removal (Dean-Stark Trap). The initial suspension turned into a brown solution at refluxing temperature. The mixture was cooled to room temperature and washed with NaOH (2N). The organic layer was dried over MgSO4. Evaporation and crystallization from acetone/ethyl ether gave an off-white solid (23.5 g, 82% yield, m.p. 139-141° C.); MS m/e 334 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH:21]=[C:20]([CH2:23]O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:10]([N:17]1[CH2:18][CH:19]=[C:20]([CH2:23][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[I:9])[CH2:21][CH2:22]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC1=CCN(Cc2ccccc2)CC1
Reactant: Oc1ccc(Cl)cc1I
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCC2=CCN(Cc3ccccc3)CC2)c(I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-iodo-phenol 4b (20.32 g, 0.08 mol), (1-benzyl-1, 2, 3, 6-tetrahydro-pyridin-4-yl)-methanol (20.5 g, 0.08 mol) and triphenylphosphine (23.58 g, 0.09 mol) in dry THF (150 mL) was added DEAD (17.4 g, 0.09 mol) at 0° C. under nitrogen atmosphere. After addition, the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and the residue was basified by Na2CO3 solution (10% 100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL×2) and brine (200 mL), dried over Na2SO4, concentrated to dryness. The residue was purified by column on silica gel to afford 1-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-1,2,3,6-tetrahydro-pyridine 4c. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J=2.4 Hz, 1H), 7.22-7.38 (m, 6H), 6.70 (d, J=8.8 Hz, 1H), 5.82 (s, 1H), 4.43 (s, 2H), 3.63 (s, 2H), 3.05 (s, 2H), 2.67 (t, J=5.6 Hz, 2H), 2.28 (s, 2H).
Reaction SMILES: [O:1]([CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27](S(C)(=O)=O)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[CH3:36][N:37]1[C:41]([NH2:42])=[CH:40][CH:39]=[N:38]1>CN(C=O)C>[Si:2]([O:1][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:42][C:41]3[N:37]([CH3:36])[N:38]=[CH:39][CH:40]=3)[N:26]=2)=[CH:21][C:20]1=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: Cn1nccc1N
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(S(C)(=O)=O)n2)cc1=O
Solvent: CN(C)C=O
Product: Cn1nccc1Nc1nccc(-c2ccn([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-1-(2-(tert-Butyldimethylsiloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)pyridine-2(1H)-one (47 mg, 0.087 mmol), 2-methyl pyrazole-3-amine (0.175 mmol, 2.0 equivalents) and anhydrous DMF (3.0 mL) were added to a 25 mL round bottomed flask equipped with a stirring bar. The flask was capped with a rubber septum and flushed with nitrogen. Under a blanket of nitrogen, sodium hydride (8.5 mg, 60% dispersion in mineral oil) was added in one portion. The flask was flushed with nitrogen, capped and stirred at room temperature. The reaction progress was monitored by LCMS, and after 30 minutes, the starting material was consumed. The reaction mixture was quenched by the addition of water (0.5 mL) and ethyl acetate (15 mL). The contents of the round bottomed flask were transferred to a 125 mL separatory funnel, and the reaction flask was rinsed several times with additional ethyl acetate. Crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one was partitioned between ethyl acetate and water (80 mL/30 mL). The ethyl acetate layer was washed once with brine, dried (MgSO4), filtered and concentrated to give crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one. The crude was taken directly into the deprotection step.
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])OC(C)(C)C)[CH2:6][CH2:5]1)=[S:3].[Cl:18][C:19]1[C:23]([Cl:24])=[C:22](C)[NH:21][C:20]=1[C:26](NC1CCNCC1)=O>>[NH2:1][C:2]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:22]2[NH:21][C:20]([CH3:26])=[C:19]([Cl:18])[C:23]=2[Cl:24])=[O:17])[CH2:8][CH2:9]1)=[S:3]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCN(C(N)=S)CC1
Product: Cc1[nH]c(C(=O)NC2CCN(C(N)=S)CC2)c(Cl)c1Cl

Procedure:
The title compound was prepared by a procedure analogous to Intermediate 125 starting from 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide (Intermediate 90, 0.5 g, 2 mmol). The product was concentrated to a solid which was purified on a silica flash column (gradient elution from 0-5% MeOH in DCM over 30 min). Purification yielded a white solid (0.22 g).
Reaction SMILES: [CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([C:6]([C:8]#[C:9][C:10]([O:12]C)=[O:11])=[O:7])=[CH:4][C:3]=2[O:2]1.[OH-].[K+].O>O1CCCC1>[CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([C:6]([C:8]#[C:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=2[O:2]1
Reactant: COC(=O)C#CC(=O)c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C#CC(=O)c1ccc2c(c1)OCO2
Reaction time: 1 h

Procedure:
A solution of 5.9 g (25.4 mmol) of methyl 3-[3,4-(methylenedioxy)benzoyl]propiolate in 60 ml of tetrahydrofuran was treated slowly at 0° with 71 ml of 3% potassium hydroxide solution and stirred at 0° for a further 1 hour The reaction mixture was treated with water and extracted once with ether. The ether phase is discarded. The aqueous phase was adjusted to pH 1 with 1N hydrochloric acid and extracted twice with ether. The combined organic phases were dried over sodium sulphate and concentrated. Crystallization of the residue from methylene chloride/ ether/hexane yielded 3-[3,4-(methylenedioxy)-benzoyl]propiolic acid of melting point 122°-124°.