Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([O:23][CH3:24])=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[C:17]([O:23][CH3:24])=[C:18]([NH:19][S:39]([C:33]3[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])(=[O:41])=[O:40])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COc1c(N)cccc1-c1nc(C(C)C)sc1-c1ccnc(Cl)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(C(C)C)sc1-c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
To a solution of 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-(methyloxy)aniline (10 g, 28 mmol), in DCM (100 mL) was added pyridine (6.6 g, 83.7 mmol) and the mixture was cooled to 0° C. 2,6-Difluorobenzene-1-sulfonyl chloride (5.9 g, 27.9 mmol) in DCM (100 mL) was added dropwise to the mixture. The reaction was stirred at rt for 4 h. Then the reaction was washed with water (200 mL), and extracted with DCM (2×200 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:1) to afford the title compound of Step H (8.7 g, 58.2% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (d, J=5.6 Hz, 1H), 7.70-7.75 (m, 1H), 7.63-7.67 (br, 1H), 7.46-7.55 (m, 1H), 7.15-7.19 (m, 2H), 6.95-7.03 (m, 2H), 6.58 (d, J=5.6 Hz, 1H), 3.35-3.40 (m, 4H), 1.44 (d, J=6.4 Hz, 6H). m/z (ES+): 537 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:29])[CH2:15][CH2:16][C:17]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:18]=3[O:19][CH2:20][C:21](O)=[O:22])[C@H:9]([CH3:30])[CH2:8]2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:29])[CH2:15][CH2:16][C:17]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:18]=3[O:19][CH2:20][C:21]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:22])[C@H:9]([CH3:30])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(OCC(=O)O)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(CCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(OCC(=O)NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
To a solution of (2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-3-oxo-propyl}-5-methyl-phenoxy)-acetic acid (0.052 g, 0.12 mmol) in methylene chloride (1 mL) was added 4-dimethylaminopyridine (0.022 g, 0.18 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.032 g, 0.17 mmol), methanesulfonamide (0.015 g, 0.16 mmol) and triethylamine (0.035 mL, 0.25 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 0.2 M aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by trituration in methylene chloride/diethyl ether/hexanes to give the title compound (0.050 g, LRMS: 520.3).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11]Cl.[N+:13]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[Na+].[Na+]>[I-].[K+].CC(C)=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:22][C:18]1[CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: Cn1c(CCl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: Cn1c(COc2cccc([N+](=O)[O-])c2)nc2ccccc21
Yield: 70.7 %

Procedure:
A mixture of 1-methyl-2-(chloromethyl)benzimidazole (9.8 g), 3-nitrophenol (7.5 g), cesium carbonate (17.6 g), sodium carbonate (5.7 g), potassium iodide (0.5 g) and acetone (250 ml) is heated at reflux overnight. The mixture is filtered and the resulting solution is partially concentrated. A crystalline solid forms which is filtered and dried, giving 10.8 g (70% yield) of title compound, m.p. 183°-185° C.
Reaction SMILES: [C:1](Cl)([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[C:9]([NH2:14])(=[O:13])[C:10]([CH3:12])=[CH2:11].O>C(Cl)(Cl)Cl>[C:1]([NH:14][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: C=C(C)C(N)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
Into the same reaction vessel as used in Example 1, ethoxalyl chloride (12.3 g; 0.09 mol) was charged, and the reaction vessel was cooled in an ice bath. A solution of methacrylamide (20.3 g; 0.24 mol) in chloroform (90.0 ml) was dropwise added thereto in 30 minutes, followed by stirring at room temperature for 3 days. The reaction mixture was shaken with chloroform (500 ml) and water (500 ml), and the chloroform layer was separated and dried over anhydrous magnesium sulfate, followed by removal of chloroform. Hydroquinone (0.01 g) was added thereto, and distillation under reduced pressure was carried out to give N-ethoxalylmethacrylamide (4.8 g). Yield, 29%.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[OH:13])[CH:2]=[CH2:3].O>C(Cl)Cl.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[CH3:3][CH:2]1[CH2:1][C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=2[O:13]1
Reactant: C=CCc1ccc(C(C)=O)cc1O
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc2c(c1)OC(C)C2
Reaction time: 8 h
Yield: 19.3 %

Procedure:
1-(4-Allyl-3-hydroxyphenyl)ethanone (863 mg, 4.90 mmol) was dissolved in methylene chloride (25 mL), which was then added with zirconium (IV) chloride (1.37 g, 5.88 mmol) at room temperature under an argon atmosphere, and stirred overnight. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using silica-gel column chromatography (n-hexane/ethyl acetate=6/1). 1-(2-Methyl-2,3-dihydrobenzofuran-6-yl)ethanone (167 mg, yield 19%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.[I-].[K+].[BH4-].[Na+]>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:11]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CCN(C(=O)Cc2ccc(Br)cc2)c2ccccc2)c1
Agent: [BH4-]
Agent: [I-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN(c1ccccc1)C2Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 20.4 %

Procedure:
A solution of 2-(4-bromophenyl)-N-{2-(3-methoxyphenyl)ethyl}-N-phenylacetamide (1.0 g, 2.4 mmol) in phosphorous oxychloride (10 mL) under nitrogen was heated to 80° C. After 15 hours, the reaction was cooled to RT and slowly poured over ice. Potassium iodide (0.78 g, 4.7 mmol) was then added to the mixture, and after 30 minutes, the quinolinium salt was extracted with ethyl acetate (2×100 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was then dissolved in methanol (25 mL), and sodium borohydride (0.27 g, 7.2 mmol) was slowly added. After 30 minutes, the reaction was concentrated and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound (0.20 g, 21% yield): 1H NMR (CDCl3) 6.6-7.4 (m, 12H), 4.82 (t, 1H), 3.60 (s, 3H), 3.58 (m, 2H), 2.6-3.2 (m 4H); EI-MS (m/z) 407.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:29]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33][C@H:32]2[OH:37])[CH2:30]1>>[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][N:34]1[CH2:35][CH2:36][C:31]2([CH2:30][CH2:29]2)[C@H:32]([OH:37])[CH2:33]1
Reactant: COC(=O)[C@H](CC=O)N1CCN(c2cccc(OC(F)(F)F)c2)CCC1=O
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Product: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(OC(F)(F)F)c2)CCC1=O
Yield: 60 %

Procedure:
In analogy to the procedure described in example 1K, (S)-4-oxo-2-[7-oxo-4-(3-trifluoromethoxy-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 60% yield as light yellow viscous oil. MS: 500.3 (MH+).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[C:4]2([C:14]3[CH:13]=[CH:12][S:11][C:10]=3[CH2:9][CH2:8][CH2:7]2)[NH:3][C:2]1=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:25]2)=CC=1>O1CCOCC1>[S:25]=[C:2]1[NH:3][C:4]2([C:14]3[CH:13]=[CH:12][S:11][C:10]=3[CH2:9][CH2:8][CH2:7]2)[C:5](=[O:6])[NH:1]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CCCc3sccc32)N1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CCCc1sccc12
Temperature: 120 °C
Yield: 100.7 %

Procedure:
6,7-Dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazolidine]-2′,5′-dione (0.5 g, 2.25 mmol) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent) (0.91 g, 2.25 mmol) were suspended in 1,4-dioxane (5 mL). The mixture was heated by microwave irradiation at 120° C. for 30 min. The solution was concentrated in vacuo and the crude residue purified on silica gel using a gradient elution of 20-100% ethyl acetate in 40-60 petroleum ether. Isolated material was further purified on silica gel using a gradient elution of 2-5% methanol in dichloromethane to afford the title compound as a colourless solid (0.54 g, 100%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[H][H].[OH-].[Na+]>[Pt]=O.C(O)(=O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(C(c2ccccc2)c2ccncc2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(C(c2ccccc2)C2CCNCC2)cc1

Procedure:
A solution of 15.7 parts of 4-[α-(p-trifluoromethylphenyl)benzyl]pyridine in 250 parts of acetic acid is heated, with agitation, at 47° C. under approximately 4 atmospheres of hydrogen and in the presence of 2 parts of platinum oxide catalyst for 2 hours. The resultant mixture is filtered, and the filtrate is stripped of solvent by vacuum distillation. The residue is poured into 3 volumes of ice water, and the mixture thus obtained is made alkaline with sodium hydroxide. This mixture is then extracted with ether. The ether extract is dried over anhydrous potassium carbonate, filtered, and the ether removed to provide 4-[(4-trifluoromethylphenyl)phenylmethyl]piperidine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][C:18]#[C:19][CH3:20])[NH:8]C(OC(C)(C)C)=O.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>C(Cl)Cl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][C:18]#[C:19][CH3:20])[NH2:8]
Reactant: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#COC[C@H](N)C(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
N-tert-butoxycarbonyl O-propynyl L-seryl glycine methyl ester (2.52 g, 8.02 mmol) was dissolved in CH2Cl2 (15 mL). Trifluoroacetic acid (15 mL) was added and the reaction mixture stirred for 2 h at room temperature. The solvent and bulk of excess TFA were removed and the residue washed with Et2O (2×15 mL). The diethyl ether was decanted off and the residue dried under vacuum before being redissolved in CH2Cl2 (70 mL). The solvent was evaporated and the residue dried under high vacuum overnight affording a brown, viscous oil (2.32 g, 88%); δH (200 MHz; d6-DMSO) 8.97 (1H, t, J 6, NH), 8.31 (3H, br s, NH3+), 4.21 (2H, d, J 2, CH2CCH), 4.16-4.05 (1H, m, CαH(propSer)), 3.96 (2H, d, J 6, CαH2(Gly)), 3.83 (1H, dd, J 11 and 4, CHH), 3.74 (1H, dd, J 11 and 6, CHH), 3.65 (3H, s, OCH3), 3.55 (1H, t, J 2, CCH).
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[N:25]=[C:26]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])[N:27]=[CH:28][C:29]=3[N:30]=2)=[CH:18][CH:17]=1)=[O:7])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[O:31][C:26]1[N:27]=[CH:28][C:29]2[N:30]=[C:22]([C:19]3[CH:20]=[CH:21][C:16](/[CH:15]=[CH:14]/[C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[C:6]([OH:7])=[O:5])=[O:39])=[CH:17][CH:18]=3)[O:23][C:24]=2[N:25]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN1C(=O)/C=C/c1ccc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1
Yield: 75.2 %

Procedure:
A solution of 55 mg (S)-1-((E)-3-{4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-phenyl}-acryloyl)-pyrrolidine-2-carboxylic acid tert-butyl ester in 2 ml of dichloromethane and 1 ml trifluoroacetic acid was stirred at room temperature for 1 h. Then the mixture was concentrated in vacuo and freeze-dried. 37 mg of the title compound were obtained.
Reaction SMILES: [N+:1](=[CH:3][CH:4]([CH3:6])[CH3:5])=[N-:2].[N+:7]([C:10]1[CH:29]=[CH:28][C:13]([CH2:14][O:15][C:16](=[O:27])[C:17](=[CH2:26])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(Cl)Cl>[C:22]([O:21][C:19]([NH:18][C:17]1([C:16]([O:15][CH2:14][C:13]2[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:29][CH:28]=2)=[O:27])[CH2:26][CH:3]([CH:4]([CH3:6])[CH3:5])[NH:1][NH:2]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)C=[N+]=[N-]
Reactant: C=C(NC(=O)OC(C)(C)C)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)C1CC(NC(=O)OC(C)(C)C)(C(=O)OCc2ccc([N+](=O)[O-])cc2)NN1
Yield: 98.4 %

Procedure:
The ethereal diazoisobutane (6) was gradually added to a solution of Boc-dehydroalanine-p-nitrobenzyl ester (2) (967 mg, 3 mmol) in CH2Cl2 (15 ml) at -10° C. to -15° C. with stirring. After stirring for 1 hr at the same temperature, the solvent was evaporated in vacuo and the resulting residue was triturated with hexane and filtered by suction to give 1.2 g of p-nitrobenzyl p-nitrobenzyl 3-t-butoxycarbonylamino-5-isopropylpyrazoline-3-carboxylate (7) (98.4%) mp 78°-79° C. (dec.). Recrystallization from AcOEt-n hexane gave colorless prisms having mp 87°-89° C. (dec.); IR (KBr) 3390(NH), 1745(C=O), 1690(C=O), 1605 (N=N).NMR (CDCl3)δ: 8.2 and 7.5 (d, d, 4H, ArH), 6.2 (br s, 1H, NH); 5.30 (s, 2H, OCH2), 4.8-5.2 (m, 1H, CH--N=N), 1.5-2.3 (m, 3H, (CH3)2CH and CH2), 1.35 (s, 9H, Boc), 1.00-1.30 (m, 3H, CH3), 0.8-1.10 (m, 3H, CH3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13]CC)=[O:12])=[C:4]([CH3:17])[CH:3]=1.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[C:4]([CH3:17])[CH:3]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Br)ccc1NC(=O)CC(=O)O
Reaction time: 4 h

Procedure:
A 6.0 gram (0.02 mole) portion of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate prepared in Example I (Compound No. 75) was dissolved in approximately 80 milliliters of ethanol and 1.2 grams (0.03 mole) of sodium hydroxide pellets were added to the resulting mixture. The mixture was stirred for four hours and then allowed to stand overnight. The mixture was then evaporated to dryness and water added to give a yellow cloudy solution. This solution was extracted with methylene chloride and then acidified with 10% hydrochloric acid causing a white precipitate to form. The white precipitate was worked up to give 1.8 grams (0.01 mole) of 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoic acid as a white solid having a melting point of 163° C.-165° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(Br)cc1
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-bromoaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[NH:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:3])[NH2:2].CC(C)([O-])C.[K+].[Na+].[Cl-].CC(O)=O>CCO>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[N:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:2]=[C:1]2[OH:3]
Reactant: CCOC(=O)C(=O)Nc1c(F)cccc1C(N)=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nc(O)c2cccc(F)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
A mixture of ethyl 2-(2-carbamoyl-6-fluorophenylamino)-2-oxoacetate (600 mg, 2.4 mmol) and potassium t-butoxide (300 mg, 6.7 mmol) in EtOH (10 mL) was stirred at rt for 5 h. Saturated aq NaCl (50 mL) and HOAc (0.5 mL) were added and the mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford ethyl 8-fluoro-4-hydroxyquinazoline-2-carboxylate (530 mg, 93%). 1H NMR (300 MHz, DMSO-d6) δ 1.39 (t, J=7.2 Hz, 3 H), 4.40 (q, J=7.2 Hz, 2 H), 7.57-7.70 (m, 1 H), 7.78 (t, J=9.2 Hz, 1 H), 7.99 (d, J=8.1 Hz, 1 H), 12.86 (s, 1 H); LC-MS (ESI) m/z 237 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1(C2C=CC(N)=CC=2)CC1>[CH:29]1([C:30]2[CH:6]=[CH:7][C:8]([N:9]3[CH2:20][CH2:19][C:6]4([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:32][CH:31]=2)[CH2:27][CH2:28]1
Reactant: CCCCCC
Reactant: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Al+]C
Agent: Nc1ccc(C2CC2)cc1
Agent: [Cl-]
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2

Procedure:
This material was prepared in analogy to example 1 step D) from 4-(2-Methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, dimethylaluminium chloride in hexane and 4-cyclopropyl-phenylamine, with concomitant cleavage of the Boc protecting group under the reaction conditions. MS (ESI): 271.2 (MH+).
Reaction SMILES: [N:1]1C=CC=CC=1.[Cl:7][C:8](Cl)([O:10]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1>C(Cl)Cl>[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1.[C:8]([Cl:7])(=[O:10])[NH2:1]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccncc1
Agent: C[C@H]1COCCN1
Solvent: ClCCl
Product: NC(=O)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Pyridine (1.60 mL, 19.8 mmol) was added dropwise to an ice cold suspension of triphosgene (2.94 g, 9.90 mmol) in DCM (20.0 mL). (S)-3-Methylmorpholine (1.00 mL, 9.90 mmol) was added and the reaction stirred for 3 hours, then quenched by dropwise addition of HCl (1M aqueous, 20 mL). The mixture was extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give (S)-3-methylmorpholine-carbamoylchloride (1.25 g, 77%). The product was used in the next reaction without purification. (S)-3-Methylmorpholine-carbamoylchloride (766 mg, 4.33 mmol) was dissolved in DCM (35.0 mL) and DIPEA (1.03 mL, 5390 mmol) was added followed by (5-fluoro-pyridin-2-yl)-hydrazine (WO2010022076, 500 mg, 3.94 mmol) and the reaction heated to 45° C. overnight. The reaction was cooled and quenched into water. The mixture was extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (574 mg, 57%). 1H NMR (300 MHz, CDCl3): 1.36 (3H, d, J=6.9 Hz), 3.30 (1H, td, J=12.5, 3.9 Hz), 3.47-3.74 (4H, m), 3.89-4.03 (2H, m), 6.41 (1H, br s), 6.45 (1H, br s), 6.73 (1H, dd, J=9.0, 3.5 Hz), 7.29 (1H, ddd, J=9.0, 7.9, 2.9 Hz), 8.04 (1H, d, J=2.9 Hz).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[CH:21][N:7]2[N:6]=1)[CH2:3][CH3:4].[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCOCC1>[CH2:11]([N:10]1[C:9](=[O:18])[C:8]2=[CH:19][CH:20]=[CH:21][N:7]2[N:6]=[C:5]1[CH:2]([NH:1][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:3][CH3:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(N)c1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCC(NC1CCCC1)c1nn2cccc2c(=O)n1Cc1ccccc1
Reaction time: 0.67 h
Yield: 71.3 %

Procedure:
A mixture of 2-(1-amino-propyl)-3-benzyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (Example 26, 50 mg, 0.16 mmol), cyclopentanone (13 mg, 0.16 mmol), anhydrous sodium acetate (26 mg, 0.32 mmol), 4 Å molecular sieves (50 mg) and 1,4-dioxane (10 mL) was stirred at room temperture for 40 min. The mixture was treated with sodium triacetoxyborohydride (51 mg, 0.24 mmol) in one portion and stirred at room temperature for 40 h. Additional portions of cyclopentanone (0.16 mmol) and sodium triacetoxyborohydride (0.16 mmol) were added to the mixture which was stirred for an additional 3.5 hours then filtered. The filtrate was partitioned between ethyl acetate and saturated sodium bicarbonate, the ethyl acetate phase washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate to give the title compound (40 mg, 71%): 1H NMR (DMSO-d6) δ 0.88 (t, 3H, J=7.15 Hz), 0.95 (m, 1H), 1.05 (m, 1H), 1.20 (m, 1H), 1.31 (m, 1H), 1.33 (m, 1H), 1.50–1.72 (m, 6H), 2.72 (m, 1H), 3.53 (m, 1H), 4.95 (m, 1H), 5.58 (m, 1H), 6.54 (s, 1H), 7.08 (s, 1H) 7.16 (s 2H), 7.24–7.35 (m, 3H), 7.35 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[F:31])[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(Cc3ccc(Cl)cc3F)n2)sc1C(=O)NCc1cccnc1
Yield: 51 %

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-4-chloro-2-fluoro-benzene as described in Example 49 and isolated as a white solid (0.075 g; 51% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56-8.58 (m, 1H), 7.71 (d, J=8 Hz, 1H), 7.46 (d, J=4 Hz, 1H), 7.26-7.31 (m, 1H), 7.10-7.17 (m, 3H), 6.85 (s, 1H), 6.07-6.15 (m, 1H), 5.36 (s, 2H), 4.62 (d, J=8 Hz, 2H), 2.75 (s, 3H). MS (M+H)+=442.1; Rt=1.35 min; HRMS (M+H)+=442.09.