Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[H-].[Na+].[Cl:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[N:30][C:31]([Cl:37])=[CH:32][CH:33]=2)[N:28]=1.Cl>O1CCCC1.O.C(OCC)(=O)C>[ClH:16].[Cl:37][C:31]1[N:30]=[C:29]2[C:34]([CH:35]=[CH:36][C:27]([N:18]3[CH:17]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:3]4[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:26])=[N:28]2)=[CH:33][CH:32]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC1CCCC(C)N1CCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1CCCC(C)N1CCCCOC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 11.9 %

Procedure:
The procedure is as in Example 7, but starting with 4-(2,6-dimethyl-1-piperidyl)butanol (8 g) in anhydrous tetrahydrofuran (220 cc), an oily suspension (50% by weight; 1.9 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (8.6 g). The residue obtained is taken up with ethyl acetate (20 cc); the insoluble product is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is taken up with water (50 cc) and 4N aqueous hydrochloric acid solution (20 cc); the remaining insoluble product is removed by filtration. The filtrate is neutralized with 4 N aqueous sodium hydroxide solution and then extracted with methylene chloride (3×100 cc); the organic extracts are combined and washed with water, dried and concentrated to dryness under reduced pressure (3 kPa) at 40° C. The residue obtained is recrystallized successively in ethyl acetate and 2-propanol, and 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[4-(2,6-dimethylpiperidino)butoxy]-1isoindolinone hydrochloride (1.6 g) is thereby obtained.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH:15]([F:17])[F:16])[N:11]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=2)[N:22]=[CH:21][N:20]=1>>[Cl:8][C:7]1[C:2]([O:29][C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][N:20]=[C:19]3[NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH:15]([F:17])[F:16])[N:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Clc1cccnc1Cl
Reactant: Nc1ccn(C(F)F)n1
Product: FC(F)n1ccc(Nc2ncnc3ccc(Oc4ncccc4Cl)cc23)n1

Procedure:
The compound of Example 135 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,3-dichloropyridine, 3-amino-1-(difluoromethyl)-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[C:5]([N+:17]([O-])=O)=[CH:4][CH:3]=1.ClC1C([N+]([O-])=O)=CC=C(Cl)N=1.C[O:32][C:33]1[C:34](N)=[CH:35][CH:36]=[CH:37][CH:38]=1.C(NC(C)C)(C)C.[O:47]1CCC[CH2:48]1>>[OH:32][C:33]1[CH:34]=[C:35]([C:2]2[N:7]=[C:6]3[N:8]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[O:15][CH3:16])[C:48](=[O:47])[NH:17][C:5]3=[CH:4][CH:3]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccccc1N
Reactant: C1CCOC1
Reactant: COc1ccccc1Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CC(C)NC(C)C
Product: COc1ccccc1-n1c(=O)[nH]c2ccc(-c3cccc(O)c3)nc21
Temperature: -78 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
6-Chloro-N-(2-methoxyphenyl)-3-nitropyridin-2-amine. 2,6-Dichloro-3-nitropyridine (3.0 g, 15.54 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −78° C. A solution of o-anisidine (1.91 g, 15.54 mmol) and diisopropylamine (2.10 g, 16.31 mmol) in tetrahydrofuran (5 mL) was added dropwise. The mixture was stirred at ambient temperature for 16 h. The solution was condensed under reduced pressure and partitioned between water and ethyl acetate (3×), organics were pooled and dried over magnesium sulfate, filtered and solvent removed under reduced pressure to give the crude product. The solid was triturated with ethyl acetate/hexanes and the resultant precipitate filtered to afford the title compound (3.53 g, 81%). MS (ESI) m/z 280.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=3[F:43])(=[O:35])=[O:34])[C:27]=2[F:44])[CH:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[C:27]([F:44])=[C:28]([NH:32][S:33]([C:36]3[C:37]([F:43])=[CH:38][CH:39]=[CH:40][C:41]=3[F:42])(=[O:34])=[O:35])[CH:29]=[CH:30][CH:31]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(N)n3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccc(-c2sc(C3CCNCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[5-(2-amino-4-pyrimidinyl)-4-(3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (94 mg, 0.145 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL, 6.49 mmol), and the reaction mixture was stirred for 1 h. the reaction mixture was concentrated and the residue was purified using RP-HPLC. The TFA salt was neutralized to the title compound (56 mg). MS (ESI): 547.1 [M+1]+.
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1)=[O:6].[F:15][C:16]1[C:17](=[O:50])[NH:18][C:19](=[O:49])[N:20]([CH:48]=1)[C@@H:21]1[O:47][C@H:25]([CH2:26][O:27]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:23]([OH:24])[CH2:22]1>O1CCOCC1>[F:15][C:16]1[C:17](=[O:50])[NH:18][C:19](=[O:49])[N:20]([CH:48]=1)[C@@H:21]1[O:47][C@H:25]([CH2:26][OH:27])[C@@H:23]([O:24][CH2:11][C:10]2[CH:13]=[CH:14][C:7]([C:5]([OH:4])=[O:6])=[CH:8][CH:9]=2)[CH2:22]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CO[C@H]2C[C@H](n3cc(F)c(=O)[nH]c3=O)O[C@@H]2CO)cc1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
Potassium hydroxide (4.30 g) and 1.70 g of 4-methoxycarbonylbenzyl bromide were added to a solution of 3.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 200 ml of dioxane. The mixture was stirred at room temperature for a day. The reaction mixture was concentrated under a reduced pressure. To the concentrate was added 200 ml of water and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was rendered acidic with acetic acid, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under a reduced pressure. The concentrate was dissolved in 50 ml of a 80% aqueous solution of acetic acid. The solution was heated to 100° C. for 2 hours. The solvent was distilled off and the residue was applied to silica gel column chromatography using 3% methanol-chloroform as an eluent, affording 650 mg of the title compound in a yield of 28%.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH3:18])[C:16]=2[F:17])[NH:10][CH:11]2[CH2:13][CH2:12]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O[CH:25]=[C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])C>>[CH:11]1([N:10]([CH:25]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:9]2[C:14]([N+:19]([O-:21])=[O:20])=[C:15]([CH3:18])[C:16]([F:17])=[C:7]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[CH:8]=2)[CH2:12][CH2:13]1
Reactant: Cc1c(F)c(N2CCNCC2)cc(NC2CC2)c1[N+](=O)[O-]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CN(c1cc(N2CCNCC2)c(F)c(C)c1[N+](=O)[O-])C1CC1)C(=O)OCC
Temperature: 150 °C

Procedure:
To 3-(1-piperazinyl)-4-fluoro-5-methyl-6-nitro-N-cyclopropylaniline (1.57 g) is added diethyl ethoxymethylenemalonate (1.45 ml) and the mixture is heated at 150° C. for 25 hours. After cooling, the reaction product is purified by silica-gel column-chromatography (dichloromethane:methanol=100:1) to give diethyl [N-cyclopropyl-N-[3-(1-piperazinyl)-4-fluoro-5-methyl-6-nitrophenyl]amino-methylene]malonate (1.50 g). The product is dissolved in acetic anhydride (7.9 ml) and thereto conc. sulfuric acid (3.16 ml) is added dropwise at 50°-60° C., followed by stirring for 30 minutes. The resultant mixture is poured into ice-water, neutralized, extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure. Purification by silica-gel column-chromatography (dichloromethane:methanol=10:1) to give ethyl 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (26 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[CH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])C.[OH-].[Na+].Cl>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]([CH3:16])[C:6]=1[C:4]([OH:5])=[O:3])=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cnn(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(This compound was prepared in close analogy to the method of Perez et al., Spanish patent appl. ES 493-459.) 2-Methyl-2H-pyrazole-3,4-dicarboxylic acid diethyl ester (2.06 g, 9.1 mmol) was suspended in a NaOH solution (0.5M in water, 20 ml, 10 mmol) and heated to reflux (30 min). If the conversion was incomplete after this time, as indicated by HPLC control, small amounts of NaOH were added in 30 min intervals. The reaction mixture was cooled, and HCl was added, and stirred for an additional 30 min (r.t.). The precipitate was filtered, washed (water, small amount) and dried under vacuum. The title compound was obtained as a white solid (1.27 g, 70%), and was used in the next step without further purification. MS (m/e)=198 [M+H+].
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[S:21][C:20]3[N:22]4[C:13](=[CH:14][N:15]=[C:16]4[CH:17]=[CH:18][CH:19]=3)[CH:12]=2)=[O:10])[CH2:4]1.C(N(CC)CC)C.Br[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)C>[C:34]1([CH2:33][CH2:32][CH2:31][N:3]2[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]3[S:21][C:20]4[N:22]5[C:13](=[CH:14][N:15]=[C:16]5[CH:17]=[CH:18][CH:19]=4)[CH:12]=3)=[O:10])[CH2:4]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(NC1CCNC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(CCCc2ccccc2)C1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.50 g (1.39 mM) of N-(3-pyrrolidinyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.17 mM) of triethylamine in ethanol (5 ml) was added 0.25 ml (1.64 mM) of 1-bromo-3-phenylpropane at room temperature, and the mixture was refluxed under nitrogen for 18 hours. To this reaction mixture was further added 0.2 ml (1.32 mM) of 1-bromo-3-phenylpropane, and the mixture was further refluxed for 3 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 20-30%) to provide N-[1-(3-phenylpropan-1-yl)pyrrolidin-3-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[I-].[CH3:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[CH2:15]
Reactant: COc1cccc2c1CCCC2=O
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCc2c(OC)cccc21
Reaction time: 1 h
Yield: 99 %

Procedure:
To a slurry of 5-Methoxy-3,4-dihydro-2H-naphthalen-1-one (25 g, 0.14 mol) and methyltriphenylphosphonium iodide (1.13 eq) in THF (250 mL) at RT was added potassium t-butoxide (1.6 eq) at such a rate as to maintain a temperature no higher than warm to the touch. The reaction was stirred for one hour and concentrated. The reaction was then azeotroped with three volumes of hexane to remove excess t-butanol. Fresh hexane was added the solution was let to stand overnight to effect trituration. The red-brown solid was removed by filtration and the filtratewas washed twice with water and was concentrated. Purification by chromatography on ISCO (330 g SiO2 cartridge: stepwise hexane and then DCM) affords the title compound as a pale yellow oil (24 g, 99%). 1H-NMR (400 MHz, CDCl3) 7.29 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.49 (s, 1H), 4.98 (s, 1H), 3.85 (s, 3H), 2.77 (t, J=6.4 Hz, 2H), 2.53-2.50 (m, 2H), 1.93-1.87 (m, 2H).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.[CH3:18][C:19]1[CH:23]=[C:22]([N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[S:21][C:20]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH:17]1([CH2:16][N:26]2[CH2:27][CH2:28][N:24]([C:22]3[S:21][C:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:19]([CH3:18])[CH:23]=3)[C:25]2=[O:29])[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(CC3CC3)C2=O)cc1C
Yield: 80 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with (bromomethyl)cyclopropane to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 80% yield: 1H NMR (300 MHz, CDCl3) δ 6.14 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.87-3.79 (m, 2H), 3.72-3.64 (m, 2H), 3.18 (d, J=7.1 Hz, 2H), 2.49 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.02-0.87 (m, 1H), 0.60-0.52 (m, 2H), 0.28-0.21 (m, 2H); MS (ES+) m/z 309.2 (M+1).
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:46][O:47][CH3:48])[C:23]([NH:25][CH:26]2[C:44](=[O:45])[N:28]3[C:29]([C:33]([O:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[O:34])=[CH:30][CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1>C(OC(C)C)(C)C>[NH2:16][C:17]1[S:18][CH:19]=[C:20]([C:22](=[N:46][O:47][CH3:48])[C:23]([NH:25][CH:26]2[C:44](=[O:45])[N:28]3[C:29]([C:33]([O:35][CH2:36][C:37]([OH:39])=[O:38])=[O:34])=[CH:30][CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)OC(C)(C)C)=CCS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a solution of anisole (5 ml) and trifluoroacetic acid (6 ml) was added tert-butoxycarbonylmethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.5 g) with stirring at ambient temperature. The reaction mixture was stirred for an hour at the same temperature. Then the resultant solution was dropwise added to diisopropyl ether (150 ml). The precipitates were collected by filtration and washed with diisopropyl ether. The precipitates were dissolved in an aqueous solution of sodium bicarbonate. The aqueous solution was adjusted to pH 2.5 with conc. hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give carboxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 0.85 g), IR and NMR spectra of which were the same as those of the object compound of Example 14.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].OC1C2N=NNC=2C=CC=1.N=C=N.C(N(CC)CC)C.Cl.[CH2:40]([O:47][P:48]([CH2:57][C@H:58]([OH:61])[CH2:59][NH2:60])([CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH2:40]([O:47][P:48]([CH2:57][C@H:58]([OH:61])[CH2:59][NH:60][C:16](=[O:18])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:13]([CH3:14])[CH3:15])([CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)=[O:49])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: N=C=N
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reaction time: 0.17 h
Yield: 26.9 %

Procedure:
To a solution of N-Cbz-L-valine (1.0 g, 3.98 mmol) dissolved in CH2Cl2 (80 mL) under nitrogen was added hydroxybenzotriazole (0.538 g, 3.98 mmol) and PS-Carbodiimide (2.25 g, 5.17 mmol). After stirring for 10 min, triethylamine (0.665 mL, 4.78 mmol) and ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride (1.44 g, 3.98 mmol) were added. The reaction was stirred for 2 h, then filtered and concentrated in vacuo. The residue was purified by flash chromatography with methanol/dichloromethane on a 35 g RediSep disposable column to give [(R)-3-((S)-2-benzyloxycarbonylamino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester (0.60 g, 1.07 mmol) as a white foam. NMR and MS spectra were substantially similar to the product obtained via Method A set forth above.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH2:20][CH3:21])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[CH:38][N:37]=[C:36]2[S:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([S:45][C:36]3[C:35]4[C:40](=[CH:41][C:42]([O:43][CH3:44])=[C:33]([O:32][CH3:31])[CH:34]=4)[N:39]=[CH:38][N:37]=3)[CH:47]=2)=[O:19])[N:7]([CH2:20][CH3:21])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CCn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCn1nc(C(C)(C)C)cc1NC(=O)Nc1cccc(Sc2ncnc3cc(OC)c(OC)cc23)c1
Temperature: 25 °C
Yield: 19.1 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-ethyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.523 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (100 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane: methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-ethyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (30 mg, 19%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) 89.12 (s, 1H), 8.70 (s, 1H), 8.53 (s, 1H), 7.85 (s, 1H), 7.52 (m, 1H), 7.43 (m, 1H), 7.35-7.36 (m, 2H), 7.25 (m, 1H), 6.04 (s, 1H), 4.00 (s, 6H), 3.93 (m, 2H), 1.21-1.29 (m, 12H); LC-MS (ESI) m/z 507 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=O)[C:4]=1[C:12]([OH:14])=O.Cl.N[CH:17]1[CH2:23][C:22](=[O:24])[NH:21][C:19](=[O:20])[CH2:18]1.C(O)(=O)C.C([N:31](CC)CC)C.NC1C=CC=C(C(O)=O)C=1C(O)=O>O.C(#N)C>[NH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[C:12](=[O:14])[N:31]([CH:23]1[CH2:17][CH2:18][C:19](=[O:20])[NH:21][C:22]1=[O:24])[C:6]2=[O:8]
Reactant: NC1CC(=O)NC(=O)C1
Reactant: CCN(CC)CC
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 22.5 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-aminophthalic acid hydrochloride (200 g, 0.92 mol, from Prosynth Ltd., Suffolk, UK), 3-aminoglutarimide hydrochloride (159 g, 0.96 mol, from Evotec OAI, Hamburg, Germany), acetonitrile (2.0 L), and acetic acid (577 g, 9.6 mol, from Fisher Scientifc) was charged into a reaction vessel. After the mixture was stirred for 15 minutes, triethylamine (465.0 g, 4.6 mol, from Aldrich, Milwaukee, Wis.) was added dropwise over 30-35 minutes while the reaction temperature was maintained at 20-25° C. Next, the reaction mixture was stirred further for 10-15 minutes and then refluxed at about 85 to 87° C. for about 5 to 7 hours or until the in-process control, i.e., HPLC AP at 240 nm, indicates that <2% of the 3-aminophthalic acid remained in the reaction mixture. After the reaction mixture was cooled to about 20 to 25° C. over 1-2 hours, 1.0 L of water was charged over 15-30 minutes at about 20 to 25° C. The resulting mixture was stirred at about 15 to 20° C. for about 20 to 30 minutes to provide a yellow solid precipitate, which was filtered, washed with DI water (3×1.0 L) and acetonitrile (2×500 mL), and then dried at about 35 to 40° C in vacuo to a constant weight at 210.0 g (84 %).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(N(CC)CC)C.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([F:32])[CH:30]=2)[N:25]=[C:24]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[OH:39])[N:23]=1>C(Cl)Cl>[F:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39])[N:23]=[C:22]2[N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: Oc1ccccc1-c1nc(Cl)c2cc(F)ccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3ccc(F)cc23)C1
Reaction time: 1 h

Procedure:
At 0° C. under an N2 atmosphere, a solution of tert-butyl(R)-pyrrolidin-3-ylcarbamate (264 mg, 1.42 mmol) and triethylamine (0.33 mL, 2.36 mmol) in CH2Cl2 was rapidly added to a stirring solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (325 mg, 1.18 mmol) in 15 mL CH2Cl2. The reaction mixture was stirred for 1 h before it was quenched with water, and the aqueous layer was extracted twice with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc/CH2Cl2 yielded tert-butyl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate. LC/MS: m/z 425.5 (M+H)+ at 2.74 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([O:24]C(OCCCCCCCC)C(CO)O)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCCCC.C([O-])(=O)CCCCCCCCCCCCCCC>>[C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)OC(OCCCCCCCC)C(O)CO
Agent: CCCCCCCCCCCCCCCC(=O)[O-]
Product: CCCCCCCCCCCCCCCC(=O)O

Procedure:
Octoxyglyceryl Behenate or Palmitate
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:17]1[CH2:22][CH2:21]O[CH2:19][CH2:18]1.ClC(OCC(C)C)=O.N1CCCC1>ClCCl>[N:17]1([C:10]([CH:9]2[CH2:13][CH2:14][CH2:15][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:12])[CH2:22][CH2:21][CH2:19][CH2:18]1
Reactant: CN1CCOCC1
Reactant: O=C(O)[C@@H]1CCCN1Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=C(C1CCCN1Cc1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A solution of 1-benzyl-L-proline (50 g) in dichloromethane (300 ml) is cooled with ice. To the solution is added N-methylmorpholine (22.5 g), and then further thereto is added dropwise isobutyl chloroformate (30 g). The mixture is stirred at the same temperature for about one hour, and thereto is added dropwise pyrrolidine (18.8 ml) at the same temperature. The mixture is warmed to room temperature, and stirred for two days. The mixture is washed twice with water (250 ml), and dried over magnesium sulfate. The mixture is concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate-n-hexane to give 2-(1-pyrrolidinyl)carbonyl-1-benzylpyrrolidine (31 g), as white powder.