Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][OH:12])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH3:13][N:14]1[C:23]2[C:18](=[CH:19][C:20]([CH2:24]Br)=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]1=[O:26].BrCC1C=CC2C(=CC=CC=2)C=1>>[CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][O:12][CH2:24][C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:14]([CH3:13])[C:15](=[O:26])[CH:16]=[CH:17]3)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(C#CCO)CCOCC1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Agent: BrCc1ccc2ccccc2c1
Product: COC1(/C=C/COCc2ccc3c(ccc(=O)n3C)c2)CCOCC1

Procedure:
The desired compound was prepared according to the method of Example 1, step 4, except substituting 4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)tetrahydropyran, prepared as in Example 3, for 4-methoxy-4-(3-hydroxyprop-1 -ynyl)tetrahydropyran, and substituting 1,2-dihydro-1-methyl-2-oxo-6-(bromomethyl)quinoline for 2-(bromomethyl)naphthalene. 1H NMR (300 MHz, CDCl3); 7.67 (1H, d, J=9 Hz), 7.52-7.58 (2H, m), 7.35 (1H, d, J=9 Hz), 6 (1H, d, J=9 Hz), 5.75 (1H, dt, J=15.5,8 Hz), 5.63 (1H, br d, J=16 Hz), 4.60 (2H, s), 4.10 (2H, dd, J=8,1 Hz), 3.67-3.8 (4H, m), 3.15 (3H, s), 1.72-1.77 (4H, m); MS (M+H)+ =344. Analysis calc'd for C20H25NO4 : C, 69.95; H, 7.34; N, 4.08; Found: C, 69.68; H, 7.16; N, 3.99
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:17]([O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([CH3:19])[CH3:18]>CCOC(C)=O>[CH:17]([O:20][C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=1)([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CC(C)Oc1cccc(B(O)O)c1
Solvent: CCOC(C)=O
Product: CC(C)Oc1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1

Procedure:
1-[2-(3-Isopropoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-Isopropoxybenzeneboronic acid following general procedures as described in these Examples. Silica gel chromatography using 30-70% EtOAc in hexanes as eluant provided 140 mg (82%) of a yellow solid. MP 149-150° C., M+H=338
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:17]3[C:18]([CH3:26])=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=34)[S:11][C:12]=2[C:13]([O:15]C)=[O:14])[CH:5]=[CH:6][CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:17]3[C:18]([CH3:26])=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=34)[S:11][C:12]=2[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn2ccccc2c1-c1nc(-c2cccc(F)c2)c(C(=O)O)s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 110.1 %

Procedure:
To a solution of methyl 4-(3-fluorophenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxylate (120 mg; 0.27 mmol) purified above in methanol (15 mL) and tetrahydrofuran (25 mL) was added 8N aqueous sodium hydroxide solution (6 mL), and the mixture was stirred at 70° C. for 1 hr. The reaction solution was cooled to 0° C., 6N hydrochloric acid was added to adjust the solution to about pH 3.0, and the reaction solution was extracted with ethyl acetate (100 mL×2). The collected organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated to give the title compound (105 mg, 91%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH2:18][CH2:17][C:16]=3[CH:20]=2)[CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>>[ClH:1].[O:19]1[C:15]2[CH:14]=[CH:13][C:12]([C:4]3[CH:3]=[C:2]([NH:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)=[CH:20][C:16]=2[CH2:17][CH2:18]1
Reactant: NCC(O)CO
Reactant: Clc1cc(-c2ccc3c(c2)CCO3)nc2ccccc12
Product: Cl
Product: OCC(O)CNc1cc(-c2ccc3c(c2)CCO3)nc2ccccc12

Procedure:
The title compound, m.p. 267-270° C. and MS: m/e=336 (M+), was prepared from 4-chloro-2-(2,3-dihydro-benzofuran-5-yl)-quinoline and (RS)-3-amino-1,2-propandiol.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH2:9])=[O:8].[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](O)=[O:23])=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:7]([C:3]1[N:2]([NH:1][C:22]([C@@H:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[O:23])[CH:6]=[CH:5][CH:4]=1)(=[O:8])[NH2:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NC(=O)c1cccn1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nn1cccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A mixture of 1-amino-1H-pyrrole-2-carboxamide (3.00 g, 24.0 mmol) and (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (7.18 g, 28.8 mmol) was dissolved in THF (240 mL). To this solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.52 g, 28.8 mmol). The reaction was stirred overnight at rt, then concentrated in vacuo. The crude residue was dissolved in CH2Cl2 then washed with water (3×200 mL) and brine (200 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to a sticky gum, which was dissolved in a 1:1 solution of CH2Cl2/Hex, then concentrated in vacuo to remove most of the CH2Cl2. The precipitate that formed was filtered and dried to give 1A (6.68 g, 78%). 1A had an analytical HPLC retention time=2.132 min (Phenomenex Luna 3.0×50 mm, 10-90% aqueous MeOH over 5 min containing 0.1% TFA) and a LC/MS M++1=357.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH:24]([OH:31])[CH:25]([CH3:30])[C:26](=[O:29])[CH2:27][CH3:28])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:31])[CH:25]([CH3:30])[C:26](=[O:29])[CH2:27][CH3:28])[CH2:20][CH2:19]1)=[O:17])([CH3:13])([CH3:12])[CH3:14]
Reactant: CCC(=O)C(C)C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(=O)C(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A solution of oxalyl chloride (0.34 mL, 3.9 mmol) in methylene chloride (12 mL) at −78° C. was treated with DMSO (0.43 mL, 6.0 mmol) and the resulting mixture was stirred cold for 10 min. A solution of 1-(t-butoxycarbonyl)-4-(1-(RS)-hydroxy-2-(RS)-methyl-3-oxopent-1-yl)piperidine (514 mg, 1.7 mmol) (from Step C) was added and the resulting solution was stirred cold for 1 h. N,N-Diisopropylethylamine (2.4 mL, 13.7 mmol) was added and the resulting mixture was warmed to 0° C. The reaction was quenched with 1.0 N HCl (25 mL) and extracted with ether (100 mL). The extract was dried over magnesium sulfate and concentrated. MPLC (Biotage) on a 40S silica cartridge using 2:1 v/v hexanes/ethyl acetate as the eluent afforded 435 mg (85%) of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.CC(O)=O.C(O[C:46]1(O[Si](C)(C)C)[CH2:48][CH2:47]1)C.[BH3-]C#N.[Na+].FC(F)(F)C(O)=O>CO>[CH:46]1([N:29]2[CH2:28][CH2:27][CH:26]([N:25]([CH3:32])[C:23]([N:11]3[CH2:12][C:13]([C:15]4[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=4[F:22])=[CH:14][C@@:10]3([CH2:9][OH:8])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])[CH2:31][CH2:30]2)[CH2:48][CH2:47]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(CO)c1ccccc1)C1CCN(C2CC2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 30 mg (0.055 mmol) of amine 7-2 in MeOH was added 30 μL (0.55 mmol) of HOAc, 33 μL (0.17 mmol) of (1-ethoxycyclopropoxy)trimethylsilane, 10 mg (0.17 mmol) of NaCNBH3 and 100 mg of 4 Å molecular sieves. The mixture was then heated at 100° C. for 10 min in a microwave reactor. After cooling to room temperature, ˜500 μL of trifluoroacetic acid was added and the mixture was stirred for 1 h. The reaction was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with water, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 15-1 as a white solid. Data for 15-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.45 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 3.15 (m, 2H), 2.9 (s, 3H), 2.3 (m, 2H), 1.9-1.6 (m, 5H), 0.5-0.4 (m, 4H) ppm. HRMS (ES) calc'd M+H for C27H31F2N3O2: 468.2457. Found: 468.2438. Resolution of the enantiomers was carried out chromatographically using a Chiralpak AD© 10×50 cm column with 15% isopropanol in hexanes (with 0.1% diethylamine) at 150 mL/min. Analytical HPLC analysis of the eluent on a 4×250 mm Chiralpak AD® column with 15% isopropanol in hexanes (with 0.1% diethylamine) at 1 mL/min indicated that inactive enantiomer has Rt=7.05 min and the active enantiomer has Rt=8.17 min.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[NH:7]1[C:15]2[C:10](=[C:11]([C:16]3[N:17]=[C:18]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:19]4[S:24][C:23]([C:25]5[CH:26]=[C:27]([S:31][CH2:32][C@@H:33]([OH:35])[CH3:34])[CH:28]=[CH:29][CH:30]=5)=[CH:22][C:20]=4[N:21]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[OH2:42]>CO>[NH:7]1[C:15]2[C:10](=[C:11]([C:16]3[N:17]=[C:18]([N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:19]4[S:24][C:23]([C:25]5[CH:26]=[C:27]([S:31]([CH2:32][C@@H:33]([OH:35])[CH3:34])(=[O:1])=[O:42])[CH:28]=[CH:29][CH:30]=5)=[CH:22][C:20]=4[N:21]=3)[CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: O
Reactant: O=S([O-])OO
Reactant: C[C@H](O)CSc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1
Agent: [K+]
Solvent: CO
Product: C[C@H](O)CS(=O)(=O)c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1
Reaction time: 1 h

Procedure:
A solution of 161 mg of oxone in 2 mL H2O was added to a mixture of 66 mg of (S)-1-(3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenylthio)propan-2-ol in 4 mL of methanol. The reaction mixture was stirred for 1 h. The mixture was filtered and the filtrate was evaporated. The product was purified by reverse phase HPLC to yield 3 mg of 138. MS (Q1) 536 (M)+
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1>O1CCOCC1>[C:16]([NH:1][C:2]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Temperature: 80 °C
Reaction time: 60 h

Procedure:
To a solution of the product from Step 1 (5.34 g) in dioxane (25 ml) was added acetic anhydride (6 ml) and pyridine (4 ml). After 60 hours of stirring at 80° C., the solution was concentrated under reduced pressure and the residue was dissolved into ethyl acetate. The organic layer was washed with 2M sodium carbonate, 10% aqueous HCl, water and brine, dried over sodium sulfate and evaporated. The product was purified by flash chromatography (ISCO, 5%-20% ethyl acetate in hexanes) to provide a beige solid (5.27 g). LRMS (ES+) m/z 262.0 (M+H)+.
Reaction SMILES: C[O-].[Na+].[C:4]1(=[O:13])[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH2:6][O:5]1.[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.C(OCC)(=O)CC>CO>[NH:14]1[CH:19]=[CH:18][C:17](=[C:20]2[C:6](=[O:5])[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:4]2=[O:13])[CH:16]=[CH:15]1
Reactant: O=C1OCC2=C1CCCC2
Reactant: O=Cc1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(=O)CC
Product: O=C1C2=C(CCCC2)C(=O)C1=C1C=CNC=C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Four portions each of 0.99 ml 5,4 M methanolic sodium methylate solution (21.4 mmol) are stirred into a solution of 2.957 g (21.4 mmol) 4,5,6,7-tetrahydro-1(3H)-isobenzofuranone (for preparation see J. Am. Chem. Soc. 118, 1-12 [1996]), 2.02 ml (21.4 mmol) pyridine-4-carbaldehyde, and 10.7 ml (93.2 mmol) ethyl propionate in 17.4 ml methanol at intervals of 5 min respectively and at 0° C. The reaction mixture is stirred for 20 min at RT, heated for 2 h under reflux, and then evaporated under vacuum. Stirring of the residue in 5 ml water, filtration, washing of the filter residue with water, and drying under HV (8 h, 100 ° C.) yields the title compound; m.p. 258-261° C.; ESI-MS: (M+H)+=228. A further, slightly impure batch of title compound may be obtained by extracting the aqueous filtrate with diethylether, adjusting the aqueous phase to pH 7 with glacial acetic acid, filtering, and washing the filter residue with water.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([OH:32])([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([O:30]C)[CH:24]=[CH:23]4)=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.BrC1C=CC(C2C=C3C(=CC=2)N=C(OC)C=C3)=CC=1.N1C=CC=CC=1.C[Si](I)(C)C>CO.C(Cl)(Cl)Cl>[OH:32][C:10]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([OH:30])[CH:24]=[CH:23]4)=[CH:18][CH:19]=2)[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: COc1ccc2cc(-c3ccc(C4(O)CCCN(Cc5ccccc5)C4)cc3)ccc2n1
Agent: COc1ccc2cc(-c3ccc(Br)cc3)ccc2n1
Agent: C[Si](C)(C)I
Solvent: c1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Oc1ccc2cc(-c3ccc(C4(O)CCCNC4)cc3)ccc2n1
Temperature: 55 °C

Procedure:
By the method described in Preparation 7, 1-benzyl-3-hydroxy-3-(4-(2-methoxyquinolin-6-yl)phenyl)piperidine is prepared from 6-(4-bromophenyl)-2-methoxyquinoline. This material (0.20 g, 0.471 mmol) is placed in a sealed tube under nitrogen with chloroform (5 mL), pyridine (0.02 ml, 0.075 mmol). and trimethylsilyliodide (0.107 ml, 0.754 mmol). The mixture is heated slowly to 55° C. in an oil bath for fifteen hours with stirring. The sealed tube is cooled to 0° C., opened and the contents diluted with methanol (50 ml). The solution is concentrated to dryness and the crude residue is purified by flash column chromatography using 10% methanol in methylene chloride to yield of 1-benzyl-3-hydroxy-3-(4-(2-hydroxyquinolin-6-yl)phenyl)piperidine as a yellow solid (0.1 g, 51%). The debenzylation is carried out as in preparation 1 to yield 3-hydroxy-3-(4-(2-hydroxyquinolin-6-yl)-phenyl)-piperidine.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[CH:37]1([O:43][C:44](Cl)=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:44](=[O:45])[O:43][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OC1CCCCC1
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (0.87 g, 0.002 mol) and sodium bicarbonate (5%, 1 mL) in toluene (10 mL) at 0° was added, dropwise, a solution of cyclohexylchloroformate (0.32 g, 0.002 mol) in toluene (5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The solvent was removed under vacuum. The residue (1.0 g) was chromatographed with 7:3 hexane-ethyl acetate to give the title compound (0.61 g, 0.0011 mol) as a yellow oil. 1H NMR (CDCl3) δ11.1(bs,1H), 7.7-7.2(m,10H), 4.6(bs,1H), 3.3(t,2H,J=5.1Hz), 3.2(t,2H,J=7.5Hz), 3.0(t,2H,J=5.2Hz), 1.9-1.2(m,26H), 0.9-0.8(m,3H).
Reaction SMILES: [NH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11](=[O:14])[C:12](=[O:13])[N:4]([C:5]=23)[CH2:3][C:2]1=[O:15].[CH2:16]1[CH2:20]O[CH2:18][CH2:17]1.[Br-].[Cl-].[NH4+].[CH2:24](OCC)[CH3:25]>>[OH:14][C:11]1([C:16]2[CH:20]=[CH:25][CH:24]=[CH:18][CH:17]=2)[C:6]2[C:5]3[N:4]([CH2:3][C:2](=[O:15])[NH:1][C:10]=3[CH:9]=[CH:8][CH:7]=2)[C:12]1=[O:13]
Reactant: CCOCC
Reactant: C1CCOC1
Reactant: O=C1CN2C(=O)C(=O)c3cccc(c32)N1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Product: O=C1CN2C(=O)C(O)(c3ccccc3)c3cccc(c32)N1
Reaction time: 8 h

Procedure:
A suspension was prepared from 4.3 of 1H-pyrrolo[ 1,2,3-de]quinoxalin-2,5,6(3H)-trione in 200 ml. of THF. 16 ml. of a 2.83 M phentlmagnesium bromide solution in diethyl ether (phenyl Grignard reagent) were added thereto while maintaining the temperature in the range 10°-15° C. The resulting reaction mixture was stirred overnight after which time, 200 ml. of a saturated aqueous amonium chloride solution were added. An additional 1500 ml. of diethylether were added and the ethereal layer decanted from the solids. The ethereal layer was dried and the ether removed therefrom in vacuo. The resulting residue, comprising 6-hydroxy-6-phenyl-1H-pyrrolo[ 1,2,3-de]quinoxalin-2,5(3H,6H)-dione melted at 259°-62° C. with decomposition after recrystallization from methanol; yield = 2.4 g.
Reaction SMILES: [OH-:1].[Na+:2].C1(C)C=CC(S(O)(=O)=[O:10])=CC=1.C([O:16][C:17](=[O:48])[C@H:18]([CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])[NH:19][C:20](=[O:40])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]2[C:37]3[C:36](=[O:38])[NH:35][C:34]([NH2:39])=[N:33][C:32]=3[NH:31][CH:30]=2)=[CH:23][CH:22]=1)C.Cl.[Na+].[Cl-]>O>[CH:23]1[C:24]([CH2:27][CH2:28][C:29]2[C:37]3[C:36]([N:35]=[C:34]([NH2:39])[NH:33][C:32]=3[NH:31][CH:30]=2)=[O:38])=[CH:25][CH:26]=[C:21]([C:20]([NH:19][C@H:18]([C:17]([O-:48])=[O:16])[CH2:41][CH2:42][C:43]([O-:45])=[O:44])=[O:40])[CH:22]=1.[CH:23]1[C:24]([CH2:27][CH2:28][C:29]2[C:37]3[C:36]([N:35]=[C:34]([NH2:39])[NH:33][C:32]=3[NH:31][CH:30]=2)=[O:38])=[CH:25][CH:26]=[C:21]([C:20]([NH:19][C@H:18]([C:17]([O-:48])=[O:16])[CH2:41][CH2:42][C:43]([O-:45])=[O:44])=[O:40])[CH:22]=1.[OH2:10].[OH2:1].[OH2:10].[OH2:10].[OH2:10].[Na+:2].[Na+:2].[Na+:2].[Na+:2]
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1)C(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1
Temperature: 2.5 °C
Reaction time: 0.54 h
Yield: 81 %

Procedure:
A 500 mL flask equipped with magnetic stirrer, ice bath and thermometer was charged with 95 mL of water containing 1.52 g of NaOH (5 eqv.) and the solution was cooled to 0-5° C. To this solution was added 5 g of N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethylester p-toluenesulfonic acid salt. The mixture was stirred at 0-5° C. for 30-35 minutes. The pH was adjusted to 7-9 by adding 1N HCl. The mixture was warmed to rt. To the solution was added 10 gr of NaCl and stirred. At the beginning everything was dissolved and a clear solution was formed. The mixture was stirred at rt for 50-60 minutes and pemetrexed disodium was precipitated. The solid was isolated by filtration and washed with 10 ml of ethanol/water (7/2 v/v). The solid was dried in a vacuum oven at 50-55° C. for 5-6 hours to give 3.19 g of pemetrexed disodium 2.5 hydrate in 81% yield as a white solid with a purity of 99.5% analyzed by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])(=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]([O:12][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])([CH3:10])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(O)c1cc(F)cc(F)c1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](OC(C)(C)c1cc(F)cc(F)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(3,5-difluorophenyl)ethanone (1.0 equiv) in THF (0.2 M) at 0° C. was added methylmagnesium bromide (1.0 M in THF, 1.15 equiv). After stirring for 4 hours the reaction was quenched by addition of NH4Cl(sat.), diluted with EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield 2-(3,5-difluorophenyl)propan-2-ol. To a solution of 2-(3,5-difluorophenyl)propan-2-ol in CH2Cl2 (0.1 M) at 0° C. was added 2.6 lutidine (6 equiv.) and than triisopropylsilyl trifluoromethanesulfonate (3.0 equiv.). After stirring for 3 hours at 0° C. and six hours at rt the solution was partitioned between EtOAc and NaHCO3(sat.), separated, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (2-(3,5-difluorophenyl)propan-2-yloxy)triisopropylsilane. (400 MHz, <cdcl3>) δ ppm 1.05-1.08 (m, 21H) 1.57 (s, 6H) 6.63 (s, 1H) 7.00 (dd, J=9.39, 2.35 Hz, 2H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:28]=[C:29]([N:32]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])[C:33]([NH2:35])=[O:34])[CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)C>>[OH2:24].[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:28]=[C:29]([N:32]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])[C:33]([NH2:35])=[O:34])[CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CCCCCO)C(N)=O)cc2n1Cc1ccc(-c2ccccc2C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccc(N(CCCCCO)C(N)=O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Product: O

Procedure:
Prepared in analogous manner to Example 72 from ethyl 4'-[(2-n-butyl-6-((5-hydroxy-n-pentyl)-aminocarbonyl-amino)-benzimidazol-1-yl)methyl]biphenyl-2-carboxylate and 2N NaOH/ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[CH2:9]([I:12])[CH2:10][CH3:11].C(OCC)(=O)C>CN(C)C=O>[IH:12].[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]1=[NH:8]
Reactant: CCCI
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCN1C(=N)N(C)CC1=O
Product: I
Yield: 46.8 %

Procedure:
9.04 g (80 mmol) of creatinine was suspended in 50 ml of dimethylformamide, and 17.0 g (100 mmol) of n-propyl iodide was added thereto. Then, the mixture was heated and stirred within a range of from 70° C. to 80° C. until creatinine was completely dissolved. The mixture was left to cool, and 500 ml of ethyl acetate was added thereto. Precipitated crystals were collected by filtration to obtain 10.6 g of 1-methyl-3-n-propyl-2-iminoimidazolidin-4-one hydroiodide. Melting point: 159°-161° C.