Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1OC1.[NH2:4][C@@H:5]1[C:20](=[O:21])[N:7]2[C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:9]([CH3:12])[CH2:10][S:11][C@H:6]12.[O:22]([CH2:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:12][C:9]1[CH2:10][S:11][C@@H:6]2[C@H:5]([NH:4][C:30](=[O:31])[CH2:29][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20](=[O:21])[N:7]2[C:8]=1[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)COc1ccccc1
Solvent: ClCCl
Solvent: C1CO1
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
A solution of ethylene oxide (12 ml) in dry methylene chloride (30 ml) was added to a solution of t-butyl 7β-amino-3-methylceph-3-em-4-carboxylate (52 g, 0.193 mole) in dry methylene chloride (200 ml) cooled in an ice-water bath. A solution of redistilled phenoxyacetyl chloride (33.2 g, 0.194 mole) in dry methylene chloride (25 ml) was added over 2 minutes with stirring. The mixture was stirred for 2 hours, washed with 3% sodium hydrogen carbonate solution (2 × 70 ml), and water, N-hydrochloric acid and brine (70 ml of each), dried and evaporated to a foam. This foam was redissolved in methylene chloride (200 ml) and part (3 ml) of the solution was reevaporated to a white foam (1.13 g), [α]D + 107°, λmax 268.5 nm (ε 7,850) 274.5 nm (ε 7,000), inflexion at 264 nm (ε 7,500), νmax (CHBr3) 3417 (NH), 1786 (azetidin-2-one), 1718 (CO2R) and 1697 and 1530 cm-1 (CONH), τ 0.99 (1H,d, J 8.5 Hz; NH), 2.5 to 3.2 (5H,m; C6H5OCH2), 4.34 (1H,dd, J 8.5, 5 Hz; C7 -H), 4.91 1H,d, J 5 Hz; C6 -H), 5.38 (2H,s; C6H5OCH2), 6.38, 6.66 (2H, AB-q, J 18 Hz; C2 -H2), 8.01 (3H,s; C3 -CH3), 8.52 (9H,s; CO2C(CH3)3) (Found: C, 58.3, 58.4; H, 5.95, 6.0; N, 6.7, 7.0; S, 7.7 C20H24N2O5S (404.5) requires C, 59.4; H, 6.0; N, 6.9; S, 7.7%).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[OH-].[Li+:24].O1CCCC1>O.C(#N)C>[Li+:24].[C:18]([C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][CH2:4][C:3]([O-:22])=[O:2])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)CCC1CCN(c2ccc(C(C)(C)C)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1ccc(N2CCC(CCC(=O)[O-])CC2)cc1

Procedure:
To 3-[1-(4-tert-butyl-phenyl)-piperidin-4-yl]-propionic acid methyl ester (295 mg; 0.97 mmol, prepared in accordance with Example 145) is added lithium hydroxide (72 mg; 3.00 mmol) dissolved in water (6.5 mL). After dilution with tetrahydrofuran (10 mL) the reaction mixture is stirred for 2-4 hours. The mixture is then diluted with acetonitrile until a precipitate is formed. The solid is collected by filtration and dried under high vacuum to deliver the desired product (468 mg) which is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(OP([CH2:29][C:30]#[N:31])(=O)OCC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:29][C:30]#[N:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1

Procedure:
A mixture of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (compound of Example 13; 13.5 g, 67 mmol), anhydrous potassium carbonate (11.22 g, 81 mmol) and cyanomethyl phosphonic acid diethylester (15.6 g, 88 mmol) in THF (70 mL) was heated at reflux for 12 h. THF was evaporated and the residue was dissolved in chloroform (2×50 mL). The resulting solution was washed with water (2×50 mL) and brine (50 mL). The organic phase obtained was dried over anhydrous sodium sulphate and concentrated to afford the title compound.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4]1([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5]1.NN>C(Cl)Cl>[CH3:1][N:2]([C:14]([NH:13][C:11]1[S:12][C:8]([CH:4]2[CH2:5][CH2:6][CH2:7]2)=[N:9][N:10]=1)=[O:15])[NH2:3]
Reactant: O=C=Nc1nnc(C2CCC2)s1
Reactant: CNN
Agent: NN
Solvent: ClCCl
Product: CN(N)C(=O)Nc1nnc(C2CCC2)s1
Temperature: 25 °C

Procedure:
A solution of methylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Cyclobutyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-methyl-4-(5-cyclobutyl-1,3,4-thiadiazol-2-yl)semicarbazide.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH:8]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:4][CH:3]=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41](O)=[O:42])=[CH:33][CH:32]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH2:8])=[CH:29][CH:30]=2)=[O:42])=[CH:33][CH:32]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@H](Cc1ccc(NC(=O)c2ccnc3ccccc23)cc1)C(=O)O
Reaction time: 4 h

Procedure:
A 250 mL cylindrical glass vessel equipped with a coarse glass frit was charged with 4-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine on Wang resin (10 g) obtained in Example 36 and a solution prepared from quinoline-4-carboxylic acid (5.2 g, 30 mmol), BOP (13.75 g, 30 mmol) and diisopropylethylamine (6.8 mL) in 70 mL of NMP. The slurry was agitated for 4 hours. The mixture was filtered and washed with dichloromethane (2×100 mL), methanol (2×100 mL) and dimethylformamide (2×100 mL). To the washed resin was added a solution of 25% piperidine in NMP (80 mL), the mixture was agitated at room temperature for 20 minutes and filtered. The process was repeated and the resulting slurry was filtered and washed with dichloromethane (2×100 mL), methanol (2×100 mL) and dimethylformamide (2×100 mL). Filtration afforded 4-[[(4-quinolinyl)carbonyl]amino]-L-phenylalanine on Wang resin suitable for use in the next step.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11].C(OP([C:21](Br)([F:23])[F:22])(=O)OCC)C>C(#N)C.O>[F:22][CH:21]([F:23])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1ccccc1O
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccccc1OC(F)F
Temperature: -20 °C
Yield: 91.7 %

Procedure:
Potassium hydroxide (105 g, 1872 mmol) was suspended in a mixture of acetonitrile (200 mL) and water (200 mL) and cooled to approximately −20° C. 1-(2-Hydroxyphenyl)ethanone (11.28 mL, 93.7 mmol) was added dropwise, followed by diethyl[bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes. The mixture was then allowed to warm to room temperature over 1 h. The mixture was extracted with ethyl acetate (3×200 mL), then the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum. The mixture was purified by flash chromatography to afford the title compound (16.0 g, 92%) as a colourless oil. Method B HPLC-MS: MH+ m/z 187, RT 1.77 minutes.
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:10].C(#[N:14])C.S(=O)(=O)(O)O.O1[C@@H]2CC3C([C@H]12)=CC=CC=3>O>[NH2:14][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: O[C@@H]1Cc2ccccc2[C@H]1O
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: c1ccc2c(c1)C[C@H]1O[C@@H]21
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
Into a 100 ml four-neck flask, 4.48 g (30.3 mmol) of trans-(±)-1,2-indandiol (II) and 40 ml of acetonitrile were introduced. This mixture was suspended. While this suspension was stirred at room temperature, 6.14 g (60.6 mmol) of 97% sulfuric acid was added thereto at room temperature in a period of 20 minutes. The temperature within the mixture increased from 19° C. to 35° C. The slurry was completely dissolved to form a slightly yellow transparent solution. The solution was stirred at 24° C. for 1 hour and then at 60° C. for 1 hour. An HPLC analysis of the contents revealed that 70.8% of cis-oxazoline derivative (IV: R=CH3) had been generated, while no trans-amide derivative (III': R=CH3, Y=OH) was detected. Then, 30 ml of water was added thereto and the resulting mixture was stirred at 60° C. for 3 hours. Acetonitrile was removed by azeotropic distillation. The remaining mixture was washed with dichloromethane and then subjected to liquid separation. When an aqueous solution of 25% sodium hydroxide was added to the water phase, a crystal deposited. This crystal was filtered off under reduced pressure, washed with water, and then dried to yield 2.70 g (yield: 59.7%) of cis-(±)-1-aminoindan-2-ol (V) as a white crystal. Its purity determined by an HPLC was 97.7%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[CH3:31][C:32]1[NH:36][CH:35]=[N:34][C:33]=1[CH2:37][CH2:38][C:39]([OH:41])=O.[NH2:42][C@H:43]([CH2:62][C:63]1[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=1)[C:44]([N:46]1[CH2:49][C:48]([O:57][CH2:58][C:59]#[C:60][CH3:61])([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH3:56])[CH2:47]1)=[O:45].[OH-].[Na+]>CN(C)C=O>[CH2:58]([O:57][C:48]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[CH3:56])[CH2:49][N:46]([C:44](=[O:45])[C@H:43]([NH:42][C:39](=[O:41])[CH2:38][CH2:37][C:33]2[N:34]=[CH:35][NH:36][C:32]=2[CH3:31])[CH2:62][C:63]2[CH:68]=[CH:67][C:66]([O:69][CH3:70])=[CH:65][CH:64]=2)[CH2:47]1)[C:59]#[C:60][CH3:61]
Reactant: CC#CCOC1(c2ccccc2C)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reactant: Cc1[nH]cnc1CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC#CCOC1(c2ccccc2C)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2nc[nH]c2C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 9.5 %

Procedure:
389 mg (1.2 mmol) of TBTU and 0.5 ml (3.7 mmol) of triethylamine are added to a solution containing 229 mg (1.2 mmol) of 3-(5-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride in 4 ml of dimethylformamide. After 5 min, 402 mg (0.9 mmol) of (R)-2-amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)-propan-1-one dissolved in 4 ml of dimethylformamide are added. The reaction medium is then stirred for 90 h at ambient temperature, and then a 1N aqueous solution of sodium hydroxide is added and the medium is extracted with a 1/1 heptane/ethyl acetate mixture. The organic phase is washed with a saturated aqueous solution of sodium chloride and then dried over sodium sulphate, filtered and concentrated. The residue obtained is purified by silica gel chromatography, elution being carried out with an 88/12 dichloromethane/methanol mixture. 45 mg of N—[(R)-2-(3-but-2-ynyloxy-3-o-tolyl-azetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide are obtained in the form of a white solid with a yield of 9%.
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[N:15]=[C:14]1[C:9]([C:10]([C:19]([OH:21])=[O:20])=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH:22]1C2=C3C(=CC=C2C=CC=1)N=C1C(C=CC=C1C(O)=O)=N3>CO.C(Cl)(=O)C>[CH3:22][O:20][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:21]
Reactant: O=C(O)c1cccc2nc3c(ccc4ccccc43)nc12
Reactant: O=C(O)c1cccc2nc3ccc4ccccc4c3nc12
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)c1cccc2nc3ccc4ccccc4c3nc12

Procedure:
The mixture of benzo[a]phenazine-11-carboxylic acid (II.20) and benzo[a]phenazine-8-carboxylic acid (885 mg), prepared as described in Reference Example 1L above, was heated to reflux in a mixture of methanol (40 mL) and acetyl chloride (920 μL) for 90 minutes. The reaction mixture was then cooled slowly to yield the title compound as a single isomer which was collected by filtration (377 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ncn2c(-c3cccc(Cl)c3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC(=O)c1ncn2c1NCC=C2c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of 5.39 g of 4-(m-chlorophenyl)-imidazo[1,5-a]pyrimidine-8-carboxamide (Example 14) in 100 ml of glacial acetic acid, was added in portions 2.8 g of sodium cyanoborohydride at room temperature under nitrogen. The mixture stirred at room temperature for 2 hours. The solvent was evaporated in vacuo to give an oil, and this was dissolved in dichloromethane, then washed with saturated sodium bicarbonate solution, The organic layer was separated, dried over anhydrous sodium sulfate and filtered through a short column of hydrous magnesium silicate. Evaporation of the solvent gave a yellow solid which was recrystallized from acetonitrile to give 3.25 g of the desired product as a yellow solid, mp 182°-184° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:27][S:28]([NH:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6])(=[O:30])=[O:29]
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CS(=O)(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[-3-[(methylsulfonyl)amino]-1-oxopropyl]hydrazide (11) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared as described above in Example 9, and methanesulfonyl chloride, in the manner described in Example 10 above, on a 2-mmol scale to yield 0.46 g (52%) of product.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([C:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH:8]=1)[CH3:6].O>CCOCC>[CH2:1]([C:10]1([OH:13])[CH2:11][CH2:12][C:7]([CH2:5][CH3:6])=[CH:8][CH2:9]1)[CH3:2]
Reactant: CCC1=CCC(=O)CC1
Reactant: CC[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CCC1=CCC(O)(CC)CC1

Procedure:
To a stirred solution of 35 ml of 3.2M ethereal ethyl magnesium bromide (Aldrich) in 75 ml of dry ether was added dropwise at gentle reflux a solution of 10.0 g of 4-ethyl-3-cyclohexen-1-one in 25 ml of ether. After one hour longer at reflux, the mixture was cooled and treated dropwise with 80 ml of water. The aqueous layer was extracted with ether and the combined ether layers was dried, concentrated, and Claisen-distilled to give 7.3 g of the desired product, b.p. 82°-86° C. (5 mm.).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([N+:27]([O-])=O)=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>[NH4+].[Cl-].[Zn]>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][C:23]([NH2:27])=[C:24]([CH3:26])[CH:25]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: Cc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncc1N
Reaction time: 1 h

Procedure:
To a solution of 2-((tert-butyldiphenylsilyloxy)methyl)-4-methyl-5-nitropyridine (1.5 g, 3.7 mmol) in 20 ml of sat. NH4Cl, were added zinc (1.7 g, 26 mmol) portionwise at 0° C. for 10 min. The reaction was stirred at the same temperature for 1 hr. The reaction was added with ethyl acetate (20 mL) and stirred for additional 1 hr. The organic layer was taken up, washed with H2O, and dried over MgSO4. The ethyl acetate was concentrated under vacuum to afford 6-((tert-butyldiphenylsilyloxy)methyl)-4-methylpyridin-3-amine in 72% (1.0 g). The compound was used for the next step without further purification. 1HNMR (CDCl3, 400 MHz) δ 1.10 (s, 9H), 2.21 (s, 3H), 4.64 (s, 2H), 5.01˜5.13 (b, 2H), 7.12 (s, 1H), 7.31˜7.71 (m, 10H), 7.89 (s, 1H). Exact mass calculated for C23H28N2OSi 376.57 found 377.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:19]2[CH2:18][N:14]2[CH2:15][CH2:16][CH2:17][C@H:13]2[CH3:12])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(Br)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C (see example 32) from 4-bromo-2-fluoro-benzoic acid (CAS 112704-79-7) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (FIA) 369/371 (MH+).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH2:19][NH:18][CH2:17][CH2:16]2>C(=O)([O-])O.[Na+].O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:19]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc2c(cc1OC)CN(c1nc(Cl)nc(Cl)n1)CC2

Procedure:
To a 0° C. stirred slurry of cyanuric chloride (8.03 g, 43.5 mM) in saturated sodium hydrogen carbonate solution (300 mL) was added 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline hydrochloride (10 g, 43.5 mM) in water (50 mL) at a rate that maintained the internal temperature below 8° C. After 10 min the product was extracted with methylene chloride, filtered through a cotton plug and concentrated to a solid. Filtration of a concentrated methylene chloride solution of the crude product through a 2×2 inch silica gel pad eluting with 50% ethyl acetate/hexanes provided pure product, 12.3 g, (83%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Br[C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2>>[NH:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:15]2[C:16]3[CH:17]=[CH:18][N:19]=[CH:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Brc1cccc2cnccc12
Product: c1cc(N[C@H]2CCNC2)c2ccncc2c1

Procedure:
Reaction of (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate and 5-bromoisoquinoline using the method of Example 16 followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[C:12]([N:25]([CH3:27])[CH3:26])[N:11]=2)=[CH:5][CH:4]=1.[NH3:28]>O1CCOCC1>[NH2:28][C:18]1[N:19]=[C:20]([CH3:22])[N:21]=[C:16]([C:15]2[C:10]([NH:9][C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:11][C:12]([N:25]([CH3:27])[CH3:26])=[N:13][CH:14]=2)[N:17]=1
Reactant: COc1ccc(Nc2nc(N(C)C)ncc2-c2nc(C)nc(SC)n2)cn1
Reactant: N
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(N(C)C)ncc2-c2nc(C)nc(N)n2)cn1
Temperature: 100 °C
Yield: 73.8 %

Procedure:
A glass microwave reaction vessel was charged with N4-(6-methoxypyridin-3-yl)-N2,N2-dimethyl-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidine-2,4-diamine (16 mg, 0.042 mmol), ammonia (0.5 mL, 23.11 mmol) (30% in water) and dioxane (1 mL). The reaction mixture was stirred and heated in an oil bath at 100° C. for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 5% MeOH/EtOAc to give 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-N4-(6-methoxypyridin-3-yl)-N2,N2-dimethylpyrimidine-2,4-diamine (11 mg, 0.031 mmol, 74.8% yield). 1H NMR (300 MHz, CDCl3) δ 11.94 (s, 1H); 9.29 (s, 1H); 8.42 (s, 1H); 8.07 (dd, J=8.92, 2.34 Hz, 1H); 6.76 (d, J=8.77 Hz, 1H); 5.29 (s, 2H); 3.95 (s, 3H); 3.23 (s, 6H); 2.48 (s, 3H). m/z (ESI, +ve ion) 354.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](/[CH:19]=C\C)=[CH:15][C:14]=3[C:22]([F:25])([F:24])[F:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:29]=[O+][O-].[BH4-].[Na+].C([O-])(O)=O.[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CO.Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][N:11]2[C:12](=[O:26])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][OH:29])=[CH:15][C:14]=3[C:22]([F:24])([F:23])[F:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C/C=C\c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(CO)cc3C(F)(F)F)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(cis-1-propenyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (182 mg, 0.46 mmol) in MeOH (5.0 mL) at −78° C. was bubbled ozone for 5 min. until the reaction turned a light blue color. After 5 min., sodium borohydride (23 mg, 0.6 mmol) was added. The reaction was stir for 1 hr and then warmed to room temp. The reaction was conc. in vacuo to a white solid and then dissolved in 1M aq. HCl. After 15 min, the reaction was diluted with EtOAc, basified with NaHCO3, and treated with di-t-butyl dicarbonate (125 mg, 0.58 mmol). After 1 h, the reaction was extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a colorless oil. The oil was purified by flash chromatography (silica gel, 0-50% EtOAc in hexanes) to give 141 mg of the desired product as a white solid. MS (ESI) 387 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>O1CCOCC1>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(F)c(=O)[nH]c2=O)cc1
Yield: 62.3 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil and 1.28 g (0.01 mole) of anhydrous potassium carbonate were suspended in 50 ml. of dioxane and reacted with 3.82 g (0.02 mole) of p-toluenesulfonyl chloride in the same manner as in Example 10. There was obtained 3.54 g (62.3% yield) of 5-fluoro-1-(p-toluenesulfonyl)uracil. Recrystallization of the product from methanol-chloroform gave leaflets melting at 241°-242°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows: