Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][NH2:14])[CH:8]=1)[CH3:2].[CH3:16][C:17]([CH3:24])([CH3:23])[C:18](=O)[CH2:19][C:20]#[N:21]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[C:20]([NH2:21])=[CH:19][C:18]([C:17]([CH3:24])([CH3:23])[CH3:16])=[N:14]2)[CH:8]=1)[CH3:2]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CCOC(=O)CCc1cccc(NN)c1
Solvent: CCO
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 85.2 %

Procedure:
A mixture of Example Y (13 g, 53.3 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (6.9 g, 55 mol) in ethanol (150 mL) was heated to reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-[3-(5-amino-3-t-butyl-pyrazol-1-yl)-phenyl]-propionic acid ethyl ester (14.3 g, 45.4 mmol) as a white solid. 1H NMR (DMSO-d6): 7.39-7.32 (m, 3H), 7.11 (d, J=6.8 Hz, 1H), 5.34 (s, 1H), 5.16 (s, 2H), 4.03 (q, J=7.2 Hz, 2H), 2.88 (t, J=7.6 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.19 (s, 9H), 1.15 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([O:19][CH2:20][C:21]3C=CC=CC=3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].BrCC#[N:32].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([O:19][CH2:20][C:21]#[N:32])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCBr
Reactant: CC(Cc1c[nH]c2c(OCc3ccccc3)cccc12)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(Cc1c[nH]c2c(OCC#N)cccc12)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 70.2 %

Procedure:
The crude {1-methyl-2-[7-hydroxy-1H-indol-3-yl]ethyl}-carbamic acid tert-butyl ester from above (29.2 g, 102 mmol theory) is dissolved in methyl ethyl ketone (300 mL) and bromoacetonitrile (20.4 mL, 306 mmol) and potassium carbonate (33.8 g, 250 mmol) is added. The mixture is heated at 80° C. for 2 hours. The solids are removed by filtration, the cake is washed with methyl ethyl ketone, and the combined filtrates are concentrated by rotary evaporation. The crude product is purified by flash chromatography (500 g silica gel, eluted with 8×500 mL dichloromethane, 4×500 mL 5% ethyl acetate/dichloromethane, 6×500 mL 10% ethyl acetate/dichloromethane). The fractions containing product are concentrated and hexane is added to the solution to precipitate out the product affording 23.7 g (70.2% yield) of racemic {1-methyl-2-[7-cyanomethoxy-1H-indol-3-yl]ethyl}-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[C:3]([O:28][CH3:29])=[CH:4][C:5]([O:26][CH3:27])=[C:6]([N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])[CH:7]=1.[F:30][C:31]([F:43])([F:42])[O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.[F-].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:8]([C:6]2[C:5]([O:26][CH3:27])=[CH:4][C:3]([O:28][CH3:29])=[C:2]([C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]([F:30])([F:42])[F:43])=[CH:38][CH:37]=3)[CH:7]=2)[C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:21][CH:20]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: COC(=O)C(=O)N(Cc1ccc(C(C)(C)C)cc1)c1cc(Cl)c(OC)cc1OC
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(=O)N(Cc1ccc(C(C)(C)C)cc1)c1cc(-c2ccc(OC(F)(F)F)cc2)c(OC)cc1OC
Temperature: 25 °C
Yield: 13.4 %

Procedure:
A mixture of methyl N-(5-chloro-2,4-dimethoxyphenyl)-N-[4-(tert-butyl)benzyl]oxamate (800 mg, 1.91 mmol), 4-(trifluoromethoxy)benzeneboronic acid (549 mg, 2.67 mmol), palladium(II) acetate (21 mg, 0.095 mmol), potassium fluoride (332 mg, 5.72 mmol), 2-(di-tert-butylphosphino)biphenyl (57 mg, 0.191 mmol) and tetrahydrofuran (3.0 ml) was refluxed for 5 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=2:1) to give the title compound (140 mg, 14%) as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([O:30][CH3:31])=[O:29])=[CH:18][CH:17]=1.O>C1COCC1.C(O)(=O)C>[CH3:31][O:30][C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:3]([C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[CH:21][CH:20]=1)=[O:29]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: COC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(=O)C(Cc1ccc(-c2ccccc2C(=O)OC)cc1)C(=O)OC
Reaction time: 0.25 h
Yield: 93 %

Procedure:
Under nitrogen atmosphere, 2.3 of methyl 3-oxoheptanoate, dissolved into 10 ml of anhydrous THF were dropped into a suspension containing 0.22 g of 80% NaH in 30 ml g of anhydrous THF. After the effervescence was over, 2.22 g of 4-bromomethyl-2'-methoxycarbonylbiphenyl, dissolved in 10 ml of anhydrous THF, were slowly dropped into the clear solution. After 15 minutes, water was added and acetic acid was added till acidic pH. The reaction mixture was extracted with AcOEt. The organic phase was washed with a NaCl saturated solution, dried on Na2SO4 and evaporated to dryness. The residue was purified by FC (eluent: hexane/AcOEt 8:2). 2.6 g of a clear oil were obtained (yield 93%); 1H-NMR (200 MHz, CDCl3)δ: 0.86 (t, 3H), 1.15-1.62 (m, 4H), 2.25-2.65 (m, 2H), 3.20 (d, 2H), 3.63 (s, 3H), 3.71 (s, 3H), 3.84 (t, 1H), 7.12-7.58 (m, 7H), 7.78 (dd, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=S)[CH2:8][O:7][C:6]=2[N:12]=1.[F:19][CH:20]([F:25])[C:21]([NH:23][NH2:24])=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]3[C:21]([CH:20]([F:25])[F:19])=[N:23][N:24]=[C:9]3[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: S=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: NNC(=O)C(F)F
Solvent: Cc1ccccc1C
Product: FC(F)c1nnc2n1-c1cc(-c3ccccc3)c(Br)nc1OC2
Yield: 22.2 %

Procedure:
A mixture of 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-thione (0.21 g, 0.654 mmol) and 2,2-difluoroacetohydrazide (0.14 g, 1.3 mmol) in xylene (6 ml) was heated at 150 degree under microwave for 60 min. The reaction solution was concentrated and the residue was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 ml). The combined organic phase was concentrated and purified by column (biotage 25 g) eluted with ethyl acetate/cyclohexane (0-60%) to afford product (55 mg). 1H NMR (500 MHz, CDCl3) 8.09 (s, 1H), 7.4-7.55 (m, 5H), 7.06 (t, 1H), 5.66 (s, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30]([C:32]1[CH:33]=[CH:34][C:35](Cl)=[N:36][CH:37]=1)#[N:31]>>[C:30]([C:32]1[CH:33]=[CH:34][C:35]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[N:36][CH:37]=1)#[N:31]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ccc(C#N)cn2)C3)cc1

Procedure:
Compound ej was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 5-cyano-2-chloropyridine. LC-MS: m/z=+499 (M+H)−.
Reaction SMILES: [C:1](=[O:36])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[C:11]2[C:6]1=[C:7]([OH:35])[CH:8]=[C:9]([CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH:10]=2)[NH2:2]>N1C=CC=CC=1.C(OC(=O)C)(=O)C.CN(C)C1C=CN=CC=1>[C:4]([O:35][C:7]1[CH:8]=[C:9]([CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH:10]=[C:11]2[C:6]=1[CH:5]([CH2:4][O:3][C:1](=[O:36])[NH2:2])[C:17]1([O:19][C:17](=[O:18])[CH3:16])[O:18][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])(=[O:3])[CH3:5]
Reactant: COC(OC)c1cc(O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(O)(O1)C2COC(N)=O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 194.1 %

Procedure:
11-Benzyloxycarbonyl-6,9-dihydroxy-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (15 mg) was dissolved in a mixture of pyridine (1.0 ml) and acetic anhydride (0.5 ml). The solution was stirred for 1 day at room temperature. To the solution was added 4-dimethylaminopyridine (catalytic amount) and the mixture was stirred for 12 hours at room temperature. The reaction mixture was evaporated in vacuo, and the residue was subjected to preparative thin layer chromatography. Development was carried out with a mixture of chloroform and methanol to afford 11-benzyloxycarbonyl-8-carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (17 mg).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[NH2:19][C:20]1[C:25]([S:26](Cl)(=[O:28])=[O:27])=[CH:24][C:23]([Br:30])=[CH:22][N:21]=1>O1CCOCC1.O>[NH2:19][C:20]1[C:25]([S:26]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]2)(=[O:28])=[O:27])=[CH:24][C:23]([Br:30])=[CH:22][N:21]=1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2cc(Br)cnc2N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of tert-butyl azetidin-3-ylcarbamate (64 mg, 0.37 mmol) and potassium carbonate (102 mg, 0.74 mmol) in dioxane (2 mL) and water (400 uL) was added 2-amino-5-bromopyridine-3-sulfonyl chloride (100 mg, 0.37 mmol, prepared according to the methods in WO2008144463). The reaction mixture was stirred for 1 h at room temperature then quenched by addition of saturated aqueous sodium bicarbonate, and the aqueous solution was extracted twice with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to provide tert-butyl 1-(2-amino-5-bromopyridin-3-ylsulfonyl)azetidin-3-ylcarbamate (120 mg, 0.30 mmol, 80% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, 1H), 8.00 (d, 1H), 5.76 (br s, 2H), 4.80 (br s, 1H), 4.50-4.36 (m, 1H), 4.11 (t, 2H), 3.75 (t, 2H), 1.42 (s, 9H); MS (EI) for C13H19BrN4O4S: 407, 409 (Br isotopes, MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:11]2=[O:39])[O:6][N:5]=1.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:40].[CH3:1][O:2][CH2:3][C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:39])[O:6][N:5]=1
Reactant: COCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-[1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (6.61 g; compound B16) in DCM (50 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (7.5 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: COC[O:4][C:5](=O)[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:14][O:15][CH3:16])=[CH:8][C:7]=1[O:17][CH2:18][O:19][CH3:20].O.[NH2:23][NH2:24]>C(O)C>[Br:12][C:10]1[C:9]([O:13][CH2:14][O:15][CH3:16])=[CH:8][C:7]([O:17][CH2:18][O:19][CH3:20])=[C:6]([CH:11]=1)[C:5]([NH:23][NH2:24])=[O:4]
Reactant: COCOC(=O)c1cc(Br)c(OCOC)cc1OCOC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COCOc1cc(OCOC)c(C(=O)NN)cc1Br
Temperature: 70 °C
Reaction time: 27 h
Yield: 45.1 %

Procedure:
5-bromo-2,4-bis-methoxymethoxybenzoic acid methoxymethylester (IM3-d: 4.36 g, 11.9 mmol), ethanol (15 mL) and hydrazine monohydrate (0.96 mL, 29.8 mmol) were placed in a 100 mL eggplant shaped flask and stirred at 70° C. for 27 hours. After completing the reaction, the reaction mixture was extracted with methylene chloride, and the organic layer was washed with saturated sodium chloride solution and then concentrated under reduced pressure. The solid material thus obtained was suspended in hexane for purification to obtain the title compound (IM4-d: 1.8 g, 46%).
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([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.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>>[CH:1]([C@@H:14]1[O:15][CH2:16][C@@H:17]([OH:18])[C@@H:19]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:20]1)([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: c1ccc(C(c2ccccc2)[C@H]2C[C@H]3O[C@H]3CO2)cc1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CN[C@H]2C[C@H](C(c3ccccc3)c3ccccc3)OC[C@H]2O)cc1

Procedure:
(1S,4R,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28d (0.02 g, 0.075 mmol) was reacted with p-methoxy-benzylamine (0.21 g, 1.50 mmol) (Procedure E) to yield (3S,4S,6R)-6-benzhydryl-4-(4-methoxy-benzylamino)-tetrahydropyran-3-ol, (+)-29g, 0.029 (94%, [α]D=(+)65, c=1, MeOH). The 1HNMR and 13CNMR were identical with (3R,4R,6S)-6-benzhydryl-4-(4-methoxy-benzylamino)-tetrahydropyran-3-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-:3])=[O:2].CN(C=O)C.[F:20][C:21]1[N:26]=[C:25]([F:27])[C:24]([F:28])=[C:23](F)[C:22]=1[F:30]>O>[F:27][C:25]1[C:24]([F:28])=[C:23]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:11]([F:12])([F:13])[F:14])[C:22]([F:30])=[C:21]([F:20])[N:26]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Nc2c(F)c(F)nc(F)c2F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (2.0 grams of 50% oil dispersion) was washed with pentane, filtered, and cooled to 0° C. A solution of 4-nitro-2-trifluoromethylaniline (6.1 grams; 0.030 mole) in 25 ml. of DMF was added over a five-minute period. The reaction mixture was allowed to stir for one hour, the temperature rising as high as 10° C. The reaction mixture was then cooled back down to 0° C. and pentafluoropyridine (5.0 grams; 0.030 mole) in 25 ml. of DMF was added. The reaction mixture was allowed to stir without further cooling for about sixteen hours, then poured over 1.8 liter of crushed ice and the volume adjusted to 1.8 liter with water. A precipitate formed and was allowed to remain in the reaction mixture for about twenty-four hours. The precipitate was then separated by filtration. It was recrystallized from ethanol, yielding 2.6 grams of a first crop (m.p. 104°-5° C.; U.S. Pat. No. 3,926,611 reports 107.7-108) and 3.0 grams of a second crop. Elemental analysis of the first crop showed
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([C:27]([O:30]CC1C=CC=CC=1)([CH3:29])[CH3:28])[N:7]=2.CO>C1COCC1.[Pd]>[ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([C:27]([OH:30])([CH3:28])[CH3:29])[N:7]=2
Reactant: COc1ccc(Cn2cnc(N)c3nc(C(C)(C)OCc4ccccc4)nc2-3)cc1OC1CCCC1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2cnc(N)c3nc(C(C)(C)O)nc2-3)cc1OC1CCCC1

Procedure:
A solution of 6-amino-8-(1-benzyloxy-1-methyl-ethyl)-3-(3-cyclopentyloxy-4-methoxy-benzyl)-3H-purine hydrochloride (2.13 g, 4.06 mmole), in THF:methanol,1:1 (60 ml), was hydrogenated at room temperature and pressure with 10% Pd-C (0.26 g) for 12 hours. The catalyst was filtered off and the solvents removed in vacuo. The residue was suspended in hot acetone, the solid collected at 0-5° C. (1.23 g) and recrystallized from methanol-acetone to give the title compound, 0.76 g (43.2%) mp 231-232° C.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:17]2[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:18]=2)[CH:10]=[CH:11][C:12]=1[O:13]C>ClCCl>[CH2:22]([C:19]1[N:18]=[C:17]([CH:16]=[CH:15][C:9]2[CH:8]=[C:7]([OH:6])[C:12]([OH:13])=[CH:11][CH:10]=2)[O:21][N:20]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCc1noc(C=Cc2ccc(O)c(O)c2)n1
Temperature: -42.5 °C
Reaction time: 0.62 h

Procedure:
To a cooled solution of 1M boron tribromide (1.52 mL, 1.5 mmol) in 2 mL dichloromethane, 0.2 g (0.6 mmol) of 5-[2-(3,4-dimethoxy-phenyl)-vinyl]-3-pentyl-[1,2,4]oxadiazole (compound of Example 39) dissolved in 1 mL of dichloromethane was added over a period of 15-20 min at −40° C. to −45° C. The reaction mixture was stirred at −40 to −45° C. for 30-45 min and allowed to attain 25° C. to 30° C. slowly, over a period of 1 h. The reaction mixture was further stirred at 25° C. to 30° C. for 4-5 h. After the completion of the reaction, the reaction mixture was quenched with 10 mL of chilled 5% sodium bicarbonate solution, below 20° C. (pH: 8-9). 10 mL of ethyl acetate was added to the reaction mixture to dissolve the solid and stirred for 10-15 min. The organic layer was separated and the aqueous layer was washed with 10 mL of 10% sodium chloride solution. The organic layer was collected and distilled to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: C([C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1)=O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1(C)C=CC=CC=1>[CH:12]([O:11][C:9]([C:8]1[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH2:4][CH:3]=1)=[O:10])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12

Procedure:
A mixture of the benzhydryl ester from Example 28 (2.5 g. 4.79 mmol). tris-(triphenylphosphine)chlororhodium (3.5 g. 4.79 mmol) and dry toluene (75 ml) was refluxed under nitrogen for 5.5 hours. The reaction mixture was cooled, the rhodium complex was removed by filtration and the filtrate was poured slowly into petroleum ether (250 ml) with stirring. The precipitated solid, which was a mixture of rhodium complex and product, was collected. The product was purified by chromatography on a silica gel column (250 g) using 99:0.5 chloroform:ethyl acetate as eluent. Fractions of 4.5 ml were collected; fractions 1-47 discarded, 48-66 contained bis-(triphenylphosphine)carbonylchlororhodium, and 67-198 contained the product. NMR data indicated the product after chromatography to be the Δ3 isomer instead of the Δ2 isomer. A decoupling experiment showed the 2-methylene group at 3.3 ppm. to be coupled with the 3-proton at 6.6 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:20]([O-])=O)[CH:4]=1>C(O)(=O)C.CO.[Fe]>[CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH2:20])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(C(N)=O)cc1OCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(N)c(C(N)=O)cc1OCc1ccccc1
Temperature: 85 °C
Yield: 87.2 %

Procedure:
A mixture of 4-methoxy-5-benzyloxy-2-nitrobenzamide (6.60 g, 21.9 mmol) and iron powder (8.14 g, 0.146 mol) in acetic acid/methanol (80 mL/80 mL) was heated at 85±5° C. for 1.5 h. The reaction mixture was allowed to cool to RT and the iron was removed by filtration, and volatiles were removed in vacuo. The residue was taken up in sat. sodium bicarbonate and the mixture was extracted with ethyl acetate (600 mL×3). The combined organic layers were washed with water (1×150 mL), brine (1×150 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 4-methoxy-5-benzyloxy-2-aminobenzamide (5.2 g, 19.1 mmol, 87%). MS 273.2. (M+). HPLC retention time 4.585 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.C(#N)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:36][NH:37][S:38]([CH3:41])(=[O:40])=[O:39]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([N:37]([CH3:36])[S:38]([CH3:41])(=[O:40])=[O:39])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNS(C)(=O)=O
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
In a 1000 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 50.0 g (172 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 20.8 g (189 mmol.) of sodium t-pentoxide, and 344 mL of acetonitrile, and the resulting mixture was stirred at 0-10° C. for 30 minutes. To the mixture was slowly added 36.1 g (189 mmol.) of p-toluenesulfonyl chloride, and the reaction was carried out at for 5 hours at room temperature. Subsequently, the reaction mixture was cooled to a temperature of 0-10° C. To the cooled reaction mixture were added 28.2 g (258 mmol.) of N-methylmethanesulfonamide and 26.5 g (241 mmol.) of sodium t-pentoxide. The mixture was kept at 0-10° C. for one hour and then heated to 75-82° C. for 2 hours under refluxing, to carry out a reaction. After the reaction was complete, the mixture was cooled to room temperature. To the cooled mixture was added 344 mL of water. The aqueous mixture was cooled to 0-10° C. and stirred for one hour, precipitating a crystalline product. The crystalline product was collected by filtration and dried, to obtain 45.3 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine as a pale yellow crystalline product. The yield was 68% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).