Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>C1COCC1.CCOC(C)=O>[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:22])=[O:21])=[CH:38][CH:37]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: COc1ccc(CN)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNS(=O)(=O)c2cccc(-c3cccc(-c4cc(-c5ccc(C(F)(F)F)cc5)cc(C)n4)n3)c2)cc1
Yield: 53.9 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-methoxybenzylamine (0.27 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.130 g, 53%) as a white solid. MS (ISP) 590.2 [(M+H)+]; mp 126° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([C:12]([F:11])([F:20])[F:21])=[CH:14][CH:15]=2)=[O:10])[CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cc(Br)ccn1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cc(Br)ccn1

Procedure:
In a manner similar to that describe in Preparation 34, 4-bromo-pyridine-2-carboxylic acid and 4-trifluoromethylaniline were converted to the title compound.
Reaction SMILES: [CH:1]1[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.N#[N+][O-:15]>>[C:1]1(=[O:15])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: C1=CCCC=CCCC=CCC1
Reactant: N#[N+][O-]
Product: O=C1CCC=CCCC=CCCC1

Procedure:
The homogenizing plate serves to back up the reaction mixture before entry into the tube bundle, in order, for example, to achieve a defined pressure drop of 100-200 mbar, for example in the reaction of 1,5,9-cyclododecatriene with dinitrogen monoxide to give cyclododeca-4,8-dienone. This example relates to a specific embodiment; in principle, it is possible to provide pressure drops of 0.01 bar to 10 bar, provided that, in principle, the pressure drop is defined essentially by the homogenizing plate and, by virtue of the pressure drop, homogeneous through-flow (with regard to the throughput) over the cross section of the tube bundle (especially at the feed end) results from the operating parameters and the flow properties of the homogenizing plate. The pressure drop is determined to a crucial degree by the operating parameter range (pressure, temperature, flow rate), which in turn depends significantly on the conversion reaction to be performed. The invention shall not be restricted to the reaction of 1,5,9-cyclododecatriene with dinitrogen monoxide; instead, the invention is suitable for performing a multitude of various conversions and reactions. Preferably, each of the holes of the homogenizing plate is arranged opposite exactly one inlet of a corresponding tube of the tube bundle. Instead of or in combination with the homogenizing plate, homogenization, which is provided by controlled backup of the reaction mixture in the feed hood before entry into the tube bundle, can also be accomplished by providing internals at the feed end of the tube bundle, or else restrictors which narrow the tube inlet in a controlled manner. Such restrictor elements can be secured, for example, by means of screw connections on or in the particular tube inlet; the restrictors provided here may, for example, be screw heads. In this case, each screw head partly covers exactly one tube inlet of a tube. The screw head can be provided with holes, for example when the screw head completely covers the tube inlet. In addition, differences in the form of the screw head or of the restrictor compared to the form of the internal cross section of the tube can reduce the tube inlet at the feed end in a defined manner.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[OH:13].[N-:14]=[N+:15]=[N-:16].[Na+].O>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[N:14]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[OH:13])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)N1CCC(Br)C(O)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC(N=[N+]=[N-])C(O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Ethyl 4-bromo-3-hydroxypiperidine-1-carboxylate (Preparation: Izamanishi, T. et al; 1982, Chem. Pharm. Bull., 30: 3617-3623) (5.1 g) was dissolved in anhydrous DMF (20 mL) under an argon atmosphere, followed by the addition of 18-crown-6 (0.27 g) and sodium azide (2.89 g). The reaction was heated at 90° C. for twenty-three hours, then stirred overnight, slowly cooling to room temperature. The reaction was then added to deionised water (150 mL) to quench it, saturated with solid sodium chloride, and extracted with EtOAc (2×200 mL). The combined EtOAc layers were washed with brine (100 mL), dried over anhydrous MgSO4 and concentrated in vacuo, yielding the title compound (4.3 g, 100%). MS (GC-EI)[(M-N2)+]: 186 for C8H14BrN4O3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][C@H:9]1[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][C@H:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(=O)O
Yield: 100 %

Procedure:
Methyl (2S)—N-(tert-butyloxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylate (2.2 g, 8.3 mmol) was dissolved in THF (100 ml). Aqueous lithium hydroxide (1M, 10.6 ml, 10.6 mmol) was added. After 3 h at room temperature the reaction mixture was diluted with ethyl acetate (150 ml), washed with 1M HCl, water, and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 95% chloroform, 4% methanol, 1% acetic acid) to give an orange oil identified as the title compound (2.1 g, 8.3 mmol 100%).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:27]([CH2:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:26][NH:25][N:24]=2)=[CH:19][CH:18]=1>C(OCC)C>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([N:25]2[CH2:26][CH:27]([CH2:28][CH2:29][CH2:30][C:31]#[N:32])[C:23]([C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=3)=[N:24]2)=[O:15])=[CH:11][CH:12]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#CCCCC1CNN=C1c1ccc(Cl)cc1
Reactant: CC(C)OC(=O)c1ccc(N=C=O)cc1
Solvent: CCOCC
Product: CC(C)OC(=O)c1ccc(NC(=O)N2CC(CCCC#N)C(c3ccc(Cl)cc3)=N2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
51.5 g of the above-prepared 4-isopropoxycarbonylphenyl isocyanate were added to a solution of 61.9 g of 3-(4-chlorophenyl)-4-(3-cyanopropyl)-2-pyrazoline in 450 ml of diethyl ether at room temperature. After stirring for 30 minutes at room temperature, 500 ml of petroleum ether (40-60) were added, after which the reaction mixture was stirred at room temperature for another hour. The crystalline precipitate was sucked off, washed with petroleum ether (40-60) and dried in air. 95.0 g Of 1-(4-isopropoxycarbonylphenylcarbamoyl)-3-(4-chlorophenyl)-4-(3-cyanopropyl)-2-pyrazoline were obtained. After stirring 10 g of the resulting product with 100 ml of diethyl ether, a product was obtained having a melting point of 109°-113° C.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([F:37])[CH2:36][O:35][CH2:34]2)[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([C:33]4([F:37])[CH2:36][O:35][CH2:34]4)=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(F)COC3)cc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C4(F)COC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(3-fluorooxetan-3-yl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 194. 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.32 (dd, J=8.7, 4.0 Hz, 1H), 8.18 (t, J=8.9 Hz, 1H), 7.93 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 5.02 (s, 2H), 4.97 (s, 2H), 4.82 (dd, J=10.3, 3.7 Hz, 1H), 4.31-4.05 (m, 1H), 4.07-3.84 (m, 2H), 3.75 (s, 3H), 3.09-2.95 (m, 1H), 2.10-1.99 (m, 1H), 1.80-1.57 (m, 5H). LCMS (ES+) m/z 538 (M+1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:26][C:27](O)=[O:28])([CH2:6][CH:7]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[NH:49]1[CH2:60][CH2:59][CH2:58][C@H:50]1[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][P:4]([CH2:26][C:27]([N:49]1[CH2:60][CH2:59][CH2:58][C@H:50]1[C:51]([O:53][C:54]([CH3:56])([CH3:57])[CH3:55])=[O:52])=[O:28])([CH2:6][CH:7]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CCOP(=O)(CC(=O)O)CC(Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)CC(Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
The mono ester product from part (e) (0.81 g., 1.94 mmole) in tetrahydrofuran (4 ml.) at 0° in an argon atmosphere was treated with carbonyldiimidazole (0.31 g., 1.0 eq.). After one hour, triethylamine (0.3 ml., 1.1 eq.) then L-proline, t-butyl ester (0.43 g., 1.3 eq.) were added to the above mixture. After stirring at room temperature for 16 hours, the reaction mixture was diluted with ethyl acetate and then washed with water, 5% sodium bicarbonate, 5% potassium bisulfate (twice), brine, dried (MgSO4), and evaporated to give 0.9 g of 1-[[ethoxy[3-phenyl-2-[[(phenylmethoxy)carbonyl]amino]propyl]phosphinyl]acetyl]-L-proline, 1,1-dimethylethyl ester as a foam. Tlc (dichloromethane/acetic acid/methanol; 100/5/5) major spot at Rf =0.5.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[CH:9][C:10]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:11]=3[CH:24]=[C:7]2[O:6][CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])O.[Na+].[Br:30]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClC(Cl)C>[Br:30][C:9]1[C:10]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:11]=2[CH:24]=[C:7]2[O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:8]=12
Reactant: BrBr
Reactant: CCN1CCOc2cc3c(cc21)CCN(C(=O)OC(C)(C)C)CC3
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN1CCOc2cc3c(c(Br)c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 860 mg of t-butyl 4-ethyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 25 ml of dichloroethane was added 1.1 g of sodium hydrogen carbonate, and further, a solution of 200 μl of bromine in 5 ml of dichloroethane was added dropwise thereto over about 30 minutes, followed by stirring at room temperature. To the reaction mixture was slowly added a 3% aqueous sodium thiosulfate solution, followed by stirring vigorously and extracting with chloroform twice. The combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 490 mg of t-butyl 5-bromo-4-ethyl-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.ONC(=O)CCC1C=CC(CC=CC2C=CC=CC=2)=CC=1.C1(CC=CC2C=CC(C(O)=O)=CC=2)C=CC=CC=1.C1(C=CCC2C=CC(C(O)=O)=CC=2)C=CC=CC=1>>[OH:1][NH:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:8][CH:7]=1
Reactant: O=C(CCc1ccc(C=CCc2ccccc2)cc1)NO
Agent: O=C(CCc1ccc(CC=Cc2ccccc2)cc1)NO
Agent: O=C(O)c1ccc(C=CCc2ccccc2)cc1
Agent: O=C(O)c1ccc(CC=Cc2ccccc2)cc1
Product: O=C(CCc1ccc(CCCc2ccccc2)cc1)NO
Yield: 99 %

Procedure:
Following a procedure analogous to that described in Example 24, step 2, but substituting the mixture of N-hydroxy-3-[4-(3-phenyl-1-propenyl)-phenyl]-propanamide and N-hydroxy-3-[4-(3-phenyl-2-propenyl)-phenyl]-propanamide (155 mg, 0.55 mmol) for olefins 54, 155.4 mg (99%) of the title compound was obtained.
Reaction SMILES: [CH2:1]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[CH2:26](Br)[C:27]#[CH:28]>>[CH2:28]([O:22][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:1][CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH3:9])[CH3:4])=[CH:25][CH:24]=1)[C:27]#[CH:26]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCOc1ccc(C(=O)O)cc1
Reactant: C#CCBr
Product: C#CCOC(=O)c1ccc(OCC=C(C)CCC=C(C)CCC=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-farnesyloxybenzoic acid with propargyl bromide, there is obtained p-farnesyloxybenzoic acid propargyl ester; B.P. 245°-250° C./0.1 mmHg.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1>>[CH3:16][C:17]1[N:18]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]3)[CH:19]=[CH:20][N:21]=1
Reactant: O=C1CCCc2cc(OCCCl)ccc21
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1CCOc1ccc2c(c1)CCCC2=O
Yield: 66 %

Procedure:
According to the method of Example 1, Step 2, 6-(β-chloroethoxy)-1-tetralone (0.208 g, 0.93 mmol) and 2-methylimidazole (0.137 g, 1.67 mmol) were reacted to provide the title compound (0.166 g, 66%) as a cream colored solid: CI-MS m/e 270 (M+), 271 (M+ +1); 1H-NMR (CDCl3): δ 7.94 (1H, d, J=8.0 Hz), 6.88 (2H, s), 6.72 (1H, dd, J=8.0 Hz, J=2.0 Hz), 6.60 (1H, d, J=2 Hz), 4.21 (4H, m), 2.85 (2H, t, J=6.0 Hz), 2.55 (2H, t, J=6.0 Hz), 2.41 (3H, s), 2.05 (2H, m).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[Cl:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].O.[NH2:35][NH2:36]>O1CCOCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:24][CH2:25]3)=[CH:16][C:15]=2[Cl:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:35][NH2:36])(=[O:3])[NH2:2]
Reactant: NN
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2Cl)n1
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(NN)c(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 55A (131 mg, 0.26 mmol) in 1,4-dioxane (3 mL) was added hydrazine hydrate (50 mg, 0.78 mmol) and the mixture was stirred at ambient temperature for 4 hours. The mixture was concentrated and the residue was washed with hexane and dried to give the title compound. The crude title compound was used in the next step without further purification. MS: 508 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[CH3:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH3:12])=[C:6]1[CH3:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1[nH]c2ccc(Br)cc2c1C
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccccc2)c2ccc(Br)cc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 3. Thus, 5-bromo-2,3-dimethyl-1H-indole (1.793 g, 8 mmol) was reacted with k-t-butoxide (0.943 g, 8.4 mmol) and benzyl bromide (1.442 g, 8.4 mmol) in DMF (20 ml) to give the product (1.872 g, 5.958 mmol, 74%) as a pink solid. 1H NMR (DMSO-d6) δ 2.18 (s, 3H), 2.26 (s, 3H), 5.38 (s, 21), 6.94 (d, J=7.3 Hz, 2H), 7.12 (dd, J=1.8, 8.6 Hz, 1H), 7.20 (t, J=7.2 Hz, 1H), 7.27 (t, J=7.2 Hz, 2H), 7.32 (d, J=8.7 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H); [EI], m/z 313/315 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[O:29][N:28]=1)=[O:25].[CH3:35][NH2:36].C1COCC1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:20](=[O:21])[N:19]([CH3:22])[C:12]3[N:13]=[C:14]([NH:36][CH3:35])[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:4][C:3]=1[NH:23][C:24]([NH:26][C:27]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[O:29][N:28]=1)=[O:25]
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)on4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)C)on4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 62.8 %

Procedure:
Following a procedure analogous to Example A1, 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (0.0635 g, 0.13 mmol) and 2.0M MeNH2/THF (0.66 ml, 1.3 mmol) were combined to afford 1-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (38 mg, 62% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.77 (s, 1H), 8.75 (brs, 1H), 8.60 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.80 (brq, J=4.4 Hz, 1H), 7.68 (s, 1H), 7.36 (d, J=12.4 Hz, 1H), 6.45 (s, 1H), 3.60 (s, 3H), 2.99 (septet, J=6.8 Hz, 1H), 2.90 (brd, J=4.4 Hz, 3H), 2.07 (s, 3H), 1.20 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 466.2 (M+H+).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1O.C(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(OCC)C>CN(C)P(N(C)C)(N(C)C)=O.C(=O)(O)[O-].[Na+]>[CH:16]1[C:14](=[O:15])[N:13]=[C:11]2[N:10]([C@@H:1]3[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@@H:2]3[O:12]2)[CH:17]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Temperature: 135 °C
Yield: 91.8 %

Procedure:
To a suspension of uridine (200 g, 819 mmoles) in hexamethylphosphoramide (HMPA) (400 ml) was added sodium bicarbonate (5.3 g, 63.1 mmoles, 0.077 equivalents (eq.)) and diphenyl carbonate (228.1 g, 1064.7 mmoles, 1.3 eq.). The mixture was heated to 135° C. for 11 h. After cooling to room temperature, diethyl ether (2 l) was added and the precipitate was filtered off. The solid was washed three times with ether (3×1 l). Water (1 l) was added to the filtrate, the aqueous layer was separated and extracted three times with methylene chloride (3×1 l). The aqueous phase was evaporated to dryness. The combined solids were recrystallized from hot methanol to yield 170 g (92%) of 2,2'-anhydrouridine. The spectral properties agreed with those reported in the literature (Hampton and Nichol (1966) Biochemistry 5:2076).
Reaction SMILES: C([C@@H](NC(C1C=C(C)C2N=C(CCC)N(CC3C=CC(C4C=CC=CC=4C4NN=NN=4)=CC=3)C=2C=1)=O)CC(=O)NOCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:55]([C@@H:62]([NH:75][C:76]([C:78]1[CH:107]=[C:106]([CH3:108])[C:81]2[N:82]([CH2:88][C:89]3[CH:94]=[CH:93][C:92]([C:95]4[CH:100]=[CH:99][CH:98]=[CH:97][C:96]=4[C:101]4[NH:105][N:104]=[N:103][N:102]=4)=[CH:91][CH:90]=3)[C:83]([CH2:85][CH2:86][CH3:87])=[N:84][C:80]=2[CH:79]=1)=[O:77])[CH2:63][C:64](=[O:74])[NH:65][O:66]CC1C=CC=CC=1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CCO.C(O)(=O)C.[Pd]>[CH2:55]([C@@H:62]([NH:75][C:76]([C:78]1[CH:107]=[C:106]([CH3:108])[C:81]2[N:82]([CH2:88][C:89]3[CH:94]=[CH:93][C:92]([C:95]4[CH:100]=[CH:99][CH:98]=[CH:97][C:96]=4[C:101]4[NH:102][N:103]=[N:104][N:105]=4)=[CH:91][CH:90]=3)[C:83]([CH2:85][CH2:86][CH3:87])=[N:84][C:80]=2[CH:79]=1)=[O:77])[CH2:63][C:64](=[O:74])[NH:65][OH:66])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CCCc1nc2cc(C(=O)N[C@@H](CC(=O)NOCc3ccccc3)Cc3ccccc3)cc(C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Pd]
Agent: CCCc1nc2c(C)cc(C(=O)N[C@@H](CC(=O)NOCc3ccccc3)Cc3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1nc2cc(C(=O)N[C@@H](CC(=O)NO)Cc3ccccc3)cc(C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 12 h

Procedure:
A mixture of 7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylic acid ((R)-1-benzyl-2-benzyloxycarbamoylethyl)amide and 7-methyl-2-propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-benzoimidazole-5-carboxylic acid ((R)-1-benzyl-2-benzyloxycarbamoylethyl)amide were dissolved in EtOH (50 mL), followed by the addition of 10% Pd/C (200 mg). The final mixture was bubbled with nitrogen gas for 5 minutes, and degassed. The reaction mixture was stirred under hydrogen (1 atm) for 12 hours, and filtered through Celite®. The filtrate was concentrated to afford a pale brown oil. The oil was dissolved in 50% aqueous acetic acid, and purified by reversed phase preparative HPLC. The desired product, compound 2-b (minor component), was isolated as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: COC(=O)c1sccc1N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: COC(=O)c1sccc1-n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
At room temperature, add 20 g (0.127 mol) of methyl 3-aminothiophene-2-carboxylate in small portions to a solution of 16.80 g (0.127 mol) of 2,5-dimethoxytetrahydrofuran in 100 ml of acetic acid. After 30 minutes' stirring at room temperature, then 90 minutes at 90° C., the acetic acid is removed under reduced pressure and the residue is taken up in 100 ml of 2N sodium hydroxide solution and extracted with diethyl ether. After washing with water and rendering colourless with animal charcoal, the ethereal phase is concentrated to dryness to yield the title compound.