Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[Cl:33])[C:9]1[C:10]2[CH2:19][N:18]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:17][CH2:16][C:11]=2[N:12]=[C:13](Cl)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]1([CH2:39][C:40]([CH:42]2[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]2)=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[C:1]([O:5][C:6]([N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[Cl:33])[C:9]1[C:10]2[CH2:19][N:18]([C:20]([CH:22]3[CH2:23][CH2:24]3)=[O:21])[CH2:17][CH2:16][C:11]=2[N:12]=[C:13]([N:45]2[CH2:44][CH2:43][CH:42]([C:40](=[O:41])[CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:47][CH2:46]2)[N:14]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CN2CCCC2)CC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1Cl)c1nc(Cl)nc2c1CN(C(=O)C1CC1)CC2
Product: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1Cl)c1nc(N2CCC(C(=O)CN3CCCC3)CC2)nc2c1CN(C(=O)C1CC1)CC2

Procedure:
In the same way as Example 92 mentioned later, 4-(N-tert-butoxycarbonyl-2-chloro-4-fluorobenzylamino)-6-cyclopropylcarbonyl-2-[4-(2-pyrrolidin-1-ylacetyl)piperidino]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine was prepared from 4-(N-tert-butoxycarbonyl-2-chloro-4-fluorobenzylamino)-2-chloro-6-cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine prepared according to Process Step 1 and tert-butyl 4-(2-pyrrolidin-1-ylacetyl)piperidinecarboxylate prepared according to Reference Example 12.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[CH:16]1([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][N:27]=[C:22]3[NH:21][C:20]2=[O:28])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1COCC1>[C:12]([O:11][C:9](=[O:10])[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([N:21]2[C:22]3=[N:27][CH:26]=[CH:25][N:24]=[C:23]3[N:19]([CH:16]3[CH2:17][CH2:18]3)[C:20]2=[O:28])[CH2:3][CH2:4]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: O=c1[nH]c2nccnc2n1C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2c(=O)n(C3CC3)c3nccnc32)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled solution (0° C.) of tert-butyl cis-4-hydroxycyclohexanecarbamate (0.682 g, 3.17 mmol, Biofine International), 1-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.5578 g, 3.17 mmol), and triphenylphosphine (1.100 ml, 4.75 mmol, Sigma-Aldrich Chemical Company) in THF (17.49 ml) was added diethyl azodicarboxylate, 40 wt. % solution in toluene (1.870 ml, 4.75 mmol, Chem Impex International) dropwise. After 10 mins, the round bottomed flask was removed from the ice bath and allowed to warm to room temperature to stir. Reaction was allowed to stir for 5 h and was then concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (0.7301 g, 1.955 mmol, 61.7% yield). LCMS showed product peak at 2.13 min (m+1=374.0). NMR showed some biproduct from DEAD reagent. Product was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[S:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1.C1N=C[N:31](C(N2C=NC=C2)=O)[CH:30]=1.CN>CN(C=O)C.C(Cl)Cl>[CH3:30][NH:31][C:26]([C:24]1[S:25][C:21]([C:19]2[O:18][N:17]=[C:16]([C:4]3[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]([CH3:15])[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:5]=3)[N:20]=2)=[CH:22][CH:23]=1)=[O:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)O)s3)n2)n1
Agent: CN
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.3 %

Procedure:
To 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-thiophene-2-carboxylic acid (Intermediate 62, 316 mg, 0.80 mmol) in anhydrous DMF (4 mL) was added CDI (190 mg, 1.17 mmol). The mixture was stirred for 2 h and then heated at 50 C for 3 h. After this time more CDI (190 mg, 1.17 mmol) was added and the mixture heated at 65 C for 18 h. After cooling to room temperature, methylamine (2 M in THF, 3.5 mL, 7 mmol) was added and the mixture stirred at room temperature for 1 hr The reaction mixture was then diluted with DCM (20 mL), extracted with aqueous sodium hydroxide solution (1M, 20 mL), saturated brine (20 mL) and dried over sodium sulfate. Evaporation of the solvent gave an orange gum which was purified by preparative HPLC (Method A) and then by chromatography on silica eluting with 4% MeOH-DCM to give the title compound (27 mg, 8%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][N:14]([CH3:21])[C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])=[N:7][C:6]=12.O.O.[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COCCOC>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH2:13][N:14]([CH3:21])[C:15](=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])=[N:7][C:6]=12
Reactant: CC(C)OC(=O)N(C)CCNc1ccn2ncc(Br)c2n1
Reactant: COc1cnccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cnccc1-c1cnn2ccc(NCCN(C)C(=O)OC(C)C)nc12
Yield: 77 %

Procedure:
To 80 mg (0.22 mmol) of isopropyl (2-((3-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino)ethyl)(methyl)-carbamate was added (3-methoxypyridin-4-yl)boronic acid dihydrate (56 mg, 0.27 mmol), K3PO4 (143 mg, 0.67 mmol), PdCl2(PPh3)2 (16.8 mg, 0.022 mmol), 3 mL of DME and 1 mL of water. This mixture was microwaved at 140° C. for 0.5 hr. After cooling, it was diluted with EtOAc, and washed with water and brine. The organic layer was dried over MgSO4, concentrated, and purified on the PREP HPLC to afford the desired product in 77% yield (66.4 mg). 1H NMR (400 MHz, Acetone) δ ppm 2.87 (br. s., 3 H) 2.99 (br. s., 3 H) 3.58-3.71 (m, 2 H) 3.73-3.82 (m, 2 H) 4.09 (s, 3 H) 4.82 (td, J=6.25, 2.91 Hz, 1 H) 6.45 (br. s., 1 H) 8.21 (br. s., 1 H) 8.35 (s, 1 H) 8.43 (d, J=6.06 Hz, 1 H) 8.58 (s, 1 H) 8.77 (br. s., 1 H); LRMS (ESI) m/e 385.0 [(M+H)+, calcd for C19H24N6O3 384.0].
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CN2C(=NCCC2)C1.C([O:52][C:53](=[O:65])[CH2:54]CCCCCCCCCBr)C.COC(C)(C)C>[Cl-].C[N+](C)(C)C.C(OCOCC)C.C1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:54][C:53]([OH:65])=[O:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCCCCCCCBr
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C1CN=C2CCCN2C1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Solvent: CCOCOCC
Solvent: c1ccccc1
Solvent: COC(C)(C)C
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-glucopyranose, 0.55 g (5 mmol) of tetramethylammonium chloride and 12.42 g (100 mmol) of DBN in 350 ml of diethoxymethane is cooled to 0° C. At 0° C., 44 g (150 mmol) of 11-bromoundecanoic acid-ethyl ester, dissolved in 50 ml of benzene, is added in drops over 30 minutes while being stirred vigorously. It is stirred for two hours at 20° C. 250 ml of methyl-tert-butyl ether is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol/50 ml of water. 60 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for five hours. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of dichloromethane, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of dichloromethane. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n-hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23]CCCCC)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]>>[CH3:10][O:11][C:12](=[O:29])[C:13]1[C:14](=[C:19]([NH:23][CH2:2][C:3]2[O:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=2)[CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reactant: O=Cc1ccc(CO)o1
Product: COC(=O)c1cccc(NCc2ccc(CO)o2)c1C(=O)OC
Yield: 76 %

Procedure:
5-Hydroxymethyl-furan-2-carbaldehyde (0.95 ml, 7.5 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (SiO2, 40/60 ethyl acetate/hexanes) to give 0.97 g (76%) of yellow oil: 1H NMR (CDCl3) δ 7.35-7.27 (m, 1H), 7.05 (bs, 1H), 6.87-6.83 (m, 2H), 6.21 (d, J=3.1 Hz, 1H), 6.17 (d, J=3.2 Hz, 1H), 4.57 (s, 2H), 4.38 (bs, 2H) 3.86 (s, 3H), 3.83 (s, 3H), 1.98 (bs, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[C:23](OS(C(F)(F)F)(=O)=O)[C:24]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:25]=4[N:26]=3)=[CH:16][CH:15]=2)=[CH:12][N:11]=[CH:10]1>O1CCOCC1.CN(C=O)C>[CH2:1]([NH:8][C:23]1[C:24]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:25]=2[N:26]=[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([C:13]3[O:9][CH:10]=[N:11][CH:12]=3)=[CH:19][CH:18]=2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(Nc3ccc(-c4cnco4)cc3)nc2OS(=O)(=O)C(F)(F)F)C1
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2c(nc(Nc3ccc(-c4cnco4)cc3)nc2NCc2ccccc2)C1
Temperature: 25 °C
Yield: 86 %

Procedure:
Benzylamine (0.030 g, 0.28 mmol) was added to tert-butyl 2-(4-(oxazol-5-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.15 g, 0.28 mmol, Example 5b) in dioxane (10 mL) and DMF (0.5 mL). The reaction was stirred at rt over night. The solvent was removed under reduced pressure and the crude product redissolved in EtOAc, washed with saturated NaHCO3 and H2O. The organic layer was dried (MgSO4), filtered and concentrated to give tert-butyl 4-(benzylamino)-2-(4-(oxazol-5-yl)phenylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.120 g, 87%). No further purification.
Reaction SMILES: O=[C:2]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH2:3][CH2:4][C:5]1[C:13]2[C:12](=O)[CH2:11][CH2:10][CH2:9][C:8]=2[NH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].ClCCl.CO.N>O1CCOCC1.O1CCCC1>[N:15]1([CH2:2][CH2:3][CH2:4][C:5]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[NH:7][CH:6]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: O=C1CCCc2[nH]cc(CCC(=O)N3CCNCC3)c21
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: c1[nH]c2c(c1CCCN1CCNCC1)CCCC2
Temperature: 70 °C
Yield: 67.4 %

Procedure:
3-(3-Oxo-3-piperazin-1-yl-propyl)-1,5,6,7-tetrahydro-indol-4-one (3.8 g, 75% pure) was dissolved in 1,4-dioxane (4×50 ml) and was added to a mixture of lithium aluminum hydride (3.9 g, 7 equiv.) in 50 ml of tetrahydrofuran at 0° C. The reaction mixture was refluxed at 70° C. overnight. Thin layer chromatography (dichloromethane: methanol: ammonia 5:1:0.1) showed one major spot. The reaction mixture was quenched by DI water (6 ml), 10% sodium hydroxide (14 ml) and DI water (15 ml). The formed solid was filtered out and washed twice with 1,4-dioxane. The filtrate was concentrated and dried under high vacuum to give 3-(3-piperazin-1-yl-propyl)-4,5,6,7-tetrahydro-1H-indole (2.3 g, 79% pure).
Reaction SMILES: [N+:1](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-:2].C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[C:29]1([C:35]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:40][CH2:39][C:38](=O)[CH:37]=[CH:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C1(C)C=CC=CC=1.C(O)(=O)C>[C:29]1([C:35]2([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:36][C:37]3[C:38](=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[NH:1][N:2]=3)[CH:39]=[CH:40]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]nc2c1C=CC(c1ccccc1)(c1ccccc1)C2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
20 cm3 of ethyl diazoacetate, followed by slow addition of 210 cm3 of a solution of lithium diisopropylamide prepared beforehand from 140.7 cm3 of 1.6M n-butyllithium and 35.55 cm3 of diisopropylamine in solution in 35 cm3 of tetrahydrofuran are added dropwise to a solution, maintained at −78° C., of 35 g of 4,4-diphenylcyclohex-2-enone in 315 cm3 of tetrahydrofuran. After addition, the reaction mixture is stirred at a temperature in the region of −78° C. for 2 hours. 28.2 cm3 of glacial acetic acid are then added and the temperature is allowed to rise to the region of 20° C. 350 cm3 of toluene are then added and the resulting solution is successively washed with 200 cm3 of saturated aqueous sodium bicarbonate solution and 200 cm3 of water. The organic phase obtained is concentrated under reduced pressure in order to remove the tetrahydrofuran. The resulting toluene phase is refluxed for 4 hours in a round-bottomed flask surmounted with a Dean-Stark trap and then concentrated to dryness under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (35–70 μm), eluting with a cyclohexane/ethyl acetate (80/20) mixture; 43.1 g of ethyl 6,6-diphenyl-6,7-dihydro-2H-indazole-3-carboxylate are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: ClC(OC(Cl)C)=O.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:30][CH2:29][N:28](CC4C=CC=CC=4)[CH2:27][C:21]=3[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C>ClCCCl>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:30][CH2:29][NH:28][CH2:27][C:21]=3[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
1-Chloroethyl chloroformate (732 mg, 5.12 mmol) was added dropwise to a mixture of N-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (1.07 g, 2.56 mmol) and diisopropylethyl amine (660 mg, 5.12 mmol) in 1,2-dichloroethane (10 mL, anhydrous) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hr. Solvent was removed in vacuo, residue was dissolved in methanol (10 mL) and was stirred at room temperature overnight. Solvent was removed in vacuo, residue was dissolved in ethyl acetate and was washed with saturated aqueous sodium bicarbonate, brine and dried over sodium sulfate. Solvent was removed in vacuo and residue was triturated by diethyl ether to yield the product as a light brown solid (303 mg, 36%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O.Cl.[NH2:11][OH:12].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:12][N:11]=[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]1[O:2][CH3:1]
Reactant: COC1CCCCC1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC1CCCCC1=NO
Temperature: 70 °C

Procedure:
A mixture of 2-methoxycyclohexanone (39.0 mmol), hydroxylamine hydrochloride (72 mmol), and sodium acetate (48.8 mmol) in ethanol and water was heated at 70° C. overnight. Ethanol was removed, and the residue was dissolved in water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to give 1-(hydroxyimino)-2-methoxycyclohexane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[O:5][C:6]=1[CH3:7].[OH:12][C:13]1[CH:18]=[C:17]([CH3:19])[O:16][C:15](=[O:20])[CH:14]=1.C1CCC(N=C=NC2CCCCC2)CC1.[Na].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:14]2[C:15](=[O:20])[O:16][C:17]([CH3:19])=[CH:18][C:13]=2[OH:12])=[O:11])[O:5][C:6]=1[CH3:7]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Cc1cc(CC(=O)O)oc1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1cc(O)c(C(=O)Cc2cc(C)c(C)o2)c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.50 g (9.73 mmol) of the 4,5-dimethyl-2-furanacetic acid, 1.22 g (9.67 mmol) of 4-hydroxy-6-methyl-2-pyrone and 2.22 g (10.7 mmol) of DCC were suspended in 30 ml of chloroform, then 244 mg (2.0 mmol) of DMAP added and stirring carried out overnight at 60° C. The reaction liquid was cooled to room temperature and the insoluble material filtered off. The mother liquor was then concentrated and the residue purified by column chromatography. The solid obtained was recrystallized from diethyl ether, and Compound 7 (488 mg, 186 mmol, 19%) obtained. This was converted to the sodium salt with an equivalent quantity of sodium hydrogen carbonate.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10](=[O:12])[CH3:11])([CH2:5][N+:6]([O-])=O)[CH:3]=[CH2:4].P(Cl)(Cl)Cl.Cl>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]([O:9][C:10](=[O:12])[CH3:11])([C:5]#[N:6])[CH:3]=[CH2:4]
Reactant: C=CC(C)(C[N+](=O)[O-])OC(C)=O
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC(C)(C#N)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 g. (0.17 m) of acetic acid (3-methyl-4-nitro-1-buten-3-yl)ester was diluted with 600 cc of pyridine. To this was added dropwise a solution of 50 g. (0.32 m) PCl3 in 50 cc of CH2Cl2 over a 1/2 hour period. The mixture was stirred overnight at room temperature. Ice, followed by 600 ml. concentrated HCl, was subsequently added to the reaction mixture. Extraction with ether and chromatographic separation of the crude product yielded acetic acid (3-methyl-3-cyano-1-propen-3-yl)ester as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cc(F)ccc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2nc(CBr)ccc2c1
Temperature: 25 °C

Procedure:
To a solution of 6-fluoro-2-methylquinoline (see C. M. Leir, J. Org. Chem., vol 42, pp 911-913, 1977) (21.67 g) in carbon tetrachloride (700 mL) were added N-bromosuccinimide (26.32 g) and benzoyl peroxide (1.62 g). The mixture was brought to reflux with two spot lights of 150 Watts. The mixture was irradiated for 24 hours at reflux. The mixture was then cooled to room temperature, evaporated to dryness and chromatographed on flash silica gel using pure toluene as eluant to give, as the slower running compound, a beige solid (11.9 g); m.p. 90°-92° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:30])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:19]=2)[C:7]=1[C:31]([O:33]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:32])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.CCOCC>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:30])[C@H:10]2[NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:19]=2)[C:7]=1[C:31]([OH:33])=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(C(=O)NCc4ccccc4)cs3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](Nc3nc(C(=O)NCc4ccccc4)cs3)[C@H]2SC1
Reaction time: 0.75 h
Yield: 80.4 %

Procedure:
A mixture of 175 mg of (6R-trans)-3-[(acetyloxy)methyl]-8-oxo-7-[[4-[[(phenylmethyl)amino]carbonyl]-2-thiazolyl]amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, trifluoroacetic acid and anisole in dichloromethane was stirred for 45 minutes. The addition of dichloromethane, ether and petroleum ether caused precipitation. The solid was collected and washed with ether and petroleum ether, giving 105 mg of the desired product.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:13]2[N:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8][CH2:7]1)=O)C>C1COCC1.C(OCC)C.O>[CH:6]1([CH2:4][OH:3])[CH:13]2[N:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)C1CCN2CCCC12
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1CCN2CCCC12
Reaction time: 12 h

Procedure:
Lithiumaluminumhydride (0.3 g) was added to a solution of hexahydropyrrolizine-1-carboxylic acid ethyl ester (0.97 g) in THF (3 ml). After 12 hours, the reaction mixture was diluted with diethyl ether and hydrolyzed by cautious addition of water (0.7 ml). The resulting precipitate was filtered off and the filtrate was concentrated. The product with the molecular weight of 141.21 (C8H15NO); MS (ESI): 142 (M+H+) was obtained in this way.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][N:15]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]3[CH2:26][CH2:25][C:24](=O)[C:21]=32)=[N:16]1>O1CCCC1.O>[CH3:14][N:15]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]3[CH2:26][CH2:25][C:24](=[CH:5][C:3]#[N:4])[C:21]=32)=[N:16]1
Reactant: Cn1cc2c3c(ccc2n1)CCC3=O
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc2c3c(ccc2n1)CCC3=CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a suspension of 60% sodium hydride (116 mg, 2.90 mmol) in tetrahydrofuran (8 mL) was added diethyl cyanomethylphosphonate (516 μL, 3.19 mmol), and the mixture was stirred at room temperature for 30 min. A solution of 2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-one (180 mg, 0.97 mmol) in tetrahydrofuran (2 mL) was added thereto, and the mixture was stirred at 50° C. for 30 min. The reaction solution was diluted with water, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=35/65→70/30) to give the title compound (138 mg, yield 68%).