Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.[C:24](Br)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:24]([N:1]([C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:3]=1)[C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Br)c1ccccc1
Reactant: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccco1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: N#Cc1c(SCCc2ccccn2)nc(N(C(=O)c2ccccc2)C(=O)c2ccccc2)nc1-c1ccco1
Temperature: 50 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
To a stirred solution of 200 mg (0.62 mmol) 2-amino-4-furan-2-yl-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile and 8 mg (0.06 mmol) 4-dimethylaminopyridine in 2 ml pyridine was added dropwise 0.73 ml (6.18 mmol) benzoyl bromide and the reaction mixture stirred at 50° C. for 3 hours. The reaction mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. Chromatography (1/2 ethyl acetate/hexane then 1/1 ethyl acetate/hexane then ethyl acetate) followed by trituration in ether afforded 100 mg (30%) N-benzoyl-N-[5-cyano-4-furan-2-yl-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidin-2-yl]-benzamide as a white crystalline solid. ES-MS m/e (%): 532 (M+H+, 68).
Reaction SMILES: C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:38]([O:40][C:41](=[O:53])[CH2:42][C@H:43]1[C:51]2[C:46](=[CH:47][C:48]([OH:52])=[CH:49][CH:50]=2)[CH2:45][CH2:44]1)[CH3:39].[CH3:54][C:55]1[N:56]=[C:57]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:58][C:59]=1[CH2:60][CH2:61]O>C1COCC1.C(Cl)Cl>[CH3:54][C:55]1[N:56]=[C:57]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[O:58][C:59]=1[CH2:60][CH2:61][O:52][C:48]1[CH:47]=[C:46]2[C:51](=[CH:50][CH:49]=1)[C@H:43]([CH2:42][C:41]([O:40][CH2:38][CH3:39])=[O:53])[CH2:44][CH2:45]2
Reactant: Cc1nc(-c2ccccc2)oc1CCO
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3oc(-c4ccccc4)nc3C)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
ADDP (0.205 g, 0.81 mmol) was added to a mixture of PPh3 (0.212 g, 0.81 mmol), ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (0.107 g, 0.49 mmol), and 2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethanol (step 4, Example 51, 0.110 g, 0.54 mmol) in THF (5 mL). The reaction was stirred overnight at rt, and additional ADDP (0.136 g, 0.54 mmol) and PPh3 (0.141 g, 0.54 mmol) were added with CH2Cl2 (5 mL). The solution was stirred for 24 hours at rt and filtered. The filtrate was evaporated and the resulting mixture was purified by Biotage using a gradient 0 to 50%. EtOAc/hexane. Gave ethyl {(1S)-5-[2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethoxy]-2,3-dihydro-1H-inden-1-yl}acetate (0.145 g, 66% yield) as yellowish oil. ES-MS m/z 406.2 ((MH)+); HPLC RT (min.) 3.89; 1H NMR (Acetone-d6) δ 7.85-7.82 (m, 2H), 7.36-7.30 (m, 3H), 6.94 (d, 1H), 6.65 (s, 1H), 6.60-6.55 (m, 1H), 4.10 (t, 2H), 3.98 (q, 2H), 3.31-3.27 (m, 1H), 3.03 (t, 2H), 3.27-2.51 (m, 3H), 2.24-2.14 (m, 2H), 2.18 (s, 3H), 1.58-1.53 (m, 1H), 1.08 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([N:13]([CH:27]([CH3:29])[CH3:28])[C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)=[O:12])=[C:4]([CH3:30])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:38]([CH3:49])([C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[CH3:49][C:38]([O:1][C:2]1[CH:3]=[C:4]([CH3:30])[C:5]([C:11](=[O:12])[N:13]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:15]2)[CH:27]([CH3:28])[CH3:29])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])([C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:44]([O:46][CH2:47][CH3:48])=[O:45]
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Oc1cc(C)c(C(=O)N(C(C)C)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-])C(=O)OCC
Temperature: 80 °C
Reaction time: 8 h
Yield: 105.5 %

Procedure:
To a solution of the obtained 2-methyl-2-propanyl (3R)-3-{[(4-hydroxy-2-methyl-5-nitrophenyl)carbonyl](2-propanyl)amino}-1-piperidinecarboxylate (138 g) in N,N-dimethylformamide (1000 ml) were added potassium carbonate (91 g), diethyl 2-bromo-2-methylmalonate (94 g), and the mixture was stirred at 80° C. for 8 hours. The reaction solution was allowed to cool to room temperature, filtered through celite, and to the filtrate were added a 5% aqueous sodium hydrogen sulfate solution and ethyl acetate, and extracted with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give diethyl methyl(5-methyl-4-{[(3R)-1-{[(2-methyl-2-propanyl)oxy]carbonyl}-3-piperidinyl](2-propanyl)carbamoyl}-2-nitrophenoxy)propanedioate (205 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([N:12]2[CH2:13][C@@H:9]([CH3:8])[CH2:10][C@H:11]2[C:14]([OH:16])=[O:15])[CH:21]=[CH:22][CH:23]=1
Reactant: C[C@@H]1CN[C@H](C(=O)O)C1
Reactant: Brc1ccc(Br)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: C[C@H]1C[C@@H](C(=O)O)N(c2cccc(Br)c2)C1
Temperature: 95 °C

Procedure:
To (4S)-4-methyl-L-proline trifluoroacetate (2.92 g, 8.17 mmol), 1,4-dibromobenzene (2.9 g, 12.27 mmol), potassium carbonate (3.95 g, 28.6 mmol), and copper iodide (315 mg, 1.64 mmol) was added dry DMF (30 mL) under dry nitrogen. The reaction flask was thoroughly degassed with dry nitrogen and heated at 95° C. for 3 days. Water and hexane were added and the organic phase was separated and discarded (to remove excess 1,4-dibromobenzene). The pH of the aqueous phase was adjusted to 3 with aqueous 10% HCl and the product extracted with EtOAc (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (AcOH/EtOAc/Hex, 0.5/49.5/50) to afford (4S)-1-(3-bromophenyl)-4-methyl-L-proline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([C:11](=[CH:20]OCC)[C:12]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])#[N:10]>>[C:9]([C:11](=[CH:20][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)[C:12]([NH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])#[N:10]
Reactant: Nc1cccc(F)c1
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Product: CCOC(=O)NC(=O)C(C#N)=CNc1cccc(F)c1

Procedure:
3-Fluoroaniline (0.05 mol) is reacted with α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide (0.05 mol) to yield α-cyano-β-(3-fluoroanilino)-N-ethoxycarbonylacrylamide, m.p. 169.5°-171.0°, which is heated at reflux in tetralin to yield 5-cyano-1-(3-fluorophenyl)uracil, m.p. 245.5°-246.5°.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][C:8]([C:27]([OH:29])=[O:28])=[C:9]([OH:26])[C:10]=2[CH2:11][C:12]2[C:21]([OH:22])=[C:20]([C:23]([OH:25])=[O:24])[CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]3)[CH:6]=1.[OH-].[Na+:31]>O1CCOCC1.O1CCOCC1.O>[CH:16]1[CH:17]=[C:18]2[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[C:21]([O-:22])=[C:12]([CH2:11][C:10]3[C:4]4[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=4)[CH:7]=[C:8]([C:27]([OH:29])=[O:28])[C:9]=3[O-:26])[C:13]2=[CH:14][CH:15]=1.[Na+:31].[Na+:31]
Reactant: O=C(O)c1cc2ccccc2c(Cc2c(O)c(C(=O)O)cc3ccccc23)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2ccccc2c(Cc2c([O-])c(C(=O)O)cc3ccccc23)c1[O-]

Procedure:
A second octreotide-pamoate complex was prepared by dissolving pamoic acid (19.4 mg, 0.05 mmol) in 0.4 N NaOH (250 μL) and dioxane (250 μL) to provide a solution of sodium pamoate in dioxane/water (1:1). Octreotide acetate (50 mg, 0.05 mmol) was dissolved in dioxane/water (1:1, 200 μL). The octreotide acetate solution was added drop wise to the sodium pamoate with mixing to provide a light yellow, homogenous solution. This material was lyophilized to dryness providing a light yellow powder (65 mg). The octreotide/pamoate ratio of this preparation was 1.02 as measured by RP-HPLC. These two preparations were used to prepare new PLGA microparticle formulations.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18]([C:22]1[N:23]=[N:24][C:25](Cl)=[CH:26][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:30][CH:29]=1)[CH2:19][CH2:20][CH3:21]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:25]2[N:24]=[N:23][C:22]([CH2:18][CH2:19][CH2:20][CH3:21])=[C:27]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:32][CH:33]=3)[CH:26]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCc1nnc(O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of trans-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (1.0 mmol) in anhydrous THF at 0° C. may be treated with sodium hydride (60% dispersion in mineral oil) (1.3 mmol). After stirring for 15 min the reaction mixture is allowed to come to room temperature. To the alkoxide solution is added 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.74 mmol). After completion of the addition, the reaction mixture is warmed to 50° C. and is stirred 3 hours. The reaction is concentrated onto SiO2, purification via flash chromatography may be used (20-50% ethyl acetate in hexanes) to provide trans-{-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-cyclohexyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([CH:19]=1)[NH2:18].N1C=CC=CC=1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>C(#N)C>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([NH:18][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH:19]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)c(Cl)n2n1
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)c(Cl)n2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
A stirred solution of 5-(3-chloro-6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylaniline (0.025 g, 0.0867 mmol) in acetonitrile (1 mL) containing pyridine (0.261 mmol) is added trimethylacetylchloride (0.0867 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford the title compound (0.030 g, 93%) as a white solid: LCMS (m/z)=373.4, 375.3 [M+H]+, tR=2.74 min. (compound same as Example 109)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2.[CH2:16]([O:18][P:19]([O:23]CC)[O:20][CH2:21][CH3:22])[CH3:17]>>[CH:10]12[CH2:15][CH:13]([CH:12]=[CH:11]1)[CH2:14][CH:9]2[CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P:19](=[O:23])([O:20][CH2:21][CH3:22])[O:18][CH2:16][CH3:17]
Reactant: BrCCCCCOCC1CC2C=CC1C2
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCCCOCC1CC2C=CC1C2)OCC
Temperature: 160 °C

Procedure:
5-[[(5-bromopentyl)oxy]methyl]bicyclo[2.2.1]hept-2-ene 5 (10 g) was added to 50 mL of triethylphosphite and the solution was heated at 160° C. under nitrogen for 20 h. The solution was cooled to room temperature and excess triethylphosphite was removed under reduced pressure. The oily residue was distilled in vacuo to give 6 as a colorless oil, b.p. 145° C., 0.15 Torr. 1H NMR (500 MHz, 25° C., CDCl3): 8 (endo isomer, ˜85%) 6.07-6.05 (m, 1H, olefinic), 5.87-5.85 (m, 1H, olefinic), 4.06-4.00 (m, 4H, POCH2CH3), 3.34-2.94 (m, 6H, CH2), 2.84 (br s, 1H, bridgehead CH), 2.73 (br s, 1H, bridgehead CH), 2.30-2.20 (m, 1H, exo CH), 1.70-1.49 (m, 9H, CH2), 1.27 (t, 6H, POCH2CH3), 0.44-0.41 (m, 1H, endo CH of CH2); (exo isomer, partial) 6.02-6.01 (m, 1H, olefinic), 2.70 (br s, 1H, bridgehead CH). 13C {1H} NMR (125 MHz, 25° C., CDCl3): δ (endo isomer) 137.0 (olefinic CH), 132.5 (olefinic CH), 74.6 (CH—CH2O), 61.4 (d, |2JC-P|=6 Hz, POCH2CH3), 49.4 (CH2 bridge), 44.0 (bridgehead CH), 42.2 (bridgehead CH), 38.9 (CH—CH2O), 29.3 (CH2), 27.4 (CH2), 27.3 (CH2), 25.7 (d, |1JC-P|=140 Hz, CH2P), 22.4 (CH2), 22.3 (CH2), 16.5 (d, |3JC-P|=5.4 Hz, POCH2CH3); (exo isomer, partial) 136.6 (olefinic CH), 75.6 (CH—CH2O), 45.0 (CH), 43.8 (CH), 41.6 (CH), 29.8 (CH2). 31P {1H} NMR (200 MHz, 25° C., CDCl3): δ 32.6
Reaction SMILES: [CH3:1][C@H:2]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]#[CH:4].[N:13]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].C(N(C(C)C)C(C)C)C>C(#N)C.[Cu]I>[C:8]([O:7][C:6](=[O:12])[NH:5][C@H:2]([C:3]1[N:15]=[N:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:4]=1)[CH3:1])([CH3:11])([CH3:10])[CH3:9]
Reactant: [N-]=[N+]=Nc1ccc(Cl)cc1
Reactant: C#C[C@H](C)NC(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](NC(=O)OC(C)(C)C)c1cn(-c2ccc(Cl)cc2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of (S)-tert-butyl but-3-yn-2-ylcarbamate (250 mg, 1.48 mmol), 1-azido-4-chlorobenzene (227 mg, 1.48 mmol, 1.0 equiv), and N-ethyl-N-isopropylpropan-2-amine (0.77 mL, 4.43 mmol, 3.0 equiv) in anhydrous acetonitrile (14.8 mL) was stirred at room temperature for 10 min. Copper(I) iodide (563 mg, 2.95 mmol, 2.0 equiv) was then added in portions. The mixture was stirred at room temperature for 30 min. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic extracts were washed with water (30 mL), saturated aqueous sodium chloride (30 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (S)-tert-butyl(1-(1-(4-chlorophenyl)-1H-1,2,3-triazol-4-yl)ethyl)carbamate (0.428 g, white solid) in 90% yield. 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 5.02 (m, 1H), 1.63 (d, J=6.8 Hz, 3H), 1.46 (s, 9H). MS m/z 323.1 (M+H)+; Rt-0.92 min.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[C:7]1([N:6]2[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:3][N:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: C1CNCCN1
Product: c1ccc(-n2nnnc2N2CCNCC2)cc1
Yield: 99.7 %

Procedure:
Using 5-chloro-1-phenyl-1H-tetrazol (2.10 g) and piperazine (10.0 g), and reaction at 100° C. in the same manner as in Example 196 (1), 1-(1-phenyl-1H-tetrazol-5-yl)piperazine (2.67 g) was obtained as a pale-yellow powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:5]=1[CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)=[NH:9].C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:26][O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:4]([O:3][CH3:2])[C:5]=1[CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[CH3:29])[N:15]=1)=[NH:9]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2)cs1
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(C2CCCN2C)cs1
Temperature: 10 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
To 72 mg (0.2 mmol) N-(2,6-dimethoxybenzyl)-N′-(4-pyrrolidine-2-yl-1,3-thiazole-2-yl)guanidine hydrochloride, Example 147, and 20 mg formaline (37% aqueous solution) were added 51 mg of sodium triacetoxyborohydride at 10° C., the mixture was then stirred for 30 minutes at 10° C. and 2 hours at room temperature. For workup, the mixture was evaporation-concentrated, the residue was dissolved in dichloromethane, was washed with water, was dried and was concentrated once again. Following chromatography of the crude product on RP-silica gel (Chromabond column, acetonitrile/water+0.1% glacial acetic acid; 0-100%), 22 mg of a white solid were obtained, ESI-MS [M+H+]=376.15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[CH:17]=[CH:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[CH3:22].[B]=O.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[CH:36]=O)[CH:29]=[CH:28]1.B(OC(C)C)(OC(C)C)OC(C)C.N1CCCCC1.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2/[CH:36]=[CH:22]/[C:21](=[O:23])[CH2:20][C:19](=[O:24])/[CH:18]=[CH:17]/[C:4]2[CH:5]=[CH:6][C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:8][C:3]=2[O:2][CH3:1])[CH:29]=[CH:28]1
Reactant: COc1cc(OCc2ccncc2)ccc1C=CC(=O)CC(C)=O
Reactant: O=Cc1cccc2cc[nH]c12
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: COc1cc(OCc2ccncc2)ccc1/C=C/C(=O)CC(=O)/C=C/c1cccc2cc[nH]c12
Temperature: 70 °C
Yield: 35.6 %

Procedure:
In a 20 mL reaction vessel were placed 88 mg (0.27 mmol) of 6-[2-methoxy-4-(4-pyridylmethoxy)phenyl]hex-5-ene-2,4-dione and 26.4 mg (0.380 mmol) of boron oxide and they were dissolved in 1.76 mL of ethyl acetate. To the mixture under stirring at 70° C., 40 mg (0.27 mmol) of 1H-indole-7-carboxaldehyde and 124 μL (0.54 mmol) of triisopropyl borate were sequentially added. After the mixture was stirred at the same temperature for 1 hour, a solution of 5.4 μL (54 μmol) of piperidine in ethyl acetate (0.27 mL) was added and the mixture was further stirred for 1 hour. To the reaction mixture was added a 1:1 solution (0.8 mL) of 1 N hydrochloric acid and saturated brine at room temperature and the mixture was stirred for 5 minutes to 1 hour (further, the mixture was neutralized with a saturated sodium bicarbonate aqueous solution as needed). The resulting organic phase was directly subjected to purification by silica gel column chromatography (hexane/ethyl acetate or methylene chloride/methanol) to give 43.5 mg (36% yield) of the title compound as a yellow powder.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([O:4][C:5]([NH:7][C:8]([CH3:27])([CH3:26])[C:9]([NH:11][C@H:12]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:13]([OH:15])=O)=[O:10])=[O:6])[CH3:3].Cl.[NH:30]1[CH2:35][CH2:34][C:33]2([C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36]2)[CH2:32][CH2:31]1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.Cl>ClCCl.[Cl-].[Na+].O>[N:30]1([C:13]([C@H:12]([NH:11][C:9](=[O:10])[C:8]([NH:7][C:5]([O:4][C:2]([CH3:3])([CH3:28])[CH3:1])=[O:6])([CH3:26])[CH3:27])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[O:15])[CH2:35][CH2:34][C:33]2([C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36]2)[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: C1=CC2(CCNCC2)c2ccccc21
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC2(C=Cc3ccccc32)CC1
Reaction time: 4 h
Yield: 87.9 %

Procedure:
To a stirred solution of α(R)-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-2,2-dimethyl-1-oxoethyl]amino]-1H-indole-3-propanoic acid (50 mg, 0.13 mmol), (Example 4, Step D) spiro[1H-indene-1,4'-piperidine]hydrochloride (28.5 mg, 0.13 mmol) (Chambers, M. et al, J. Med. Chem. 1992, 35, 2033-2039), HOBT (17.3 mg, 0.13 mmol) and N-methylmorpholine (14.1 μL, 0.13 mmol) in dichloromethane (5 mL) at room temperature was added EDC (49.3 mg, 0.26 mmol). The reaction mixture was stirred for four hours and poured into a mixture of brine (10 mL) and HCl (3N, 1 mL). The mixture was extracted with ethyl acetate (20 mL) and the organic extract was dried (MgSO4) and evaporated. The residue was purified by silica gel column eluting with a solvent gradient of 40-60% ethyl acetate in hexane to give the product (63.6 mg, 89%).
Reaction SMILES: O[C:2]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13](=[O:19])[O:14]C(C)(C)C)[CH2:5][CH2:4][CH2:3]1.[OH-].[K+]>C(O)C>[C:2]12([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:12][C:13](=[O:14])[O:19]1)[CH2:3][CH2:4][CH2:5]2
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C1(O)CCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1Nc2ccccc2C2(CCC2)O1
Yield: 57.7 %

Procedure:
A solution of tert-butyl [2-(1-hydroxycyclobutyl)phenyl]carbamate (0.86 g, 3.3 mmol) in ethanol (30 mL) was stirred with potassium hydroxide (0.39 g, 6.9 mmol) at room temperature for 3 hours. The product was extracted with ethyl acetate (50 mL), dried with sodium sulfate, and concentrated to give spiro[3,1-benzoxazine-4,1′-cyclobutan]-2(1H)-one (0.36 g, 58%) as a white solid. 1H NMR (DMSO-d6): δ 10.21 (s, 1H), 7.47 (dd, 1H, J=7.6, 1.2 Hz), 7.28 (td, 1H, J=7.6, 1.4 Hz), 7.08 (td, 1H, J=7.5, 1.2 Hz), 6.9 (dd, 1H, J=7.9, 0.9 Hz), 2.49-2.41 (m, 2H), 2.06-1.96 (m, 2H), 1.88-1.77 (m, 2H). MS (ESI) m/z 190 ([M+H]+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH2:13][C@H:12]2[N:9]([C:10](=[O:24])[C@@H:11]2[C@H:14]([O:16][Si](C(C)(C)C)(C)C)[CH3:15])[C:8]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[O:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>CO.Cl>[C:1]([O:4][C:5]1[CH2:13][C@H:12]2[N:9]([C:10](=[O:24])[C@@H:11]2[C@H:14]([OH:16])[CH3:15])[C:8]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[O:26])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(COC(=O)C2=CC=C(OC(C)=O)C[C@@H]3[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N23)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(COC(=O)C2=CC=C(OC(C)=O)C[C@@H]3[C@@H]([C@@H](C)O)C(=O)N23)cc1
Yield: 42.3 %

Procedure:
To a solution of 4-methoxybenzyl (7R,8S)-5-acetoxy-8-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-9-oxo-1-azabicyclo[5.2.0]non-2,4-diene-2-carboxylate (88 mg, 0.17 mM) in methanol (6 ml) was added hydrochloric acid (10 drops, 2N). After 6 hours the solvent was evaporated and the product purified by chromatography on silica (10 ml), eluting with ethyl acetate/dichloromethane, (1:1) to give 4-methoxybenzyl (7R,8S)-5-acetoxy-8-[(1R)-1-hydroxyethyl]-9-oxo-1-azabicyclo[5.2.0]non-2,4-diene-2-carboxylate (29 mg, 39%).