Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][C:17]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH2:20]2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:19][CH2:18][C:17]4([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[O:21][CH2:20]4)[CH2:16][CH2:15]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Reactant: c1ccc2c(c1)OCC21CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)COc3ccccc34)nn2)n1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
A solution (4 ml) of 3-Chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (69 mg), spiro[1-benzofuran-3,4′-piperidine] (62 mg) and potassium carbonate (54 mg) in N,N-dimethylformamide was stirred at 70° C. overnight. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The residue was purified by silica gel chromatography (33% ethyl acetate/hexane) to give the object product (42 mg, 35%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2([NH:14][C:15]([C:17]3([NH:20][C:21]([C:23]4[N:27]5[C@@:28]([CH2:41][C:42]6[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=6)([CH3:40])[C:29](=[O:39])[N:30]([C:31]6[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=6)[C:26]5=[N:25][CH:24]=4)=[O:22])[CH2:19][CH2:18]3)=[O:16])[CH2:13][CH2:12]2)[CH:6]=1.[C:50](OC(=O)C)(=[O:52])[CH3:51]>C(Cl)Cl>[C:50]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2([NH:14][C:15]([C:17]3([NH:20][C:21]([C:23]4[N:27]5[C@@:28]([CH2:41][C:42]6[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=6)([CH3:40])[C:29](=[O:39])[N:30]([C:31]6[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=6)[C:26]5=[N:25][CH:24]=4)=[O:22])[CH2:18][CH2:19]3)=[O:16])[CH2:12][CH2:13]2)[CH:6]=1)(=[O:52])[CH3:51]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5cc(CN)ccn5)CC4)CC3)n21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Product: CC(=O)NCc1ccnc(C2(NC(=O)C3(NC(=O)c4cnc5n4[C@](C)(Cc4ccc(C#N)cc4)C(=O)N5c4cc(Cl)cc(Cl)c4)CC3)CC2)c1
Reaction time: 0.08 h
Yield: 62.6 %

Procedure:
(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid {1-[1-(4-aminomethyl-pyridin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-amide dihydrochloric acid salt (40 mg, 0.0539 mmol) was suspended in DCM (1 mL). TEA (0.038 mL, 0.269 mmol) was then added and the reaction mixture became homogeneous. Acetic anhydride (0.00624 mL, 0.0646 mmol) was then added. Stirred for 5 min. Solvent was evaporated. The resultant crude product was purified by reverse phase HPLC using 30-100% ACN/water as the gradient. Solvent was evaporated. The product was redissolved in 10% MeOH/DCM and filtered through a basic (NH2) cartridge. Solvent was evaporated to afford 24 mg of the title compound as a white solid, m/z 711.7 [M+1]+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]([C:19](=[O:25])[CH:20](OCC)O)=[CH:15][C:10]=1[C:11]([O:13]C)=O)C1C=CC=CC=1.[F:26][C:27]1[CH:28]=[C:29]([C:34]2[N:38]=[C:37]([CH3:39])[N:36]([CH2:40][CH2:41][C:42]([NH2:45])([CH3:44])[CH3:43])[N:35]=2)[CH:30]=[C:31]([F:33])[CH:32]=1>>[F:33][C:31]1[CH:30]=[C:29]([C:34]2[N:38]=[C:37]([CH3:39])[N:36]([CH2:40][CH2:41][C:42]([NH:45][CH2:20][CH:19]([C:16]3[CH:17]=[CH:18][C:9]([OH:8])=[C:10]([CH2:11][OH:13])[CH:15]=3)[OH:25])([CH3:43])[CH3:44])[N:35]=2)[CH:28]=[C:27]([F:26])[CH:32]=1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(C(=O)OC)c1
Reactant: Cc1nc(-c2cc(F)cc(F)c2)nn1CCC(C)(C)N
Product: Cc1nc(-c2cc(F)cc(F)c2)nn1CCC(C)(C)NCC(O)c1ccc(O)c(CO)c1

Procedure:
The compound is obtained according to general working method A from 121 mg (0.35 mmol) of methyl 2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-benzoate and 98 mg (0.35 mmol) of 3-[3-(3,5-difluoro-phenyl)-5-methyl-[1,2,4]triazol-1-yl]-1,1-dimethyl-propylamine. Yield: 9 mg (6%); mass spectroscopy [M+H]+=447.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[N:14]=1.O>CN(C=O)C>[OH:19][C:15]1[N:14]=[C:13]([NH:12][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])[CH:18]=[CH:17][CH:16]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: Nc1cccc(O)n1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccc(O)n1
Temperature: 85 °C
Yield: 29.5 %

Procedure:
A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8 and 1.5 g (12.8 mM) of 2-amino-6-hydroxypyridine in 25 ml of anhydrous DMF was heated at 85° C. for 5 hrs., cooled, and poured into 100 ml of water. The resulting precipitate was collected, washed successively with water, ethanol, ethyl acetate, and ether. Recrystallization from ethanol gave 1.0 g of the above urea as a yellow solid, m.p. 233°-234° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[Cl:16])=[N:6][CH:7]=1.[N+:17]([C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23])([O-:19])=[O:18].O.CO>O1CCOCC1>[N+:17]([C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([NH:24][C:25]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([O:8][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[C:10]([Cl:16])[CH:11]=1)=[O:26])=[O:23])([O-:19])=[O:18]
Reactant: O=C=NC(=O)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Oc2ncc(Br)cn2)c(Cl)c1
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(Oc2ncc(Br)cn2)c(Cl)c1
Yield: 84.5 %

Procedure:
Into a flask, a solution obtained by dissolving 6.80 g of the above 4-(5-bromo-2-pyrimidinyloxy)-3-chloroaniline in 30 ml of dioxane, was introduced, and a solution obtained by dissolving 5.76 g of 2-nitrobenzoylisocyanate in 30 ml of dioxane, was dropwise added thereto, and then the mixture was reacted at room temperature for 9 hours. After the completion of the reaction, the product was poured into water, subjected to filtration and washed with hot water. The crystals thereby obtained were put into methanol, and stirred, and then subjected to filtration again, to obtain 9.42 g of the desired product having a melting point of from 234 to 236° C.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH:16]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[CH3:40].[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:37])([F:38])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH3:40])[CH:16]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(NC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 500 mg of benzyl carbamate prepared in Example 4, Step B and 0.12 mL of iodomethane in 5 mL of DMF was added 60 mg of 60% sodium hydride in mineral oil. After 2 hours, the reaction was quenched with 2N hydrochloric acid and water and extracted twice with ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 25% ethyl acetate in hexanes to obtain 500 mg of title compound as an oil. NMR (CDCl3): δ1.80-2.0 (m, 3H), 2.0-2.2 (m, 1H), 2.80 and 2.87 (2 br s, 3H), 3.05-3.15 (m, 1H), 3.9-4.0 (m, 1H), 4.36 and 4.40 (2 s, 1H), 4.4-4.55 (m, 1H), 4.55-4.85 (2 br m, 1H), 4.91 and 5.03 (2 br s, 2H), 7.0-7.3 (m, 10H), 7.58 (br s, 2H), 7.72 (s, 1H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[O:7])CCC.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=2)=[O:7]
Reactant: COCCN
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O
Product: COCCNC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and 2-methoxy-ethylamine in analogy to example B-5; MS-(+)-ion: M+1=339.0.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([CH2:23][CH2:24][F:25])[C:19]([O:21][CH3:22])=[O:20])=O)(C)(C)C>Cl.CO>[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)([CH2:23][CH2:24][F:25])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C(CCF)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: Cl
Solvent: CO
Product: COC(=O)C(CCF)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from Step A (100 mg, 0.217 mmol) and 4 N HCl/MeOH (10 mL) was stirred at room temperature for 2 h. After removing the solvent, the residue was dried in vacuo to afford the title compound as brown oil. LC/MS m/z=361.1[M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[O:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)[CH3:30].C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C4C=CC=CC=4)=C(C)C=3)=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[C:22]([C:35]4[CH:34]=[CH:33][CH:32]=[C:31]([O:29][CH3:30])[CH:36]=4)[C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Reactant: COc1cccc(B(O)O)c1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(-c4cccc(OC)c4)c3)cn2)CC1

Procedure:
5′-(3′-Methoxy-6-methyl-biphenyl-3-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 3-methoxylphenyl boronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester, above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C28H31N3O4 [M+H]+: 474.2388. Found: 474.2390
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19][CH3:20])=[O:18])[C:7](=[N:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:6][CH2:5][O:4][CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(#N)C.C(O)(=O)C>[CH3:1][C:2]1([C:17]([O:19][CH3:20])=[O:18])[C@H:7]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COC(=O)C1(C)COCCC1=N[C@H](C)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)C1(C)COCC[C@H]1N[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 36.5 %

Procedure:
Methyl 3-methyl-4-((R)-1-phenylethylimino)-tetrahydro-2H-pyran-3-carboxylate (crude, 13.53 mmol) in acetonitrile-acetic acid (1:1, 80 mL) was treated with NaBH(OAc)3 and stirred for 2.5 h at 0° C. Following concentration in vacuo, the residue was dissolved in ethyl acetate (200 mL), washed with saturated NaHCO3 until the aqueous phase was basic, dried over MgSO4, and purified by chromatography with 20% ethyl acetate/hexane to yield 1.37 g (37% in 2 steps) of (4R)-methyl 3-methyl-4-((R)-1-phenylethylamino)-tetrahydro-2H-pyran-3-carboxylate. MS: (M+H)+=278.1.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.O.[NH2:36][CH:37]1[C:43]2([CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)[O:42][C:41]2[CH:49]=[CH:50][CH:51]=[CH:52][C:40]=2[NH:39][C:38]1=[O:53].[NH:54]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C@H:55]([C:57](O)=[O:58])[CH3:56]>CN(C=O)C.CCOC(C)=O>[O:58]=[C:57]([NH:36][CH:37]1[C:43]2([CH2:44][CH2:45][O:46][CH2:47][CH2:48]2)[O:42][C:41]2[CH:49]=[CH:50][CH:51]=[CH:52][C:40]=2[NH:39][C:38]1=[O:53])[C@@H:55]([NH:54][C:60](=[O:61])[O:62][C:63]([CH3:66])([CH3:65])[CH3:64])[CH3:56]
Reactant: NC1C(=O)Nc2ccccc2OC12CCOCC2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1C(=O)Nc2ccccc2OC12CCOCC2
Reaction time: 48 h
Yield: 90.6 %

Procedure:
A solution of HBTU (550 mg, 1.45 mmol, Eq: 1.2) and HOBT.H2O (222 mg, 1.45 mmol, Eq: 1.2) in DMF (8 mL) were added to a solution of 3-amino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-4(5H)-one (0.3 g, 1.21 mmol, Eq: 1.00), BOC-Ala-OH (229 mg, 1.21 mmol, Eq: 1.00) and TEA (367 mg, 505 μl, 3.62 mmol, Eq: 3) in DMF (8 mL). After 2 d, the mixture was poured into EtOAc, washed with 1:1 sat NaHCO3/sat NaCl, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford tert-butyl (2S)-1-oxo-1-(4-oxo-2′,3′,4,5,5′,6′-hexahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-3-ylamino)propan-2-ylcarbamate (0.46 g, 91%) as a white foam. MS m/z 420.0 (MH+)
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([NH2:24])[C:18](=[CH:22][CH:23]=1)[C:19](O)=[O:20]>>[F:13][C:14]([F:25])([F:26])[C:15]1[CH:16]=[C:17]2[C:18]([C:19](=[O:20])[N:6]3[C:5]4[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=4[NH:3][C:2]3=[N:24]2)=[CH:22][CH:23]=1
Reactant: Cc1cc2nc(Cl)[nH]c2cc1C
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Product: Cc1cc2[nH]c3nc4cc(C(F)(F)F)ccc4c(=O)n3c2cc1C

Procedure:
3-Trifluoromethyl-8,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chloro-5,6-dimethylbenzimidazole and 4-trifluoromethylanthranilic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1N.N([O-])=O.[Na+].[BrH:16]>O>[Br:16][C:3]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Br
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2-methyl-6-nitroaniline (75.0 g, 0.493 mole) and 40 ml of hydrobromic acid (48% solution) in 135 ml of water was cooled to 0°. During a one hour period a solution of sodium nitrite (36.2 g, 0.51 mole) in 60 ml of water was added to the reaction mixture. The mixture was suction filtered through a sintered glass funnel, collecting the filtrate in a flask cooled by a dry ice-acetone bath. The filtrate was placed in a jacketed addition funnel cooled by a dry ice-acetone bath. During a five minute period this solution was added to a stirred mixture of cuprous bromide (77.8 g, 0.51 mole) in 165 ml of hydrobromic acid (48% solution). After complete addition, the mixture was stirred at room temperature for approximately 18 hours, heated at reflux for two hours, then steam distilled. The distillate was extracted with methylene chloride and the extract washed with 2 N aqueous sodium hydroxide, followed by several portions of saturated aqueous sodium chloride solution. The organic phase was passed through phase separation filter paper and evaporated under reduced pressure to give 1-bromo-2-methyl-6-nitrobenzene (17 g) as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[OH:6])[CH:3]=[CH2:4].Br[CH2:15]Br>CCOCC.[Zn].[Cu]Cl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([CH:5]([OH:6])[CH:2]([CH:3]2[CH2:15][CH2:4]2)[CH3:1])=[CH:8][CH:9]=1
Reactant: BrCBr
Reactant: C=CC(C)C(O)c1ccc(Cl)cc1
Agent: Cl[Cu]
Agent: [Zn]
Solvent: CCOCC
Product: CC(C1CC1)C(O)c1ccc(Cl)cc1
Yield: 72.7 %

Procedure:
3-Methyl-4-(4-chlorophenyl)but-1-en-4-ol (63.68 g, approximately 90% pure, approximately 292 mmol), dibromomethane (45.5 ml, 648 mmol), zinc dust (84.75 g, 1.296 mol) and copper(I) chloride (12.83 g, 130 mmol) in dry ether (180 ml) were heated under reflux in a sonic bath for 31/2 hours. The mixture was then filtered (celite) and the filtrate poured into 2M hydrochloric acid. The mixture was extracted with ether and the combined extracts washed with water, saturated aqueous sodium bicarbonate solution and water, dried and evaporated in vacuo. Chromatography [SiO2, hexane-ethyl acetate (100:0) to (80:20)] gave 1-(4-chlorophenyl)-2-cyclopropylpropan-1-ol (44.72 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](O)[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[N:5]2[CH:9]=[CH:10][N:11]=[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(Cl)cc2nccn12
Product: Clc1cc2nccn2c(Cl)n1
Temperature: 120 °C

Procedure:
38.3 g (225.86 mmol) of 7-chloroimidazo[1,2-c]pyrimidin-5-ol are suspended in 450.2 g (2936 mmol) of phosphoryl chloride under argon and heated at 120° C. for 4 h. After this time, the excess phosphoryl chloride is removed in vacuo, and the residue is distilled together with toluene. The residue is suspended in water, the pH is brought to 7 with saturated aqueous sodium bicarbonate solution, and the precipitated solid is filtered off with suction. The latter is washed with water and dried over phosphorus pentoxide for 18 h. 33.5 g (67% of theory) of the product are obtained as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:24](O)=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:24]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCOCC1
Yield: 91 %

Procedure:
In substantially the same manner as in Example 5, morpholine (278 μl) was condensed with Boc-p-fluoro-L-phenylalanine (900 mg, manufactured by Bachera Fein Chemikalien AG, Switzerland) to give N-(Boc-p-fluoro-L-phenylalanyl)morpholine (1.02 g) as a white powder (yield 91%). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate as obtained in Reference Example 8 (333 mg) to yield the title compound (compound 69; 520 mg) as a white powder (yield 63%).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:7]([NH:9][C:10]([NH:12][C@H:13]([C:21]([OH:23])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH3:8].[NH2:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27].[NH2:32][C@H:33]([C:35](O)=[O:36])[CH3:34]>>[CH2:7]([NH:9][C:10]([NH:12][C@H:13]([C:21]([OH:23])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH3:8].[NH2:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27].[CH2:1]([NH:6][C:35](=[O:36])[C@H:33]([CH3:34])[NH2:32])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: C[C@H](N)C(=O)O
Reactant: CC(C)CCN
Agent: CC(C)[C@H](N)C(=O)O
Agent: CCNC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)CCNC(=O)[C@H](C)N

Procedure:
The compound was prepared by the standard resin cleavage procedure for amines of Example 57, Step 1, using isoamyl amine (1.5 mL) and N-ethylcarbamoyl-phenylalanine-valine-alanine-® Pam resin (151 mg, Preparation 5). Purification of the product was effected by using the purification procedure of Example 57, Step 2, affording the product as a white solid.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[C:7]1([S:17](Cl)(=[O:19])=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O>[C:7]1([S:17]([OH:19])=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S(O)c1cccc2ccccc12
Reaction time: 1 h

Procedure:
To 500 ml of an aqueous solution of 122 g of sodium sulfite was added 110 g of α-naphthalenesulfonyl chloride. While cooling the mixture with water, 20% aqueous solution of 36 g of sodium hydroxide was dropwise added to the mixture so as to keep the reaction mixture at a pH of about 8. After about one hour, the reaction mixture became uniform. To the mixture was added 135 ml of 35% hydrochloric acid was dropwise added. The formed grayish-white crystals were recovered by filtration and air-dried. The yield was 91.4 g (98% of theoretical value).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]2([CH2:20][N:19]([C:21](=[O:23])[CH3:22])[CH2:18]2)[CH2:9]1)=O)(C)(C)C>Cl.CCOC(C)=O>[ClH:17].[C:21]([N:19]1[CH2:18][C:10]2([C:11]3[C:16](=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[NH:8][CH2:9]2)[CH2:20]1)(=[O:23])[CH3:22]
Reactant: CC(=O)N1CC2(C1)CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N1CC2(CNc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-6′-chloro-1′,2′-dihydrospiro[azetidine-3,3′-indole]-1′-yl-carboxylic acid tert-butyl ester was (56 mg) was taken up in saturated HCl in EtOAc (5 mL). The reaction was stirred for 1 hour at ambient temperature and then concentrated in vacuo. The residue was taken up in MeOH and concentrated in vacuo again to yield the title compound. MS: [M+H]+=237.
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].C([O:21][CH2:22][CH3:23])(=O)C>C(Cl)Cl>[OH:21][C:22]1[CH:23]=[CH:2][C:1]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)=[CH:3][C:8]=1[CH2:7][CH2:6][CH3:5]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1O

Procedure:
This compound was obtained by reacting rac-3,4-dihydro2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 4-iodo-2-propylphenyl under the conditions described in Example 1. The product was isolated by chromatography over the 40 fold amount of silica gel using 10% (V/V) of ethyl acetate in methylene chloride. It was crystallized from ether/hexane to give off-white crystals with m.p. 154°-156°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1>C(O)(=O)C.C(O)C.[Pt](=O)=O>[CH3:1][CH:2]1[NH:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cn1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CCC(NC(=O)OC(C)(C)C)CN1
Temperature: 25 °C
Reaction time: 9 h
Yield: 86.7 %

Procedure:
To a solution of tert-butyl (6-methylpyridin-3-yl)carbamate (9.00 g) in a mixture of acetic acid-ethanol (1:1, 100 ml) was added platinum (IV) oxide (900 mg), and the mixture was stirred under hydrogen pressure (0.4 MPa) at room temperature for 9 hours. To the mixture was further added platinum (IV) oxide (2.0 g), and the mixture was stirred for 10 hours. The reaction mixture was filtered on celite, and thereto was added toluene. The mixture was concentrated under reduced pressure, and to the residue was added a 5% aqueous potassium carbonates solution. The mixture was extracted with chloroform, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product (8.03 g) of the title compound as a colorless oil.