Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([N:18]1[C:22]([NH2:23])=[CH:21][C:20]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)=[N:19]1)=O)(C)(C)C.[OH:36][CH2:37][CH2:38][O:39][C:40]1[CH:49]=[CH:48][C:43]([C:44](OC)=[O:45])=[CH:42][CH:41]=1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:20]2[NH:19][N:18]=[C:22]([NH:23][C:44](=[O:45])[C:43]3[CH:42]=[CH:41][C:40]([O:39][CH2:38][CH2:37][OH:36])=[CH:49][CH:48]=3)[CH:21]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccc(OCCO)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(OCCO)cc3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
A solution of NaHMDS in THF (1 M, 1.15 ml, 1.15 mmol, 2 eq) was added dropwise at ambient temperature to a mixture of tert-butyl-5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]pyrazole-1-carboxylate (200 mg, 0.58 mmol, 1 eq) and methyl 4-(2-hydroxyethoxy)benzoate (136 mg, 0.69 mmol, 1.2 eq) in THF (1 ml). The reaction mixture was stirred at ambient temperature for 1 h. It was then concentrated and the crude product was purified by reverse-phase prep. HPLC (basic) using a gradient of acetonitrile in water containing 1% ammonium hydroxide solution. The clean fractions were taken and evaporated to afford the title compound as a colourless solid (29 mg, 12% yield); 1H NMR (399.902 MHz, DMSO) δ 2.89 (4H, s), 3.77-3.72 (8H, m), 4.07 (2H, t), 4.88 (1H, t), 6.34-6.33 (1H, m), 6.43 (2H, d), 6.46 (1H, s), 7.01 (2H, d), 7.98 (2H, d), 10.46 (1H, br.s), 12.12 (1H, br.s). MS: m/z 412 (MH+)
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)=[CH:4][C:3]=1[CH3:15].[F:16][C:17]1[CH:18]=[CH:19][C:20](B2OC(C)(C)C(C)(C)O2)=[C:21]2[C:25]=1[C@H:24]([O:26][C:27]1[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=1)[CH2:23][CH2:22]2.BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:15][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[N:11][N:12]([CH3:14])[N:13]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:20]1[CH:19]=[CH:18][C:17]([F:16])=[C:25]2[C:21]=1[CH2:22][CH2:23][C@H:24]2[O:26][C:27]1[CH:40]=[CH:39][C:30]2[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=2[CH:28]=1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nnn(C)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from 5-(4-bromo-3,5-dimethylphenyl)-2-methyl-2H-tetrazole and methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.26 min; Mass spectrum (ESI+): m/z=529 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([NH2:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[N+:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:17][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([O-:10])=[O:9]
Reactant: CCCCCCN
Reactant: O=[N+]([O-])c1cccc(Br)c1
Product: CCCCCCNc1cccc([N+](=O)[O-])c1
Yield: 59.4 %

Procedure:
Using the general procedure, 3-bromonitrobenzene (202 mg, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol) at 100° C. for 22 h. Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (6:1) as eluent afforded the desired product as a light yellow solid (132 mg, 59% yield). Rf=0.5 (hexane/ethyl acetate=5:1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[O:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34]2[NH:38][CH:37]=[N:36][N:35]=2)[CH2:29][CH2:28]1>>[O:18]=[C:17]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:22]([CH2:23][CH2:24][CH3:25])[N:35]2[N:36]=[CH:37][N:38]=[C:34]2[N:33]1[CH:30]1[CH2:29][CH2:28][O:27][CH2:32][CH2:31]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: c1nnc(NC2CCOCC2)[nH]1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ncnn12
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1 g) and N-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-amine (0.25 g) was stirred at 250° C. for 15 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.3 g, 44%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[C:5](=[C:6]([OH:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:17]([O-])([O-:19])=[O:18].[K+].[K+]>>[OH:13][C:11]1[C:10]2[C:5](=[C:6]([OH:14])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(C(F)(F)F)nc2c(O)cccc12
Agent: [K+]
Product: O=C(O)c1ccc2c(O)cc(C(F)(F)F)nc2c1O
Temperature: 170 °C
Reaction time: 168 h

Procedure:
2-Trifluoromethyl-4,8-dihydroxyquinoline (6.0 g) and K2CO3 (11.0 g) are mixed in a stainless steel bomb. The bomb is flushed and evacuated 3× with 100 psi CO2. The reaction vessel is then pressurized to 800 psi CO2 and heated to 170° C., reaching a final pressure of 1200 psi. The bomb remains at this temperature and pressure for 7 days. The reaction vessel is cooled to room temperature, the pressure is released, and the reaction mixture is dissolved in 300 mL hot water. Any undissolved material is filtered and the filtrate is acidified with conc. HCl. A precipitate at pH 7 is collected (starting material). The filtrate is further acidified to pH 4 where a tan solid is collected (starting material+desired product). Since most of the solid collected is starting material, this material is reacted in the bomb for 7 more days. The same workup as before is done, with the only precipitate collected at pH 4.5. The desired product is filtered, dried, and recrystallized very slowly with EtOAc/hexanes (0.41 g).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][S:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:16][C:15]2[CH:17]=[CH:18][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(N=Cc2ccc(C)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-methylbenzaldehyde and 4-methylthioaniline as starting materials, the title compound was obtained as a slightly yellow powder (yield 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(OCC)(=O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(4-fluorophenyl)quinazoline-4-carboxylic acid (100 mg, 0.37 mmol, 1.00 equiv), 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (88 mg, 0.41 mmol, 1.10 equiv), oxolane (10 mL), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 170 mg, 0.45 mmol, 1.20 equiv) and DIEA (241 mg, 1.87 mmol, 5.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of ethyl acetate. The resulting mixture was washed with 1×100 mL of saturated aqueous sodium bicarbonate, 1×100 mL of ammonia (5%) and 1×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:1) or purified by Prep-HPLC with the following conditions (Sunfire Prep): Column, C18 Sum 15*190 mm; mobile phase, A: HCOOH B: CH3CN; Detector, UV 254 nm. This resulted in 30 mg (19%) of 2-[[2-(4-fluorophenyl)quinazolin-4-yl]carbonyl]-5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.90 (2t, 2H), 3.48 and 4.03 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.39 and 4.92 (2s, 2H), 6.30-6.33 (m, 0.4H), 6.69-6.78 (m, 1H), 6.90-6.92 (m, 0.6H), 7.36-7.44 (m, 2.7H), 7.69-7.79 (m, 1H), 7.86-7.97 (m, 1H), 8.06-8.17 (m, 2H), 8.53-8.61 (m, 2H), 8.69 and 8.73 (2s, 1H); 19F (282 MHz, DMSO-d6) δ −110.2; MS (ESI) m/z 430 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:25])([O:7][C:8]([F:24])([F:23])[C:9]([F:22])([F:21])[O:10][C:11]([F:20])([F:19])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:3]([F:6])([F:5])[F:4].[CH2:26]([O:32][C:33]1[CH:34]=[N:35][C:36]([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[N:37][CH:38]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O>[CH2:26]([O:32][C:33]1[CH:38]=[N:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH2:17][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:11]([O:10][C:9]([F:22])([F:21])[C:8]([F:24])([F:23])[O:7][C:2]([F:25])([F:1])[C:3]([F:6])([F:5])[F:4])([F:20])[F:19])=[CH:43][CH:44]=2)=[N:35][CH:34]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Solvent: O
Product: CCCCCCOc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 4-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromobutane (14.9 g, 32.0 mmol, Example 19) with 5-hexyloxy-2-(4-hydroxyphenyl)pyrimidine (8.0 g, 29.4 mmol). The resulting product was isolated by addition of water (160 mL), followed by filtration and recrystallization from ethanol. The recrystallized precipitate was dried at about 130° C., and the resulting product was further purified by distillation using a Kugelrohr apparatus (b.p. 190-205° C. at 0.3 torr; yield of 15.2 g).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:28][C@H:27]([CH3:29])[C@@H:25]([OH:26])[C@H:23]2[OH:24])=[C:15]([S:30][NH2:31])[N:14]=1>C(O)C>[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:28][C@H:27]([CH3:29])[C@@H:25]([OH:26])[C@H:23]2[OH:24])=[C:15]([S:30]([NH2:31])=[O:6])[N:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@H]1O[C@@H](n2cnc3c(SN)nc(N)nc32)[C@H](O)[C@@H]1O
Solvent: CCO
Product: C[C@H]1O[C@@H](n2cnc3c(S(N)=O)nc(N)nc32)[C@H](O)[C@@H]1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
A solution of m-chloroperoxybenzoic acid (0.10 g, 0.5 mmol) in ethanol (10 mL) was added dropwise to an ice-cooled stirred solution of 41 (0.15 g, 0.5 mmol) in ethanol (25 mL), during 15 min. The reaction mixture was allowed to stand at 0° C. overnight and then evaporated to dryness under reduced pressure. The residue was triturated with a mixture of ethanol (2 mL) and ethyl ether (30 mL). The precipitated crystalline product was collected by filtration and dried at 80° C. for 3 h to yield 70 mg (45%) of the title compound, mp >100° C. (dec.). IR (KBr): 1050 (vs, s, S=O), 3100-3600 (NH2, OH)cm-1 :UV: λmax (pH 1) 330 nm (ε 3,600): λmax (pH 7) 324 nm (4,400): λmax (pH 11) 321 nm 4,300): 1H NMR (DMSO-d6): δ 1.30 (d, 3, CH3), 5.80 (d, 1, J 5.25 Hz, C1'H), 6.51 (s, 2, SONH2, exchanged with D2O), 6.98 (s, 2, NH2, exchanged with D2O), 8.40 (s, 1, C8H), and other sugar protons. Anal. Calcd. for C10H14N6O4S (314.32): C, 38.21; H, 4 49; N, 26.74; S, 10.20. Found: C, 37.98; H, 4.41; N, 26.51; S, 9.91.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O.CCOCC>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][N:26]=[N+:27]=[N-:28])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@H]3C[C@H]3N2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1[C@H](CN=[N+]=[N-])C[C@H]2C[C@H]21
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of (1R,3S,5R)-3-(toluene-4-sulfonyloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (0.400 g, 1.08 mmol) and NaN3 (0.420 g, 6.47 mmol) in dry DMSO (8 mL) was stirred at 65° C. overnight. After cooling, the mixture was diluted with Et2O and washed with water (×3) and brine (×2). The organics were dried (phase separator) and concentrated in vaccuo to give the title compound as a colorless oil. MS (LC-MS): 239.0 [M+H]+; tR (HPLC conditions k): 3.78 min. The material thus obtained was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][NH:6][C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1.[N:16]([O-])=[O:17].[Na+].[OH-].[Na+]>CO.C(O)(=O)C.O>[CH3:1][C:2]1([CH3:15])[CH2:7][N:6]([N:16]=[O:17])[C:5]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: O=N[O-]
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CN(N=O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
In a mixture of 34 ml of methanol and 2.07 ml of acetic acid was dissolved 3 g of 3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine. Then, a solution of 2.0 g of sodium nitrite in 6.6 ml of water was added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with aqueous sodium hydroxide solution, concentrated under reduced pressure and extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 3.2 g of 3,4-dihydro-2,2-dimethyl-6-nitro-4-nitroso-2H-1,4-benzoxazine.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=CC=CN=2)CCCC1.Cl[C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39]>N1C=CC=CC=1>[CH:41]([O:40][C:38]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)(=[O:24])=[O:23])=[O:39])([CH3:43])[CH3:42]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(=O)OC(C)C)s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
100 mg of crude 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (see Example 1(f) above) was dissolved in pyridine (4 mL, dried over 4 Å molecular sieve) and cooled on ice. Pyrrolidinopyridine (39.5 mg, 0.266 mmol) and iso-propyl chloroformate (1M in toluene, 2.66 mL, 2.66 mmol) were then added to the mixture. The mixture was stirred overnight under N2 atmosphere at 50° C. Evaporation and co-evaporation with acetonitrile to remove the solvents, followed by purification using preparative LC/MS (30% acetonitrile to pure acetonitrile, reverse phase) gave the title compound (52.6 mg, 0.114 mmol).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][CH:14]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:22][CH2:23][CH2:24][CH:4]2[NH:3]1.[N-:26]=[N+:27]=[N-:28].[Na+].[NH4+].[Cl-].Cl>CN(C=O)C>[NH:26]1[C:20]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][C:9]3[CH:10]=[CH:11][C:6]4[N:5]5[CH2:22][CH2:23][CH2:24][CH:4]5[NH:3][S:2](=[O:1])(=[O:25])[C:7]=4[CH:8]=3)=[CH:14][CH:15]=2)=[N:21][N:28]=[N:27]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=S1(=O)NC2CCCN2c2ccc(Oc3ccc(Cc4nnn[nH]4)cc3)cc21
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A suspension of 300 mg (0.844 mmol) of the product obtained in Step A, 164 mg (2.53 mmol) of sodium azide and 113 mg (2.11 mmol) of NH4Cl in 3 ml of DMF is stirred at 110° C. for 24 hours. The reaction mixture is allowed to return to ambient temperature and is poured into 20 ml of 1N HCl. Extraction (AcOEt), drying (MgSO4) and evaporating to dryness are carried out. The residue is triturated in Et2O and the precipitate is filtered off to yield the title product.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([C:5]1[O:6][C:7]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc2nc(C(C)(C)C)oc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cccc(C(=O)O)c2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.6 %

Procedure:
A mixture of methyl 2-tert-butylbenzoxazole-7-carboxylate (0.41 g, 1.77 mmol), lithium hydroxide monohydrate (222 mg, 5.30 mmol) and tetrahydrofuran/water (5:1, 6 mL) was stirred at room temperature for 17 h. The reaction mixture was cooled to 0° C., adjusted to pH 2 using 1 N HCl, and then extracted with dichloromethane (2×200 mL). The combined organic phase was washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated to afford the desired 2-tert-butylbenzoxazole-7-carboxylic acid (336 mg, 86%) as a pink solid: 1H NMR (300 MHz, DMSO-d6) δ 13.20 (br s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 1.45 (s, 9H); MS (ESI+) m/z 220 (M+H).
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[S:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)=[S:29])=[CH:23][CH:22]=1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: O
Product: S=C(Nc1ccc(Cl)cc1)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
4-Amino-1-[2-(3-indolyl)ethyl]piperidine hydrate is treated with 4-chlorophenyl isothiocyanate in the manner described in Example 10 to obtain the title compound as the hydrochloride.
Reaction SMILES: CCCC[Sn]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])(CCCC)CCCC.[CH:28]([N:31]([CH:35]([CH3:37])[CH3:36])[CH2:32][CH2:33]O)([CH3:30])[CH3:29].O>C1C=CC=CC=1>[CH2:24]([Sn:15]([O:14][CH2:33][CH2:32][N:31]([CH:35]([CH3:37])[CH3:36])[CH:28]([CH3:30])[CH3:29])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)N(CCO)C(C)C
Solvent: c1ccccc1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)OCCN(C(C)C)C(C)C

Procedure:
2-Diisopropylaminoethyl Tributylstannyl Ether is prepared from 89.4 gm (0.15 mole) bis(tributyltin) oxide and 43.5 gm (0.30 mole) 2-diisopropylaminoethanol in 200 ml benzene. This is stirred and heated to reflux in a system that contains a Dean-Starke tube. After refluxing for 23 hours a total of 2.6 ml of water (theory 2.7 ml) had collected in the Dean-Starke tube. Solvent is stripped off on a rotating evaporator to provide 134.3 gm of orange liquid. This is fractionated at reduced pressure with collection at 147°-155° C. at 0.4 mm of 87.6 gm of straw liquid (Percent theory - 73). Infrared spectral analysis shows this liquid to be the desired ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:11](=[O:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CN(N)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NN(C)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of N-methylhydrazinecarboxylic acid tert-butyl ester (0.62 g, 4.20 mmol) in methylene chloride (10 ml) was added acetic acid anhydride (0.79 ml, 8.40) and pyridine (1.36 ml, 16.80 mmol) and the mixture was stirred overnight. Then methylene chloride (50 ml) was added and the mixture was washed with water (3×10 ml), dried (MgSO4), filtered and concentrated in vacuo to give 0.32 g (41%) of N'-acetyl-N-methylhydrazinecarboxylic acid tert-butyl ester as an oil.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].[C:19](O)(=[O:24])[CH2:20][C:21](O)=[O:22]>C(O)(=O)C>[CH3:8][N:9]1[C:21](=[O:22])[CH2:20][C:19](=[O:24])[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]1=[O:11]
Reactant: O=C(O)CC(=O)O
Reactant: CNC(=O)Nc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(=O)N(c2ccccc2)C1=O
Temperature: 90 °C

Procedure:
Acetic anhydride (16 ml, 0.17 mole) was added dropwise over three hours to a solution of 1-methyl-3-phenylurea (6 g, 0.04 mole) and malonic acid (4.6 g, 0.04 mole) in acetic acid (40 ml) at 60° C. After the addition was completed, the temperature was raised to 90° C. and maintained for four hours. The solvent was evaporated and the resulting residue treated with 0.1N NaOH (50 ml). After filtration, the solution was acidified with 0.2N HCl (120 ml). The solution was evaporated to dryness under reduced pressure, leaving solid 1-methyl-3-phenyl-2,4,6-(1H,3H,5H)- pyrimidinetrione upon cooling. It was recrystallized from ethanol to yield colorless crystals, m.p. 122.5°-123° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][C:14]([CH2:16][C:17]#[N:18])=[CH:13][C:12]=2[CH:19]=1>CO>[OH:3][N:2]=[C:17]([NH2:18])[CH2:16][C:14]1[S:15][C:11]2[CH:10]=[CH:9][C:8]([Br:7])=[CH:19][C:12]=2[CH:13]=1
Reactant: N#CCc1cc2cc(Br)ccc2s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(Cc1cc2cc(Br)ccc2s1)=NO
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
To a stirred solution of hydroxylamine hydrochloride (3.86 g, 0.056 mol) in MeOH (100 mL) was added sodium methoxide (25 wt % in MeOH, 10.33 g, 0.056 mol). Stirring was continued for 15 minutes and 5-bromo-2-benzthiophenylacetonitrile (7.0 g, 0.028 mol) was added. The resulting mixture was refluxed for 2 days, cooled, and concentrated. The residue was diluted with H2O. The solid was collected by filtration, purified by column chromatography (eluant: EtOAc/hexane, 2:3) to give 4.0 g (50%) of product as a white solid.