Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C([Li])CCC.Cl[C:20]([O:22][CH3:23])=[O:21]>O1CCCC1>[CH3:23][O:22][C:20]([C:11]1[N:10]([CH3:13])[N:9]=[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[CH:12]=1)=[O:21]
Reactant: Cc1ccc(C)n1-c1ccn(C)n1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(-n2c(C)ccc2C)nn1C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 44.1 %

Procedure:
A solution of 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (Intermediate 7, 0.56 g, 3.21 mmol) (Intermediate 7) in tetrahydrofuran (26.8 mL) cooled to −78° C. was treated dropwise with a 2.5M solution of n-butyllithium in hexanes (1.44 mL, 3.60 mmol). The reaction was stirred at −78° C. for 1.5 h. After this time, the reaction was treated dropwise with methyl chloroformate (0.28 mL, 3.63 mmol). After this time, the cooling bath was removed. The reaction continued to stir for 1 h, at which time the reaction was concentrated in vacuo. The residue was then partitioned between water (100 mL) and diethyl ether (3×75 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel column chromatography (ISCO, 40 g, 5-10% ethyl acetate/hexanes) afforded 5-(2,5-dimethyl-pyrrol-1-yl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (0.33 g, 44%) as an off-white solid; ES+-HRMS m/e calcd for C12H15N3O2 [M+H+] 234.1237, found 234.1237.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1.[NH:29]1[CH:33]=[N:32][C:31]([NH2:34])=[N:30]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[NH:34][C:31]3[N:32]=[CH:33][NH:29][N:30]=3)[CH:17]=2)=[O:13])[NH:3]1
Reactant: O=C(O)CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1
Reactant: Nc1nc[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCOc1cccc(CNC(=O)c2nc3ccccc3c(=O)[nH]2)c1)Nc1nc[nH]n1
Temperature: 40 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
A solution of 4-{[3-({[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)phenyl]oxy}butanoic acid obtained in Reference Example 44 (100 mg, 0.262 mmol), 1H-1,2,4-triazol-3-amine (26.4 mg, 0.314 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (60.3 mg, 0.314 mmol) and 1-hydroxybenzotriazole (42.5 mg, 0.314 mmol) in DMF (5 mL) was stirred at 40° C. for 5 hr. Water was added to the reaction mixture, and the resulting solid was collected by filtration, washed with water and IPE, and dried to give the title compound as a white powder (95.0 mg, 73%).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([OH:32])[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:42]OC.CI.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CNC1N=NN(C)N=1.FC(F)(F)C1C=CC(C#N)=CC=1>>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([O:32][CH3:42])[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)CC2CCCC2)n1
Reactant: COC
Agent: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: N#Cc1ccc(C(F)(F)F)cc1
Solvent: CI
Product: COC(CC1CCCC1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1

Procedure:
1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-2-cyclopentylethanol was converted to the methyl ether with methyl iodide using a procedure analogous to that used for the preparation of N-(2-(cyclohexyl(methoxy)methyl)-5-trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine. LC-MS Calc. 609.5, found 610.5 (M+H). Examples 71-73 were prepared by an analogous series of reactions from 2-((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazole-5-yl)amino)methyl)-4-(trifluoromethyl)benzonitrile using the appropriate Grignard reagent and alkylating agent
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[CH:7]1[CH:12]([C:13]2=[O:18])[CH2:11][CH:10]=[CH:9][CH2:8]1)([O-])=[O:2].N1C=CC=CC=1>O>[OH:2][NH:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)c2c(NO)cccc21
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 5.0 parts of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone with 50 parts of pyridine was stirred at 70° C for 1 hour and then poured into 500 parts of water to precipitate crystals. After cooled to 20°C, the crystals were recovered by filtration, washed with water and dried under reduced pressure to obtain 4.5 parts of 1-hydroxylaminoanthraquinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[OH:18])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH2:30][C:29]2[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:28]=2[F:27])=[C:4]([F:20])[CH:3]=1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(Cl)cc2F)c(OCc2ccc(F)cc2F)c1
Temperature: 25 °C

Procedure:
To a solution of compound 2a (0.59 g, 2 mmole) in anhydrous acetone (10 mL) were added potassium carbonate (0.69 g, 5 mmole) and 2,4-difluorobenzyl bromide (0.56 mL, 4.4 mmol) and refluxed 8 hr. After cooled to room temperature, the reaction mixture was filtered through Celite and concentrated. The residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, then concentrated and recrystallized with hot methanol.
Reaction SMILES: [BH4-].[Na+].C(O)C.[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=1[O:27][CH3:28])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([CH2:20][CH:21]([N+:24]([O-:26])=[O:25])[CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=1[O:27][CH3:28])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCC(=Cc1ccc(OC)c(OCc2ccccc2)c1)[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(Cc1ccc(OC)c(OCc2ccccc2)c1)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
Finely powdered sodium borohydride (3.38 g, 89.3 mmol) was covered with THF (40 mL) and ethanol (40 mL) and cooled to 0° C. 257 (13.95 g, 44.5 mmol) was dissolved in THF (120 mL) and added slowly over 2 h via dropping funnel. The reaction mixture was stirred for 4 h at 0° C. and then for 60 h at room temperature. Hydrochloric acid (2M, 45 mL) was added very carefully. The two layers were separated and the organic layer was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2: 100 g, hexane/ethyl acetate 90:10) to give the title compound (8.83 g, 62%) as yellow solid. 1H NMR (270 MHz, CDCl3) δ 0.91 (3H, t, J 7.4, CH2CH3), 1.62-1.79 (1H, m, one of CHCH2CH3), 1.81-2.00 (1H, m, one of CHCH2CH3), 2.88 (1H, dd, J 14.3, 6.0, one of ArCH2CH), 3.12 (1H, dd, J 14.3, 8.3, one of ArCH2CH), 3.84 (3H, s, OCH3), 4.42-4.55 (1H, m, CHNO2), 5.11 (2H, OCH2Ph), 6.65 (1H, d, J 1.9, CH), 6.69 (1H, dd, J 8.2, 1.9, CH), 6.80 (1H, d, J8.0, CH), 7.25-7.45 (5H, m, OCH2C6H5).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:16]1([O:22][CH2:23][CH:24]2[O:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:25][CH:24]([OH:26])[CH2:23][O:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=S1(=O)CCN(c2ccc(OCC(O)COc3ccccc3)cc2)CC1
Yield: 58.3 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (2.3 g, 10 mmol), phenylglycidyl ether(1.5 g, 10 mmol) and ethyltriphenylphosphonium bromide (0.1 g) are reacted and purified as described for compound 102 to afford a light yellow liquid 2.2 g (58%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:15]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]2[CH:13]=[C:12]3[C:7]([O:8][CH2:9][C:10](=O)[NH:11]3)=[CH:6][C:5]=2[O:4][C:3]1([CH3:27])[CH3:26].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])O.[Na+]>>[CH3:26][C:3]1([CH3:27])[C@@H:2]([OH:1])[C@H:15]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]2[CH:13]=[C:12]3[C:7]([O:8][CH2:9][CH2:10][NH:11]3)=[CH:6][C:5]=2[O:4]1
Reactant: CC1(C)Oc2cc3c(cc2[C@@H](NCCc2ccccc2)[C@@H]1O)NC(=O)CO3
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Product: CC1(C)Oc2cc3c(cc2[C@@H](NCCc2ccccc2)[C@@H]1O)NCCO3
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To (±)-trans-7-hydroxy-6,6-dimethyl-8-(2-phenylethylamino)-7,8-dihydro-1H,6H-4,5-dioxa-1-aza-anthracene-2-one (67 mg, 0.18 mmol), lithium aluminum hydride (1M solution in tetrahydrofuran, 910 μL, 0.91 mmol) was added at room temperature, and the resulting mixture was stirred at 90° C. for 0.5 hour. Upon the completion of the reaction, saturated sodium hydrogencarbonate aqeuous solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (ethyl acetate) and the aimed product was obtained (yield: 59%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20]O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CO)CC1
Reactant: c1nc[nH]n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2Cn2cncn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 1-Boc-4-(hydroxymethyl-phenyl)-piperazine (300 mg, 1.02 mmol, 1.0 eq.), 1,2,4 triazole (104 mg, 1.53 mmol, 1.5 eq.), triphenylphosphine (535 mg, 2.04 mmol, 2.0 eq.) and THF at 0° C. under nitrogen was added DEAD (0.321 mL, 2.04 mmol, 2.0 eq.) slowly so that temperature of reaction does not rise above 10° C. After addition was completed, the ice bath was removed and the reaction mixture was stirred at r.t. overnight. Methanol was added and the mixture was stirred for about 15 minutes. The mixture was then concentrated. Purification by flash chromatography (35 g SiO2, linear gradient 50-70% EtOAc/Hexane for 15 minutes and 70% EtOAc for 18 minutes) afforded Boc protected title compound (200 mg, 0.5 mmol, 57%). LRMS (ESI+): 344.1 (M+1)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[N:12]=[C:11]([C:13]2[S:17][C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:15][C:14]=2[C:24]2[C:25]([F:42])=[C:26]([NH:30][S:31]([C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[F:41])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:10]=[CH:9][N:8]=1>C(Cl)Cl>[Cl:6][C:7]1[N:12]=[C:11]([C:13]2[S:17][C:16]([N:18]3[CH2:23][CH2:22][N:21]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:20][CH2:19]3)=[N:15][C:14]=2[C:24]2[C:25]([F:42])=[C:26]([NH:30][S:31]([C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[F:41])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:10]=[CH:9][N:8]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCNCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Yield: 32.9 %

Procedure:
Methanesulfonyl chloride (0.05 mL, 0.7 mmol) was added to a stirring solution of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-piperazinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.40 g, 0.66 mmol) and TEA (0.32 mL, 2.3 mmol) in DCM (10 mL) at rt. LCMS analysis indicated clean conversion to product. The reaction was quenched with water and the whole was extracted with DCM. The combined organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated onto silica gel. Purification by flash chromatography afforded the title compound of Step D (0.14 g, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 7.25-7.63 (m, 5H), 6.50 (d, J=5.3 Hz, 1H), 3.69 (br. s., 4H), 3.27 (br. s., 4H), 2.93 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Cl[CH:25](Cl)[C:26]([O:28]C)=[O:27].Cl>O.CN(C)C=O>[C:9]1([C:6]2[C:5]3[CH:15]=[CH:16][C:2]4[O:1][CH:25]([C:26]([OH:28])=[O:27])[O:17][C:3]=4[C:4]=3[O:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(Cl)Cl
Reactant: Oc1ccc2c(-c3ccccc3)noc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)C1Oc2ccc3c(-c4ccccc4)noc3c2O1
Reaction time: 5 h
Yield: 57.3 %

Procedure:
A mixture of 6,7-dihydroxy-3-phenyl-1,2-benzisoxazole (2.1 g), potassium carbonate (7.7 g), methyl dichloroacetate (2.7 g) and N,N-dimethylformamide (50 ml) was stirred at 90°-100° C. for 5 hours. After addition of water (100 ml), the mixture was stirred at 90°-100° C. for 30 minutes, and after acidifying it with hydrochloric acid, extracted with ether. The ether layer was washed with water, dried and evaporated to remove the solvent. The residue was recrystallized from acetonitrile to give 1.5 g of 3-phenyl-1,3-dioxolo[4,5-g]-1,2-benzisoxazole-7-carboxylic acid. m.p.: 187°-190° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:3]1([N:8]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1I
Product: CCCCCCCCCCCCCc1nc2ccccc2n1-c1ccccc1
Yield: 85 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-Iodo-2-nitrobenzene (125 mg, 0.5 mmol) and myristanilide (182 mg, 0.6 mmol) as starting materials to yield the title compound as colorless oil (160 mg, 85%). 1H NMR (DMSO) δ 0.74 (t, J=6.9 Hz, 3 H), 1.14-1.28 (m, 20 H), 1.68 (p, J=7.6 Hz, 2 H), 2.83 (t, J=7.6 Hz, 2 H), 7.14 (d, J=8.1 Hz, 1 H), 7.29 (dd, J=8.1, 7.7 Hz, 1 H), 7.47 (dd, J=8.1, 7.7 Hz, 1 H), 7.56-7.68 (m, 5 H), 7.74 (d, J=7.7 Hz, 1 H); 13C NMR δ 13.9, 22.0, 26.3, 26.4, 28.3, 28.4, 28.7, 28.8, 28.9, 29.9, 31.2, 110.7, 116.9, 123.5, 123.7, 127.2, 129.6, 130.1, 134.2, 135.0, 137.6, 154.7. HRMS (FAB): cal. for C26H36N2 [M+H+]: 377.2957; found: 377.2953.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[C:15]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:16]=[CH:17][CH:18]=3)[C:13]([C:28]#[N:29])=[CH:12]2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[CH2:21]([O:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[C:13]([C:28]#[N:29])=[CH:12][N:11]2[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:30])=[O:3])=[CH:10][CH:9]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3c(OCc4ccccc4)cccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cn(-c2ccc(C(=O)O)cc2)c2cccc(OCc3ccccc3)c12
Temperature: 50 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 4-(4-benzyloxy-3-cyanoindol-1-yl)benzoic acid ethyl ester (0.16 g) in ethanol (2 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.4 mL), and this mixture was stirred at 50° C. overnight. Ethanol was removed under reduced pressure, and to this reaction mixture was added 2 mol/L hydrochloric acid (3 mL). The precipitated solid was collected by filtration, and this solid was washed with water and n-hexane to give the title compound (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][C@H:13]2[NH:25][CH:26]([CH3:28])[CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.O1CCOCC1.BrC1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:38][C:39]4[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=4[N:41]=3)[CH2:14][C@H:13]2[NH:25][CH:26]([CH3:27])[CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(C)C)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC(C)C)C3)sc12
Yield: 33.2 %

Procedure:
The same operation as in Example (196c) was performed using tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(isopropylamino)piperidine-1-carboxylate obtained in Example (211a) (24.0 mg, 0.058 mmol), 4 N hydrochloric acid/1,4-dioxane (2 mL), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (18 mg, 0.064 mmol) and sodium carbonate (61 mg, 0.580 mmol), to obtain 10 mg of the title compound (33%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[N:14]=[CH:15][CH:16]=[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:12]3=[N:11][C:10]=2/[CH:24]=[CH:25]/[C:26]2[CH:35]=[CH:34][C:33]3[C:32]([C:36]([OH:38])=[O:37])=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=2)[CH:6]=[CH:7][CH:8]=1.C[O-].[Na+:41]>>[Na+:41].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[N:14]=[CH:15][CH:16]=[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:12]3=[N:11][C:10]=2/[CH:24]=[CH:25]/[C:26]2[CH:35]=[CH:34][C:33]3[C:32]([C:36]([O-:38])=[O:37])=[CH:31][CH:30]=[CH:29][C:28]=3[N:27]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2c(/C=C/c3ccc4c(C(=O)O)cccc4n3)nc3c(N4CCOCC4)ccnn23)c1
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(-c2c(/C=C/c3ccc4c(C(=O)[O-])cccc4n3)nc3c(N4CCOCC4)ccnn23)c1

Procedure:
Compound 77b (28 mg, 0.055 mmol) was treated with NaOMe (0.11 mL, 0.055 mmol) using the procedures described in Example 73, Step H to afford the title compound 149. 1H NMR (400 MHz, CD3OD) δ (ppm): 8.99 (d, J=9.1 Hz, 1H), 7.92-8.04 (m, 3H), 7.87 (d, J=7.6 Hz, 1H), 7.59-7.79 (m, 3H), 7.49 (t, J=8.1 Hz, 1H), 7.22-7.35 (m, 2H), 7.08 (dd, J=7.8, 2.3 Hz, 1H), 6.23 (d, 1H), 4.07-4.12 (m, 4H), 3.93-3.99 (m, 4H), 3.88 (s, 3H). Mass spectrum (LCMS, ESI pos.) Calcd. For C29H25N5O4 508.2 (M+H). found 508.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:16]([CH3:37])([CH3:36])[S:17](=[O:35])(=[O:34])[CH2:18][C@:19]([C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[CH2:31][CH:32]=[CH2:33])([CH3:21])[N:20]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:39]O.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:38])[N:7]([C:15]1[C:16]([CH3:37])([CH3:36])[S:17](=[O:35])(=[O:34])[CH2:18][C@:19]([C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[CH2:31][CH2:32][CH2:33][OH:39])([CH3:21])[N:20]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCc1ccc([N+](=O)[O-])cc1[C@]1(C)CS(=O)(=O)C(C)(C)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2CCCO)CS(=O)(=O)C1(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 59.9 %

Procedure:
A solution of (R)-tert-butyl-N-(5-(2-allyl-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)-N-tert-butoxycarbonyl-carbamate (623 mg, 1.129 mmol), in THF (11 ml) was cooled to 0° C. and borane tetrahydrofuran complex, 1.0 M in THF (1.13 ml, 1.13 mmol) was added dropwise. The mixture was stirred for 1.5 h at 0° C., then quenched with water (1 ml) and allowed to warm up to rt. The mixture was recooled to 0° C. and hydrogen peroxide (30% solution) (1.15 ml, 11.29 mmol) and sodium hydroxide (2N solution) (1.129 ml, 2.259 mmol) then were added and stirred at rt for 30 min. The mixture was partitioned between EtOAc (20 ml) and water (10 ml), organic layer was washed with brine and concentrated. The residue was purified by FC on 12 g RediSep Gold column using 20-100% EtOAc in heptane to afford (R)-tert-butyl-N-(5-(2-(3-hydroxypropyl)-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)-N-tert-butoxycarbonyl-carbamate (385 mg, 0.676 mmol, 60% yield). LC/MS (ESI+) m/z=592 (M+Na).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[N:4][CH:3]=1.[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C)C=O>[N:32]([C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[NH:24][C:23]4=[O:31])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[N:4][CH:3]=1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1cncc(Cl)n1)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cncc(C(=O)N2CCC(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)CC2)n1
Reaction time: 24 h
Yield: 105.1 %

Procedure:
A mixture of 0.15 g of 1,3-dihydro-1-{1-[1-(6-chloro-2-pyrazinecarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one, 0.26 g of sodium azide and 5 mL of anhydrous N,N-dimethylformamide was stirred for 24 h, then concentrated to dryness under reduced pressure. The residue was partitioned between 50 mL of chloroform and 5 mL of saturated sodium carbonate and the organic extracts dried over MgSO4. Removal of solvents under reduced pressure and drying under vacuum gave 0.16 g of crude 1,3-dihydro-1-{1-[1-(6-azido-2-pyrazinecarbonyl)piperidin-4-yl]piperidin-4-yl}-2H-benzimidazol-2-one.
Reaction SMILES: CO.O.[OH:4][C:5]([CH3:34])([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:6]=[CH:7][CH:8]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH:9]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][Si](C)(C)C>C(O)(=O)C.C(OCC)C>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:9]1[CH:8]([CH:7]=[CH:6][C:5]([OH:4])([CH3:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:16][CH2:15][C:10]21[O:14][CH2:13][CH2:12][O:11]2
Reactant: CCCCCC(C)(O)C=CC1CCC2(OCCO2)C1CCCCCCCO[Si](C)(C)C
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CCCCCC(C)(O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
Methanol (30 ml.), water (15 ml.) and glacial acetic acid (3 drops) were added to 7-(3-hydroxy-3-methyloct-1-enyl)-6-(7-trimethylsilyloxyheptyl)-1,4-dioxaspiro[4,4]nonane (0.5 g.) and the mixture was stirred at room temperature for 30 minutes. An excess of diethyl ether was then added and the resulting solution was washed with dilute aqueous sodium bicarbonate solution and sodium chloride solution respectively, and dried over sodium sulphate, to give crude 6-(7-hydroxyheptyl)-7-(3-hydroxy-3-methyloct-1-enyl)-1,4-dioxaspiro[4,4]nonane (0.33 g.), νmax 3400 cm-1, pure enough to use in the next stage.