Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:13]=[C:12]([NH2:14])[NH:11][N:10]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH:31]([C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1)=O.C(O)(=O)C.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:13]=[C:12]([NH:14][CH2:31][C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:35][CH:34]=3)[NH:11][N:10]=2)[CH:5]=[C:4]([C:15]([F:18])([F:16])[F:17])[C:3]=1[C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2c(Cl)cc(Nc3n[nH]c(N)n3)cc2C(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)S(=O)(=O)c1ccc(-c2c(Cl)cc(Nc3n[nH]c(NCc4ccc(C(=O)OC(C)(C)C)cc4)n3)cc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
To a solution of N3-(2-chloro-4′-(isopropylsulfonyl)-6-(trifluoromethyl)biphenyl-4-yl)-1H-1,2,4-triazole-3,5-diamine (135 mg, 294 μmol) in MeOH (3.5 ml) was added tert-butyl 4-formylbenzoate (85 mg, 412 μmol) followed by acetic acid (52.4 mg, 50 μl, 873 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (42.4 mg, 396 μmol) was added and the stirring was continued for 3 days. The reaction mixture was poured into 0.1N HCl solution (20 ml) and the resulting suspension was filtered to collect the solid. The crude material was purified by flash chromatography (silica gel, 24 g, 3% to 5% MeOH in DCM) to afford a white solid as desired product (94 mg, 49% yield). MS +m/z: 650 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[CH2:32][CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[CH2:32][CH2:33][NH:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1C(=O)c2ccccc2C1=O
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (1.50 g, 5.47 mmol) and (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde (2.27 g, 12 mmol) under nitrogen in glacial acetic acid (50 mL) was treated with sodium triacetoxyborohydride (2.56 g, 12.1 mmol) at ambient temperature. After stirring for 30 min., 40 mL of glacial acetic acid (40 mL) was added, to dilute the reaction, followed by 0.17 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde and 0.45 g sodium triacetoxyborohydride. After stirring another 2½ h, the reaction was heated to 45° C. for another hour. The reaction was evaporated in vacuo and the residue was triturated with water (500 mL), filtered, and washed with water. The resulting solid was dissolved in CH2Cl2 dried over MgSO4, filtered and evaporated in vacuo. The residue was dissolved in CH2Cl2 and chromatographed on silica gel eluting with 0-50% EtOAc in hexanes to provide the product as an solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (t, J=7.1 Hz, 3 H), 3.5 (q, J=6.2 Hz, 2 H), 3.8 (t, J=6.0 Hz, 2 H), 3.9 (s, 2 H), 4.2 (q, J=7.0 Hz, 2 H), 7.1 (ddd, J=9.1, 6.9, 1.8 Hz, 2 H), 7.3 (m, 3 H), 7.6 (t, J=6.2 Hz, 1 H), 7.7 (d, J=1.6 Hz, 1 H), 7.8 (m, 4 H); ES+MS: 447 (M+H+).
Reaction SMILES: C([O:4][C:5]([C@@H:7]1[CH2:22][C@@:15]2([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:23])[CH:13]=2)[O:8]1)=O)CC.O.[NH2:25][NH2:26]>C(O)C>[F:23][C:12]1[CH:13]=[C:14]2[C@:15]3([C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]3)[CH2:22][C@@H:7]([C:5]([NH:25][NH2:26])=[O:4])[O:8][C:9]2=[CH:10][CH:11]=1
Reactant: CCCOC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)[C@@H]1C[C@]2(NC(=O)NC2=O)c2cc(F)ccc2O1
Yield: 46.7 %

Procedure:
To a solution of (2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxylic acid n-propyl ester (30.0 g, 93.1 mmol) in 600 ml of ethanol was added hydrazine hydrate (46.6 g, 0.931 mol). After refluxing the mixture under an argon atmosphere for 2 hours, the reaction mixture was evaporated in vacuo to dryness. To the residue was added 100 ml of saturated aqueous sodium chloride and the aqueous layer was extracted with ethyl acetate (300 ml×5). The combined ethyl acetate layers were washed with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 17.3 g (Yield: 63.1%) of crude crystals. The crystals were recrystallized from ethanol to give colorless needles of the desired compound (12.8 g, 46.7%).
Reaction SMILES: [ClH:1].CC1(C)CC(C2C=CC=C([C:19]([F:22])([F:21])[F:20])C=2)C2C(=CC(OCCNC)=CC=2)O1.Cl.[CH3:30][C:31]1([CH3:53])[CH2:40][CH:39]([C:41]2[CH:46]=[CH:45][C:44](F)=[CH:43][CH:42]=2)[C:38]2[C:33](=[CH:34][C:35]([O:48][CH2:49][CH2:50][NH:51][CH3:52])=[CH:36][CH:37]=2)[O:32]1.Cl.CC1(C)CC(C2C=CC=CC=2)C2C(=CC(OCCNC)=CC=2)O1.Cl.CC1(C)CC(C2C=CC=C(F)C=2)C2C(=CC(OCCN(C)C)=CC=2)O1>>[ClH:1].[CH3:30][C:31]1([CH3:53])[CH2:40][CH:39]([C:41]2[CH:46]=[CH:45][C:44]([C:19]([F:22])([F:21])[F:20])=[CH:43][CH:42]=2)[C:38]2[C:33](=[CH:34][C:35]([O:48][CH2:49][CH2:50][NH:51][CH3:52])=[CH:36][CH:37]=2)[O:32]1
Reactant: CNCCOc1ccc2c(c1)OC(C)(C)CC2c1ccc(F)cc1
Reactant: CNCCOc1ccc2c(c1)OC(C)(C)CC2c1cccc(C(F)(F)F)c1
Agent: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1cccc(F)c1
Agent: CNCCOc1ccc2c(c1)OC(C)(C)CC2c1ccccc1
Agent: Cl
Product: CNCCOc1ccc2c(c1)OC(C)(C)CC2c1ccc(C(F)(F)F)cc1

Procedure:
A strictly analogous procedure led to the production of 2,2-dimethyl-7-methylaminoethyloxy-4-(3-trifluoromethylphenyl)chroman hydrochloride, m.p. 182°-184° C, to 2,2-dimethyl-7-methylaminoethyloxy-4-(4-fluorophenyl)chroman hydrochloride, m.p. 222°-224° C, to 2,2-dimethyl-7-methylaminoethyloxy-4-phenylchroman hydrochloride, m.p. 191°-193° C, and to 2,2-dimethyl-7-dimethylaminoethoxy-4-(3-fluorophenyl)chroman hydrochloride, m.p. 168°-171.5° C.
Reaction SMILES: C([C@@:3]12[N:10]([C:11](=[O:37])[CH:12]([NH:25][C:26](=[O:36])[C:27]3[CH:32]=[CH:31][C:30]([CH:33]=[N:34][NH2:35])=[CH:29][CH:28]=3)[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C(C)(C)C)=[CH:16][CH:15]=3)[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)C.FC(F)(F)C(O)=O>>[NH2:35][N:34]=[CH:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([NH:25][CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[C:11]([N:10]2[CH:7]3[CH2:8][CH2:9][C@@H:3]2[CH2:4][CH2:5][CH2:6]3)=[O:37])=[O:36])=[CH:32][CH:31]=1
Reactant: CC[C@]12CCCC(CC1)N2C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)c1ccc(C=NN)cc1
Solvent: O=C(O)C(F)(F)F
Product: NN=Cc1ccc(C(=O)NC(Cc2ccc(O)cc2)C(=O)N2C3CCC[C@H]2CC3)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of 150 mg of ethyl (S)-8-[2-(4-aminoiminomethyl-benzoylamino)-3-(4-t-butoxyphenyl)propionyl]-8-azabicyclo[3.2.1]octan-endo-3-yloxyacetate hydrochloride is stirred at room temperature in 5 ml of CH2C2 and 2.5 ml of trifluoroacetic acid and evaporated. With ether the residue gives crystals which are filtered off under suction and dissolved in 5 ml of EtOH. 40 mg of NaOH dissolved in 1 ml of water are added to the solution and the mixture is stirred at room temperature. The reaction solution is neutralized with 1N hydrochloric acid and evaporated. Chromatography of the residue on silica gel RP-18 with water/THF gives 75 mg of (S)-8-[2-(4-aminoiminomethyl-benzoylamino)-3-(4-hydroxyphenyl)propionyl]-8-azabicyclo[3.2.1]octan-endo-3-yloxyacetic acid, MS: 495 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.Cl.[CH3:31][O:32][NH2:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:33][O:32][CH3:31])=[O:18])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CONC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 64.5 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (96 mg, 0.228 mmol) obtained in Example 12 in methylene chloride (3 ml), O-methylhydroxyamine hydrochloride (23 mg, 0.273 mmol), 1-hydroxybenzotriazole (31 mg, 0.228 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52 mg, 0.273 mmol) and 4-methylmorpholine (59 μl, 0.546 mmol) were added. The reaction solution was stirred for 5 days at room temperature, and was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with 65% ethyl acetate/hexane was concentrated under reduced pressure to obtain a white solid. The resulting solid was washed with ethylacetate-hexane, and then was collected by filtration, to obtain the title compound (66 mg, 0.147 mmol, 64%) as a white powder.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][C@@H:15]([N:37]=[N+:38]=[N-:39])[CH2:16][CH2:17][C@H:18]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[O:7][C@H:6]1[N:40]1[CH:48]=[N:47][C:46]2[C:41]1=[N:42][C:43]([NH:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])=[N:44][C:45]=2[NH2:49])(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[NH2:49][C:45]1[N:44]=[C:43]([NH:50][CH2:51][CH2:52][NH:53][C:54]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:55])[N:42]=[C:41]2[C:46]=1[N:47]=[CH:48][N:40]2[C@@H:6]1[O:7][C@H:8]([CH2:14][C@@H:15]([N:37]=[N+:38]=[N-:39])[CH2:16][CH2:17][C@H:18]([NH:26][S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:29])=[O:28])[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C[C@H](CC[C@H](NS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)N=[N+]=[N-])O[C@H]1n1cnc2c(N)nc(NCCNC(=O)OC(C)(C)C)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N[C@@H](CC[C@@H](C[C@H]2O[C@@H](n3cnc4c(N)nc(NCCNC(=O)OC(C)(C)C)nc43)[C@H](O)[C@@H]2O)N=[N+]=[N-])C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture consisting of Compound 28A in methanol is added potassium carbonate (10 molar equivalents) and the mixture stirred for 30 minutes at room temperature. Acetic acid is added to neutral pH and the solution is stirred 30 minutes. Solvent is evaporated and the mixture is partitioned between ethyl acetate and water. The organics are washed with brine, dried and evaporated. The residue is chromatographed on silica gel to obtain the title intermediate.
Reaction SMILES: O[CH2:2][C:3]([CH2:14]O)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.CCN(C(C)C)C(C)C.[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CC#N.[Cl-].[Na+].O.CC(=O)OCC>[CH2:40]([N:47]1[CH2:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:14]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CN(Cc2ccccc2)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a solution of diethyl 2,2-bis(hydroxymethyl)malonate (4.4 g, 20 mmol) in CH3CN (50 mL) was added Tf2O (7.1 mL, 11.85 g, 42 mmol) at −20° C., followed by two batches of DIEA (6.45 g, 50 mmol). After 0.5 hr, benzylamine (3.21 g, 35 mmol) was added at −20° C. The mixture was stirred at 70° C. for 2 hr. 100 mL of EA and 100 mL of brine were added. Organic layers were dried over Na2SO4. Purified by chromatography column on silica gel eluting with PE/EA to afford 4.8 g (82%) of diethyl 1-benzylazetidine-3,3-dicarboxylate as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.34 (m, 2H), 7.22-7.27 (m, 3H), 4.17 (q, J=7.2 Hz, 4H), 3.56 (s, 2H), 3.51 (s, 4H), 2.39 (s, 3H) and 1.17 (t, J=7.2 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Br:12].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][C:3]=1[Br:12]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Nc1c(Br)cc(C(=O)O)cc1Br
Product: Nc1c(Br)cc(C(=O)Cl)cc1Br
Yield: 73.4 %

Procedure:
In a flask equipped with a reflux condenser, 88.5 g (0.3 mole) of 4-amino-3,5-dibromobenzoic acid and 68 g (0.33 mole) of phosphorus pentachloride were reacted under reflux for one hour. After removal of phosphorus oxychloride under reduced pressure by means of an aspirator, the reaction product is subjected to vacuum distillation to obtain 69 g of 4-amino-3,5-dibromobenzoic acid chloride (yield: 73%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(OC)cc2)CC1
Reaction time: 2 h
Yield: 78 %

Procedure:
To 10 g (19.4 mmol) of ethyl 1-[(R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-propionyl]-4-cyclohexylpiperidine-4-carboxylate (cf. preparation 19-1) in 80 mL of dichloromethane are added, at room temperature, 20 mL of trifluoroacetic acid. The reaction medium is stirred for 2 hours and the solvents are then evaporated off. Diethyl ether and a few drops of dichloromethane are added to the oil obtained, and the white solid obtained is filtered off and then dried. 8 g of ethyl 1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate trifluoroacetate are obtained in a yield of 78%.
Reaction SMILES: [Br-].[CH3:2][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:12]([O:19][C:20](=[O:37])[CH2:21][CH2:22][C:23](=O)[CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O>[CH2:12]([O:19][C:20](=[O:37])[CH2:21][CH2:22][C:23](=[CH2:2])[CH2:24][CH2:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(CCC(=O)OCc1ccccc1)CCC(=O)OCc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(CCC(=O)OCc1ccccc1)CCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
Methyltriphenylphsphonium bromide (536 mg, 1.5 mmol) was suspended in anhydrous THF (1.0 mL) at −5° C. A THF solution of NaHMDS (1.0 M, 1.5 mL, 1.5 mmol) was added dropwise to keep the temperature below 0° C. The mixture was stirred at 0° C. for 0.5 h before cooled to −78° C. To this ylid solution was added a solution of dibenzyl-4-oxopimelate (354 mg, 1.0 mmol) in THF (1.0 mL) dropwise to keep the temperature below −50° C. The temperature was allowed to rise to room temperature in 1.5 h with stirring after addition. The reaction mixture was then poured in icy water (25 mL) and extracted with Et2O (2×25 mL). The organic layer was washed with brine (20 mL) and dried over Na2SO4. The solvent was removed under vacuum and the residue was subjected to silica chromatography (EtOAc/hexanes, up to 1/10) to give compound B4 (197 mg). The yield was 56%. 1H NMR (200 MHz, CDCl3) δ 7.37 (m, 10H), 5.11 (s, 4H), 4.78 (d, 2H, J=1.1 Hz), 2.53 (m, 4H), 2.39 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 173.3, 146.6, 136.4, 129.0, 128.7, 110.5, 66.9, 33.2, 31.6; MS (MALDI-TOF) calcd (M+Na+) 375.4, found 375.6.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.[CH3:18][O:19][CH2:20][C:21]1[CH:25]=[CH:24][O:23][C:22]=1[Sn](C)(C)C>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:22]3[O:23][CH:24]=[CH:25][C:21]=3[CH2:20][O:19][CH3:18])[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2n1-c1cccc(I)c1
Reactant: COCc1ccoc1[Sn](C)(C)C
Product: COCc1ccoc1-c1cccc(-n2c(N)nc3ccccc32)c1

Procedure:
2-Amino-1-[3-(3-methoxymethyl-2-furyl)phenyl]benzimidazole was prepared from 1-(2-amino-1-benzimidazolyl)-3-iodobenzene and 3-methoxymethyl-2-trimethylstannylfuran by method C. mp 134°-136° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[C:11](Br)=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[Br:14])=[O:4].C([Li])CCC.[CH3:22][S:23]SC.Cl>C(OCC)C.CCCCCC>[F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C:6]1[C:11]([S:23][CH3:22])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[Br:14])=[O:4]
Reactant: Cc1cc(Br)c(NC(=O)C(F)(F)F)c(Br)c1
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1cc(C)cc(Br)c1NC(=O)C(F)(F)F
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Under an atmosphere of argon, 69.3 g (95% by weight pure, 182 mmol) of N-(trifluoroacetyl)-2,6-dibromo-4-methylaniline in 900 ml of dry diethyl ether were cooled to a temperature of −70° C. At this temperature, 153 ml of a 2.5M solution (382.5 mmol) of n-butyllithium in hexane were added dropwise. The mixture was subsequently stirred at this temperature for another 30 minutes. At this temperature, a solution of 51.5 g (547 mmol) of dimethyl disulfide in 100 ml of dry diethyl ether was then added dropwise. The contents were stirred at this temperature for 1 h and then at RT for 3 h and subsequently poured into 1000 ml of 1M hydrochloric acid. After phase separation, the aqueous phase was extracted with diethyl ether, the combined organic phases were dried and the filtrate was freed of the solvents. The residue was stirred with heptane for 30 minutes and then filtered. 46.6 g of N-(trifluoroacetyl)-2-bromo-4-methyl-6-(methylthio)aniline were obtained as residue.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=1[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1.N1CCCCC1>C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[C:17]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[CH:18]=1)[C:7](=[O:13])[NH:8]2
Reactant: COc1ccc(C=O)cc1-c1cccs1
Reactant: O=C1Cc2c(CCO)cccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C=C2C(=O)Nc3cccc(CCO)c32)cc1-c1cccs1
Yield: 46.9 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (1.6 g, 9.2 mmol), 4-methoxy-3-thiophen-2-yl-benzaldehyde (2 g, 9.2 mmol) and piperidine (4.5 mL, 85 mmol) in ethanol (46 mL) was heated to reflux for overnight. The reaction mixture was concentrated and the residue was chromatographed on a column of silica gel to give 1.63 g (47%) of 4-(2-hydroxy-ethyl)-3-(4-methoxy-3-thiophen-2-yl-benzylidene)-1,3-dihydro-indol-2-one as a yellow orange solid. 1HNMR (300 MHz, DMSO-d6) δ 10.53 (s, br, 1H, NH), 8.73 (d, J=2.1 Hz, 1H), 8.10 (dd, J=2.2 & 9.1 Hz, 1H), 7.74 (s, 1H, H-vinyl), 7.56-7.65 (m, 2H), 7.07-7.22 (m, 3H), 6.81 (d, J=7.5 Hz, 1H), 6.68 (dd, J=0.6, 7.5 Hz, 1H), 4.87 (t, J=4.5 Hz, 1H, OH), 3.97 (s, 3H, OCH3), 3.68-3.75 (m, 2H, CH2CH2OH), 3.09 (t, J=4.5 Hz, 2H, CH2CH2OH).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]#[C:14][C:15]1[CH:16]=[C:17]([CH:23]([N:25]([CH:41]2[CH2:43][CH2:42]2)[C:26]([C@@H:28]2[O:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]2)=[O:27])[CH3:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:23]([N:25]([CH:41]2[CH2:43][CH2:42]2)[C:26]([C@@H:28]2[O:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:29]2)=[O:27])[CH3:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cc1C#CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cc1CCCN
Reaction time: 7 h
Yield: 67.7 %

Procedure:
to a solution of tert-butyl (2R)-2-{[{1-[3-(3-{[(benzyloxy)carbonyl]amino}prop-1-yn-1-yl)-4-methoxyphenyl]ethyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate (2.82 g) in methanol (25 mL) was added 10% palladium on carbon (282 mg), and the mixture was stirred under hydrogen for 7 hours. An insoluble was filtered off, and then the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (eluent: chloroform→chloroform/methanol=33/1) to give tert-butyl (2R)-2-{[{1-[3-(3-aminopropyl)-4-methoxyphenyl]ethyl}(cyclopropyl)amino]carbonyl}morpholin-4-carboxylate [Ex(295-4)] (1.49 g) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]([CH:28]3[CH2:30][CH2:29]3)[C:17]3[O:24][C:21]4([CH2:23][CH2:22]4)[CH2:20][C:19]([CH3:26])([CH3:25])[C:18]=3[CH:27]=2)=[CH:8][CH:7]=1)[CH3:5].[OH-].[Na+]>CO>[CH:28]1([C:16]2[C:17]3[O:24][C:21]4([CH2:23][CH2:22]4)[CH2:20][C:19]([CH3:25])([CH3:26])[C:18]=3[CH:27]=[C:14]([C:13]#[C:12][C:9]3[CH:8]=[CH:7][C:6]([CH:4]([CH3:5])[C:3]([OH:31])=[O:2])=[CH:11][CH:10]=3)[CH:15]=2)[CH2:29][CH2:30]1
Reactant: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-phenyl}-propionic acid methyl ester (Intermediate 1, 0.072 g, 0.174 mmol) in methanol (5 mL) was treated with a 1M solution of sodium hydroxide (1 mL, 1 mmol) and the resulting reaction mixture was heated at 55° C. for 4 h. The reaction mixture was cooled to ambient temperature and the volatiles were evaporated in vacuo to a residue that was diluted with 10% hydrochloric acid till neutral and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid after flash column chromatography over silica gel (230-400 mesh) (0.04 g, 57%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.O>C(Cl)Cl>[N:10]1([CH2:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: ClCc1ccncc1
Reactant: C1COCCN1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: c1cc(CN2CCOCC2)ccn1
Reaction time: 50 h
Yield: 84.4 %

Procedure:
A suspension of 4-picolyl chloride hydrochloride (10.0 g, 60.98 mmol) in 100 ml of methylene chloride at room temperature is treated with morpholine (26.52 g, 304.9 mmol, 5.0 equiv.) at once. After stirring for 50 h, the reaction mixture is poured into 250 ml of water, extracted six times with ethylacetate, three times with ethylacetate-methanol (9:1) and the combined organic extracts are dried over Na2SO4. The concentrated filtrate is chromatographed with 350 g of silica gel, packed and eluted with acetone-methylene chloride (1:2), to give 9.17 g (84%) of 4-(4-morpholinyl)methylpyridine as a yellow liquid.