Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@H:2](C)[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][CH2:5]1.[CH2:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:40]([O:44][C:45](=[O:53])[NH:46][CH:47]1CCNCC1)([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:40]([O:44][C:45]([NH:46][CH:47]1[CH2:24][CH2:23][N:20]([CH2:18][C@@H:3]([N:4]2[CH2:5][CH2:6][CH:7]([O:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:8][CH2:9]2)[CH3:2])[CH2:21][CH2:22]1)=[O:53])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCN(CC)CC
Reactant: C[C@@H](O)CN1CCC(OC(=O)C(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](CN1CCC(NC(=O)OC(C)(C)C)CC1)N1CCC(OC(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of alcohol 53 (1.26 g, 5.16 mmol) and triethylamine (1.43 ml, 10.32 mmol) in 80 ml of DCM is cooled to −78 C. Triflic anhydride (0.85 ml, 5.16 mmol) is slowly added and stirring continued for 1 hour. The mixture is then allowed to warm up to 0 C and cooled back to −78 C after 15 minutes. A solution of piperidin-4-yl-carbamic acid tert-butyl ester, 3, (1.03 g, 5.16 mmol) in 40 ml of DCM is slowly added at −78 C. After complete addition, the cooling bath is removed and the dark solution is allowed to warm up to room temperature. The mixture is washed twice with water, dried over sodium sulphate, filtered and evaporated. The crude is purified by chromatography on silicagel using DCM (saturated with ammonia) and MeOH (1%).
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[C:11]([C:14]1[CH:19]=[CH:18]C=[CH:16][CH:15]=1)(=[O:13])[CH3:12].Cl.[CH3:21][CH2:22][O:23][CH2:24][CH3:25]>C1C=CC=CC=1>[CH2:22]([O:23][C:24]1[CH:16]=[CH:15][C:14]([C:11]([CH2:12][C:1]([O:5][CH2:6][CH3:7])=[O:8])=[O:13])=[C:19]([CH3:18])[CH:25]=1)[C:21]1[CH:16]=[CH:15][CH:14]=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOCC
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1C

Procedure:
Diethyl carbonate (19.5 g, 165 mmol) was dissolved in ether (100 mL) and 50% suspension of sodium hydride in oil (8.0 g, 167 mmol) was carefully added. A solution of the above acetophenone (16.7 g, 69.3 mmol) in benzene (100 mL) was added and the mixture was refluxed for 5 h. After cooling, the mixture was poured on ice with concentrated hydrochloric acid (50 mL); the organic layer was separated, dried with anhydrous potassium carbonate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/chloroform 1:1) affording ethyl 4-benzyloxy-2-methylbenzoylacetate.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=O.[Cl-:24].C[NH3+].[C:27]([BH3-])#[N:28].[Na+]>>[ClH:24].[CH3:27][NH:28][CH2:7][C:6]1[CH:5]=[C:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:2]=1[CH3:1]
Reactant: [Cl-]
Reactant: [BH3-]C#N
Reactant: Cc1c(C=O)cc(-c2ccccc2)n1S(=O)(=O)c1ccccc1
Agent: C[NH3+]
Agent: [Na+]
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1C
Product: Cl
Yield: 35.2 %

Procedure:
Using 2-methyl-5-phenyl-1-phenylsulfonyl-1H-pyrrole-3-carbaldehyde (0.27 g), methylammonium chloride (0.68 g) and sodium cyanoborohydride (0.28 g), a procedure as in Example 4 was performed to give the title compound as colorless crystals (yield 0.11 g, 35%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.CCN(CC)CC.[CH2:29]([O:36][C@H:37]([C:64]([F:67])([F:66])[F:65])[C@@H:38]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[C:56]([Cl:62])[C:55]=1[CH3:63])[C:39]([NH:41][NH:42][C:43](=O)[C:44]1[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=1)=[O:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.C1COCC1>[CH2:29]([O:36][C@H:37]([C:64]([F:65])([F:67])[F:66])[C@@H:38]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[C:56]([Cl:62])[C:55]=1[CH3:63])[C:39]1[O:40][C:43]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)=[N:42][N:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](OCc2ccccc2)C(F)(F)F)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](OCc2ccccc2)C(F)(F)F)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a solution of triphenylphosphine (180 mg, 0.69 mmol) in DCM (10 mL) was added I2 (174 mg, 0.69 mmol) at 0° C. After all the Iodine was dissolved completely, Et3N (0.20 mL, 1.43 mmol) was added, followed by a solution of N′-((2R,3S)-3-(benzyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-4,4,4-trifluorobutanoyl)-4-cyanobenzohydrazide (180 mg, 0.32 mmol) in DCM (2 mL) and THF (2 mL). After addition, the reaction mixture was allowed to warm to room temperature and stirred for an additional 30 min. The reaction was quenched with saturated aq. sodium thiosulfate (1 mL) and diluted with DCM (100 mL). The organic layer was separated and washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by flash chromatography to provide the title compound 4-((1R,2S)-2-(benzyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-3,3,3-trifluoropropylamino)-2-chloro-3-methylbenzonitrile (170 mg, 98%). 1H NMR (400 MHz, CDCl3, δ in ppm) 7.98 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.09˜7.17 (m, 5H), 6.45 (d, J=8.4 Hz, 1H), 5.22 (b, 2H), 5.01 (d, J=11.5 Hz, 1H), 4.69 (d, J=11.5 Hz, 1H), 4.52 (m, 1H), 2.34 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[N:11]1([CH2:17][CH2:18][NH:19][C:6]2[CH:5]=[CH:4][C:3]([N+:8]([O-:10])=[O:9])=[CH:2][CH:7]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: NCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.2 %

Procedure:
A 50 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.187 mL, 1.77 mmol), 2-Morpholin-4-yl-ethylamine (0.299 g, 2.30 mmol) and dioxane (9.0 mL). To the solution, diisopropyl ethyl amine (0.463 mL, 2.66 mmol) was added dropwise and allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3×30 mL), and with brine (2×30 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording (2-Morpholin-4-yl-ethyl)-(4-nitro-phenyl)-amine as a yellow solid (0.315 g, 1.26 mmol, 71% yield).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([C:13]2[C:14]([CH3:25])=[N:15][O:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:21]3[CH:22]=[CH:23][C:18]([C:17]4[O:16][N:15]=[C:14]([CH3:25])[C:13]=4[C:10]4[O:9][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:12][N:11]=4)=[CH:19][CH:20]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1-c1nnc(Cc2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4-c4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 2-benzyl-5-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1,3,4]oxadiazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[OH:6][C:7]1[CH:29]=[CH:28][C:10]([CH:11]=[CH:12][CH2+:13]2[C:18]3[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:17]=3[CH:16]=[C:15]([CH3:27])O2)=[CH:9][CH:8]=1.O.[NH2:31][NH2:32]>C(O)C>[OH:6][C:7]1[CH:29]=[CH:28][C:10]([CH:11]=[CH:12][C:13]2[C:18]3[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:17]=3[CH2:16][C:15]([CH3:27])=[N:32][N:31]=2)=[CH:9][CH:8]=1
Reactant: COc1cc2c(cc1OC)[CH2+](C=Cc1ccc(O)cc1)OC(C)=C2
Reactant: NN
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Product: COc1cc2c(cc1OC)C(C=Cc1ccc(O)cc1)=NN=C(C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.5 g (10.6 mM) of 1-(4-hydroxystyryl)-3-methyl-6,7-dimethoxy-2-benzopyrylium perchlorate (m.p. 298° to 300° C. d.) are suspended in 90 ml of 99.5% ethanol, 1.6 ml (31.8 mM) of 100% hydrazine hydrate are added, and the solution is stirred for 2 hours at room temperature. After evaporation at reduced pressure the residue is suspended in 100 ml of water, filtered, washed with 3×5 ml of water, the crude product is resuspended in hot water, filtered, washed with 3×5 ml of water and dried at 80° to 100° C. Yield 2.65g, m.p. 205° to 207° C. (decomp.). This crude product is purified by refluxing in 12 ml of ethanol and subsequent drying. Yield 2.37 g (66.4%), m.p. 209° to 211° C. (decomp.).
Reaction SMILES: [OH-].[Na+].Cl[S:4]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH:8]=1)(=[O:6])=[O:5].[NH:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17].C1(C)C=CC=CC=1>O>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([S:4]([N:16]([CH2:18][C:19]([OH:21])=[O:20])[CH3:17])(=[O:6])=[O:5])=[CH:8]1
Reactant: CNCC(=O)O
Reactant: O=S(=O)(Cl)c1csc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(CC(=O)O)S(=O)(=O)c1csc2ccccc12
Temperature: 60 °C
Reaction time: 6.5 h

Procedure:
6 g of NaOH, 23.27 g of 3-chlorosulphonyl-benzothiophene and 13.36 g of sarcosine are added to a mixture of 200 ml of toluene and 200 ml of water and stirred for 6.5 hours at 60° C. For working up, the aqueous phase is separated off and the organic phase is extracted with 100 ml of 2 N NaOH solution. The combined aqueous phases are acidified with conc. HCl and then extracted twice with 300 ml of ethyl acetate. After washing with saturated aqueous saline solution and drying over magnesium sulphate the organic phase is concentrated by evaporation. The crude product obtained is recrystallised from 100 ml of dichloroethane. Yield: 13.14 g. M.p.: 139-140° C.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[NH2:29][NH2:30].C(OCC)C>C(Cl)Cl>[NH:29]([C:26]([CH:23]1[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]1)=[O:28])[NH2:30]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NN
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reaction time: 2 h

Procedure:
Carbonyl diimidazole (3.57 g, 22 mmol) was added to a solution of 1-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid (4.59 g, 20 mmol) in methylene chloride (50 mL) and stirred for two hours until gas evolution ceased. Then hydrazine (0.8 mL, ˜26 mmol) was added to the reaction and the reaction was stirred at room temperature for another two hours. The reaction was diluted with more methylene chloride and washed with sat'd aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered and the solvent evaporated to give a viscous residue. Trituration with diethyl ether afforded tert-butyl 4-(hydrazinocarbonyl)-piperidine-1-carboxylate as an off-white solid.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[N:13]3[C:14]([CH3:27])=[CH:15][C:16]([C:18]([NH:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:19])=[CH:17][C:12]3=[N:11][C:10]=2[C:28]2(C)[CH2:30][CH2:29]2)[CH2:4][CH2:3]1.FC1(F)CCC(CC2N3C(C)=CC(C(O)=O)=CC3=NC=2C(C)C)CC1.Cl.NC1CCOCC1>>[F:32][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[N:13]3[C:14]([CH3:27])=[CH:15][C:16]([C:18]([NH:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:19])=[CH:17][C:12]3=[N:11][C:10]=2[CH:28]([CH3:29])[CH3:30])[CH2:4][CH2:3]1
Reactant: Cc1cc(C(=O)NC2CCOCC2)cc2nc(C3(C)CC3)c(CC3CCC(F)(F)CC3)n12
Agent: Cc1cc(C(=O)O)cc2nc(C(C)C)c(CC3CCC(F)(F)CC3)n12
Agent: Cl
Agent: NC1CCOCC1
Product: Cc1cc(C(=O)NC2CCOCC2)cc2nc(C(C)C)c(CC3CCC(F)(F)CC3)n12

Procedure:
Compound 100 (62.0 mg, yield 72%) was obtained in the same manner as in step 4 of Example 49, using 3-(4,4-difluorocyclohexylmethyl)-2-isopropyl-5-methylimidazo[1,2-a]pyridine-7-carboxylic acid obtained in step 5, and 4-aminotetrahydropyran hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])=[CH:8][C:7]([CH3:21])=[CH:6][N:5]2[C:22]=1[C:23]([O:25]CC)=[O:24].[OH-].[Li+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])=[CH:8][C:7]([CH3:21])=[CH:6][N:5]2[C:22]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)ccc(F)c3F)cc(C)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCc2c(F)ccc(F)c2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
5.07 g (12.87 mmol) of ethyl 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate Example 265A were dissolved in 275 ml of THF/methanol (5/1), 64.4 ml of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at 40° C. for 3.5 h. At 0° C., the mixture was acidified to about pH 4 with 6 N aqueous hydrochloric acid and concentrated. The solid formed was filtered off, washed with water and dried under reduced pressure. This gave 4.77 g (98% of theory; purity about 93%) of the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[CH:25](O)[C:26]([O-:28])=[O:27].[CH3:30]O>C(Cl)Cl>[CH3:30][O:28][C:26](=[O:27])[CH2:25][O:23][C:21]1[N:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: CO
Reactant: CC(O)C(=O)[O-]
Solvent: ClCCl
Product: COC(=O)COc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2

Procedure:
Following the procedures of Example 426, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and methylglycolate were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-5% methanol in DCM) to give [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-acetic acid methyl ester as a yellow (88 mg, 24%). LCMS: RT=3.09 min, [M+H]+=385
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]#[N:15])=[CH:5][CH:4]=1.[H-].[Na+].[C:18](=O)([O:21]C)[O:19][CH3:20].Cl>O1CCCC1>[C:14]([CH:13]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)[C:18]([O:19][CH3:20])=[O:21])#[N:15]
Reactant: COC(=O)OC
Reactant: COc1ccc2cccc(CC#N)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C#N)c1cccc2ccc(OC)cc12

Procedure:
(7-Methoxy-naphth-1-yl)acetonitrile (20 g) is dissolved in 150 ml of anhydrous tetrahydrofuran. Sodium hydride (202.8 mmol) is added at ambient temperature, and the mixture is refluxed for 30 minutes. Dimethyl carbonate (12 ml) is added with caution, and the reaction mixture is refluxed for 30 minutes. The mixture is poured into ice-cold water, and the aqueous phase is acidified with 21 ml of 37% hydrochloric acid solution and then extracted twice with 100 ml of ether. The organic phase is washed with water, dried, decoloured and evaporated. The oil obtained is precipitated from ether, and the precipitate formed is filtered off under suction and then recrystallised to yield the title product in the form of a white solid.
Reaction SMILES: [ClH:1].Cl.O[CH2:4][CH:5]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>S(Cl)(Cl)=O>[Cl:1][CH2:4][CH:5]1[CH2:10][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][N:6]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cl
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Yield: 99.4 %

Procedure:
A suspension of 23 g (62.3 mmol) of 2-hydroxymethyl-1,4-diphenylmethyl piperazine, dihydrochloride in 79 ml thionyl chloride was heated 4 hours under reflux. The solution was cooled and excess thionyl chloride was evaporated under reduced pressure. The residue was crystalized in ethanol, dried with acetone to yield 19.5 g of title compound dihydrochloride M.P. 234° C. dec.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.Cl.[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH:18]=[CH:17]2>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:30]2[CH2:29][CH2:28][N:27]([S:24]([C:19]3[CH:18]=[CH:17][C:16]4[C:21](=[CH:22][CH:23]=[C:14]([Cl:13])[CH:15]=4)[CH:20]=3)(=[O:26])=[O:25])[CH2:32][CH2:31]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: Cc1cc(Br)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In the same manner as in Referential Example 12, a reaction was conducted using 4-bromo-2-methylbenzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([NH2:12])[C:4]=2[N:3]=1.[O:13]=[C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]1[CH2:24][CH2:25][CH2:26][CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([NH:12][CH2:27][CH2:26][CH2:25][CH2:24][N:15]3[C:16](=[O:23])[C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]3=[O:13])[C:4]=2[N:3]=1
Reactant: Cc1ccc2c(n1)C(N)CCC2
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2c(n1)C(NCCCCN1C(=O)c3ccccc3C1=O)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 2-methyl-5,6,7,8-tetrahydroquinolin-8-ylamine (237 mg, 1.46 mmol) in CH2Cl2 (20 mL) at room temperature under inert atmosphere was added 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (159 mg, 0.731 mmol) followed by sodium triacetoxyborohydride (309 mg, 2.92 mmol). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added and the mixture was extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated. The resultant material was purified by column chromatography on silica gel (10:1:0.5 CH2Cl2: MeOH: NH4OH) to provide the product as a yellow oil (210 mg, 79%): 1H NMR (CDCl3): δ 1.56-1.83 (m, 6H), 1.90-2.04 (m, 2H), 2.04-2.18 (m, 2H), 2.47 (s, 3H), 2.64-2.80 (m, 4H), 3.70-3.76 (m, 3H), 6.90 (d, 1H, J=7.8 Hz), 7.24 (d, 1H, J=7.8 Hz), 7.69-7.73 (m, 2H), 7.81-7.85 (m, 2H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][C:4]1=[O:66])[CH3:2].C(N(S(F)(F)[F:73])CC)C.C(#N)C>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([F:73])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(F)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC

Procedure:
Treatment of 17-ethyl-1-hydroxy-14-triisopropylsilyloxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone with diethylaminosulfur trifluoride (DAST) in THF followed by 48% aqueous HF/acetonitrile deblocking as in Example 64, yielded 17-ethyl-1,14-dihydroxy-12-[2'-(4"-fluoro-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:23]([OH:26])[C:24]#[CH:25]>O1CCCC1.CCOCC.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][CH2:23][OH:26])=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: C#CCO
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C#CCO)cc1
Temperature: 50 °C

Procedure:
To a degassed solution of 1-bromo-4-tert-butylbenzene (5 g, 23.5 mmol) in tetrahydrofuran (25 mL) was added in the following order: copper(I) iodide (134 mg, 0.704 mmol), tetrakis(triphenylphosphine)palladium (813 mg, 0.704 mmol), and 1,8-diazabicyclo[5.4.0]-undec-7-ene (4.2 mL, 28.1 mmol). The resulting mixture was degassed again and a solution of propargyl alcohol (1.64 mL, 28.2 mmol) in tetrahydrofuran (2 mL) was added over period of 10 min. The reaction mixture was slowly heated up to 50° C. and then stirred at this temperature over night. The mixture was diluted with ether (50 mL), washed with water (20 mL), 15% hydrochloric acid (2×20 mL) and saturated aqueous solution of sodium hydrogen carbonate (25 mL). The organic solution was dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 5:1) affording 3-(4-tert-butylphenyl)prop-2-yn-1-ol.