Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(Cl)Cl>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][N:13]2[CH2:12][CH2:11][CH:10]([O:9][C:8]3[CH:16]=[CH:17][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=3)[CH2:15][CH2:14]2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OCCN2CCC(Oc3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 90 °C
Yield: 75.7 %

Procedure:
A mixture of 4-(4-nitrophenoxy)piperidine hydrochloride (1.15 g, 5.80 mmol), 1-bromo-2-(4-nitrophenoxy)ethane (1.43 g, 5.80 mmol), K2CO3 (1.60 g, 11.80 mmol), and DMF (15 mL) was heated at 90° C. for 6 hours. The mixture was cooled, diluted with CH2Cl2, and washed with water. The organic phase was dried (MgSO4) and concentrated to give 1.70 g (80%) of N-2-(4-nitrophenoxy)ethyl-4-(4-nitrophenoxy)piperidine as a yellow solid. 1H NMR (DMSO-d6): δ 8.10 (m, 4H), 7.05 (d, 4H), 4.60 (m, 1H), 4.15 (t, 2H), 2.78 (m, 4H), 2.40 (t, 2H), 1.95 (m, 2H), 1.65 (m, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][CH2:14][C@H:15]([N:17]([CH3:19])[CH3:18])C)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[CH3:20]O>>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C@H:14]([CH3:20])[CH2:15][N:17]([CH3:18])[CH3:19])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CO
Reactant: C[C@H](CNc1ccnc2cc(Cl)ccc12)N(C)C
Agent: Cl
Product: C[C@H](CN(C)C)Nc1ccnc2cc(Cl)ccc12

Procedure:
Analogously to Example 33c, starting from (R)-2-amino-1-chloro-N-(7-chloro-quinolin-4-yl)-propane hydrochloride there is prepared (R)-N1 -(7-chloro-quinolin-4-yl)-N2,N2 -dimethyl-propane-1,2-diamine hydrochloride; white crystals; m.p.: >260° C., [a]D =-132° (c=1.0, MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11]CC=C)[CH:6]=[O:7].[OH-].[Na+].[C:17]1(C)[CH:22]=C(C)C=C(C)[CH:18]=1>>[CH2:22]([C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[OH:11])[CH:6]=[O:7])[CH:17]=[CH2:18]
Reactant: C=CCOc1ccc(C=O)cc1OC
Reactant: Cc1cc(C)cc(C)c1
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(C=O)cc(OC)c1O

Procedure:
3-Methoxy-4-(2-propenyloxy)benzaldehyde (19.7 g, 0.100 mol) was heated under reflux in 75 ml mesitylene (1,3,5-trimethylbenzene) for 20 hours. After cooling, 250 ml 2N sodium hydroxide were added to the reaction mixture. The aqueous phase was washed two times with diethyl ether. The aqueous phase was subsequently acidified with concentrated hydrochloric acid under ice cooling and then extracted with ethyl acetate. After drying and concentrating the organic phase, there remained a light orange-colored oil that crystallized on cooling.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][CH:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([NH2:23])=[O:22]>>[NH2:23][C:21](=[O:22])[CH:20]([NH:19][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(C)C(N)C(N)=O
Agent: Cl
Product: CC(C)(C)C(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-3,3-dimethyl-butanamide hydrochloride (1:1) (CAN 359844-68-1) as starting materials, LC-MS (UV peak area/ESI) 100%, 346.2113 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[NH:8])[O:4][N+:5]([O-:7])=[O:6].Cl.[CH3:10]N.Cl>>[CH3:1][NH:2][C:3](=[N:8][CH3:10])[O:4][N+:5]([O-:7])=[O:6]
Reactant: CN
Reactant: CNC(=N)O[N+](=O)[O-]
Agent: Cl
Product: CN=C(NC)O[N+](=O)[O-]
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a suspension of 1-methyl-2-nitroisourea (1.0 g) in a buffer solution of a tris(hydroxymethyl)aminomethanehydrochloric acid (tris-hydrochloric acid buffer solution, 1.0 M, pH: 7.5, 10 ml), methylamine hydrochloride (0.6 g) was added at room temperature. After stirring for 3 hours, an aqueous hydrochloric acid (4 M) was added, and then the solution was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and it was then concentrated under reduced pressure. The residual oil was purified with silica gel column chromatography (hexane/ethyl acetate: 2/1) and then recrystallized (ethyl acetate-hexane), to obtain the desired compound (0.8 g) as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:22]1[C:23]([CH3:32])=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[O:26][CH2:25]2)[CH2:3][N:4]1[CH2:21][CH2:20][C:7]2([C:11](=[O:12])[N:10]([C:13]3[CH2:14][O:15][C:16](=[O:19])[C:17]=3[CH3:18])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH3:32][C:23]1[C:22]([C@@H:2]([NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:3][N:4]2[CH2:5][CH2:6][C:7]3([C:11](=[O:12])[N:10]([C:13]4[CH2:14][O:15][C:16](=[O:19])[C:17]=4[CH3:18])[CH2:9][CH2:8]3)[CH2:20][CH2:21]2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][O:26][C:27]2=[O:31]
Reactant: CC1=C(N2CCC3(CCN(C[C@H](N)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(N2CCC3(CCN(C[C@H](NS(C)(=O)=O)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-8-(2-amino-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (30 mg, 0.068 mmol) and triethylamine (29 μL, 0.20 mmol) in DCM (2 mL) was added methanesulfonyl chloride (5.3 μL, 0.068 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. TLC indicated the reaction was complete. Evaporation of the solvent afforded the residue, which was taken up into small amount of DCM and purified by preparative TLC (dichloromethane: methanol=10:1) to give the title compound. 1H NMR (400 MHz, CDCl3): δ 7.63 (dd, J=8.0 Hz, J=8.8 Hz, 2H), 5.30 (s, 2H), 5.15 (s, 2H), 4.95-4.92 (m, 1H), 4.00 (t, J=7.2 Hz, 2H), 2.94-2.91 (m, 1H), 2.82-2.78 (m, 1H), 2.72 (s, 3H), 2.65-2.59 (m, 1H), 2.42-2.39 (m, 1H), 2.38-2.24 (m, 4H), 2.21-2.18 (m, 1H), 2.07 (t, J=7.2 Hz, 2H), 1.92 (s, 3H), 1.86-1.72 (m, 2H), 1.52-1.47 (m, 2H). MS-ESI (m/z): 518 (M+1)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=2[O:28][CH:29]([CH3:31])[CH3:30])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:29]([O:28][C:22]1[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C:20]([NH:19][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=2)[CH2:7]1)=[O:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccc(C(F)(F)F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccc(C(F)(F)F)cc3C2)c1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
The mixture of 2-(2-isopropoxy-3-methyl-benzoylamino)-5-trifluoromethyl-indan-2-carboxylic acid ethyl ester (94) (690 mg, 1.5 mmol) and KOH (1.5 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved. The resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until pH˜4. The precipitate is filtered to give a pure product (95) as a pale brown solid (495 mg, 78%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:14]([NH2:16])=[O:15])[C:11]([NH:12][NH2:13])=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:17][C:18]([CH3:20])=O>>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:14]([NH2:16])=[O:15])[C:11]([NH:12][N:13]=[C:18]([CH3:20])[CH3:17])=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NN)c(C(N)=O)cnc21
Reactant: CC(C)=O
Product: CCn1ncc2c(NN=C(C)C)c(C(N)=O)cnc21
Reaction time: 8 h

Procedure:
14 g. of well pulverized 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (0.0635 mol.) are dissolved in 500ml. of anhydrous acetone and the solution is allowed to stand overnight. Then excess acetone is removed in vacuo and the residual 1-ethyl-4-[2-(1-methylethylidene)hydrazino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide is recrystallized from ethyl acetate, m.p. 217°-218°, yield 9.75 g. (59%).
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9].Br[CH2:13][CH2:14][CH3:15]>CS(C)=O>[CH2:13]([N:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([O:10][CH3:11])=[O:9])[CH2:14][CH3:15]
Reactant: COC(=O)c1ccc[nH]1
Reactant: CCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCn1cccc1C(=O)OC
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of 9 g potassium hydroxide in 25 ml dimethylsulfoxide are added 5 g methyl pyrrole-2 carboxylate and 10 g 1-bromo-propane. After stirring for one hour, the reaction mixture is poured over 100 g crushed ice, after which the solution is extracted with ethyl ether. After drying, the solvent is evaporated under reduced pressure, to give 5 g crude methyl 1-propyl-pyrrole-2-carboxylate.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([C:18]([CH:20]2[CH2:22][CH2:21]2)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:23]([NH2:26])[CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH:20]1([CH:18]([NH:26][CH2:23][CH2:24][CH3:25])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][CH2:21]1
Reactant: CCCN
Reactant: O=C(c1ccccc1)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCNC(c1ccccc1)C1CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
4 Å molecular sieves and 100 mg of para-toluenesulphonic acid are added to 10 g of cyclopropyl phenyl ketone in 60 ml of anhydrous toluene, followed by 6 g of propylamine. Imine formation is monitored by gas chromatographic assay. After heating for 6 hours at 55° C., the reaction mixture is cooled, the molecular sieves are filtered off and the solution is evaporated to dryness under vacuum. The residue is taken up in 100 ml of anhydrous ethanol. The solution is cooled to 0° C. and 2.65 g of sodium borohydride are added portionwise. After stirring overnight at room temperature, the mixture is evaporated to dryness under vacuum and the residue is taken up in water, hydrolysed with 1N hydrochloric acid in order to bring the pH to 2, and washed with ethyl acetate. The pH is brought to 9 by addition of 2N sodium hydroxide and the mixture is then extracted several times with methylene chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27](O)=[O:28])[CH:21]=[CH:20]3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)(=O)C([Cl:37])=O>>[CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]([Cl:37])=[O:28])[CH:21]=[CH:20]3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Treat a solution of 6-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carboxylic acid (0.11 g, 0.246 mmol) in CH2CL2 (1.0 mL) dropwise with oxalyl chloride (0.13 mL, 1.48 mmol). Stir the solution at RT for 1 h and concentrate to give 6-{1-[4-(3,3-dimethyl-2-oxobutoxy)-3-methylphenyl]-1-ethylpropyl}naphthalene-2-carbonyl chloride (“the acid chloride”). Treat a mixture of methylglycine HCl (0.031 g, 0.25 mmol) and Et3N (0.51 mL, 0.37 mmol) in CH2CL2 (3 mL) with a solution of the acid chloride (0.057 g, 0.123 mmol) in CH2CL2 (1 mL). Stir the reaction at RT for 16 h and concentrate. Dissolve the residue in THF (0.5 mL) and MeOH (1.0 mL) and treat with 2N NaOH (0.24 mL, 0.48 mmol). Heat the solution to 50° C. for 16 h, concentrate, dilute with CH2CL2 and water (10 mL each). Acidify the resulting mixture to pH 1 using 5N HCl. Wash the organic layer with brine, dry over Na2SO4, and filter. Concentrate the filtrate and purify by silica gel radial chromatography (10:90 MeOH:CH2CL2) to give the title compound as a white solid (0.021 g, 34%). MS (ES) m/e 504 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]=[CH:19][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(CNc2cc(Br)ccc2N)cc1
Solvent: COC(OC)OC
Solvent: O
Product: COc1ccc(Cn2cnc3ccc(Br)cc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 886.7 %

Procedure:
To a solution of 5-bromo-N-(4-methoxybenzyl)benzene-1,2-diamine (550 mg, crude) in HC(OMe)3 (20 mL) was added TsOH.H2O (30 mg, 0.16 mmol). The mixture was stirred at 100° C. for 4 h. The reaction solution was then concentrated and the residue was washed with water and extracted with EtOAc. The organic layer was concentrated to give the desired product (450 mg, 79% yield) and the crude product used in next step without further purification. LCMS (m/z): 318.1 [M+H]+
Reaction SMILES: [C:1]1([N:7]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:8](=[O:50])[CH2:9][C@@H:10]2[O:15]C(C)(C)[O:13][C@H:12]([CH2:18][CH2:19][N:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:22]([C:38]([NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:39])=[C:21]3[CH:47]([CH3:49])[CH3:48])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:20]([CH2:19][CH2:18][CH:12]([OH:13])[CH2:11][CH:10]([OH:15])[CH2:9][C:8]([N:7]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:50])[C:21]([CH:47]([CH3:49])[CH3:48])=[C:22]([C:38]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:39])[C:23]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26][CH:27]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)OC(C)(C)O1
Agent: Cl
Solvent: CO
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(O)CC(O)CC(=O)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide is dissolved in methanol (300 mL) and reacted by adding 1.0N hydrochloric acid (100 mL) and stirring for 12 hours at room temperature. The white crystalline solid [R-(R*,R*)]-5-(4-fluorophenyl)-β,δ-dihydroxy-2-(1-methylethyl)-N,N,4-triphenyl-3-[(phenylamino)carbonyl]-1H-pyrrole- 1-heptanamide is isolated by filtration (mp 228.5°-232.9° C., uncorrected). FTIR (KBr) 3400 (broad), 2850, 1640 cm-1 ;
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC>O1CCOCC1.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:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(C)(C)OC(=O)NCc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccccn2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of tert-butyl-3-iodobenzylcarbamate (166 mg, 0.50 mmol) in Dioxane (1.5 mL) was added Pd(PPh3)4 (58 mg, 0.05 mmol) and 2-(tributylstannyl)pyridine (275 mg, 0.75 mmol). After stirring at 100° C. for 2 h, it was concentrated and the residue was purified by column chromatography to give tert-butyl-3-(pyridin-2-yl)benzylcarbamate (111 mg).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[N:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:47][C:42]1[CH:43]=[C:44]([CH3:46])[CH:45]=[C:40]([NH:39][CH2:38][CH2:37][NH:36][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[CH:20][CH:19]=2)[N:41]=1
Reactant: Cc1cc(C)nc(NCCN)c1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCNc2cc(C)cc(C)n2)cc1
Reaction time: 0.75 h
Yield: 78.9 %

Procedure:
4-geranyloxybenzoic acid(2.30 g) was dissolved in chloroform(50 ml) and triethylamine(2.33 ml), and then diphenylphosphinic chloride(1.48 ml) was added thereto while being cooled with ice. After being stirred for 45 minutes, the mixture, with 2-(2-aminoethylamino)-4,6-dimethylpyridine(1.90 g) added thereto, was stirred for 3 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.79 g of the aimed compound.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([S:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[K+].Cl>C1COCC1.CN(C=O)C>[OH:27][C:25]1[CH2:24][S:23][C:21](=[O:22])[C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=1
Reactant: CCCCCCCCCCCCOc1ccc(CC(=O)SCC(=O)OCC)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(C2=C(O)CSC2=O)cc1
Reaction time: 1 h
Yield: 0.5 %

Procedure:
In a mixture of THF (50 ml) and DMF (10 ml) was dissolved ethyl S-(4-dodecyloxyphenyl)acetylthioglycolate (2.8 g, 6.6 m mol). To the solution was added at room temperature potassium tertiary butoxide (1.1 g, 10 m mol). The solution was stirred for one hour, to which was then added 2N HCl (20 ml), followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: ethyl acetate). The crude crystals obtained were recrystallized from IPE to obtain 2,5-dihydro-4-hydroxy-3-(4-dodecyloxyphenyl)thiophen-2-one (5-h, 13 mg, 0.5%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[N:2]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH2:6][C:4]1[N:3]=[N:2][S:1][CH:5]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1csnn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1csnn1
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
A solution of 1,2,3-thiadiazol-4-ylmethanol (0.75 g, 6.5 mmol) in dichloromethane (20 mL) was cooled to 5° C. under a nitrogen atmosphere and treated with triethylamine (1.018 mL, 7.3 mmol) and methanesulfonyl chloride (0.565 mL, 7.3 mmol). After 15 min, the ice-bath was removed and the reaction mixture was stirred for 2 h. The solution was washed with 1N hydrochloric acid solution (2×2 mL) and water, dried (MgSO4 +MgO) and concentrated. The residue was purified by chromatography (silica gel column 1.5×21 cm) with ether as eluting solvent to give 0.90 g (71%) of 1,2,3-thiadiazol-4-ylmethanol methanesulfonate;
Reaction SMILES: [CH2:1]1[CH2:26][O:25][C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[OH:22])[C:4]2([CH3:24])[CH3:23])[O:2]1.C1C[O:30]CC1>>[CH2:26]1[CH2:1][O:2][C:3]2([CH2:20][CH2:19][C@@:18]3([CH3:21])[C@@:5]([OH:30])([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][CH2:11][C@@H:12]3[OH:22])[C:4]2([CH3:24])[CH3:23])[O:25]1
Reactant: CC1(C)C2=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC12OCCO2
Reactant: C1CCOC1
Product: CC1(C)C2(CC[C@]3(C)[C@H]4CC[C@]5(C)[C@@H](O)CC[C@H]5[C@@H]4CC[C@@]13O)OCCO2
Reaction time: 24 h
Yield: 23 %

Procedure:
To a stirred solution of 3,3-ethylenedioxy-4,4-dimethyl-5-androsten-17β-ol (190 mg) in THF (3.5 ml) at 0° C., under N2, 1M BH3.THF complex in THF (3.3 ml) was added in five portions over 5 days. The reaction mixture was cautiously quenched by dropwise addition of H2O at 0° C. (1.5 ml), followed by 4N NaOH (0.16 ml) and by 30-32 wt. % H2O2 solution in water (0.056 ml). After 24 h, EtOAc and brine were added, the phases were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (SiO2, n-hexane/DCM/acetone 80/10/10) to give 3,3-ethylenedioxy-4,4-dimethylandrostan-5α,17β-diol (80 mg, 23%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][CH:5]=1.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromomethylbenzoic acid methyl ester (831 mg) was dissolved in DMF (12.5 ml) and added with dipropylamine (971 μl) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution, and subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off, thereby obtaining the subject compound (883 mg) as a brown solid.
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:2]2[CH:21]=[CH:20][C:5]3[N:6]=[C:7]([C:12]4[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=4)[C:15]#[N:16])[CH2:8][C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[CH:26][CH:25]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: N#Cc1cccc(C2=Nc3ccc(I)cc3NC(=O)C2)c1
Product: COc1ccc(C#Cc2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)cc1
Yield: 58.6 %

Procedure:
Prepared from 3-(7-iodo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile (Example 1) (290 mg, 0.75 mmol) and 4-methoxy-phenylacetylene (350 mg, 1.57 mmol) according to the general procedure F. Obtained as a light yellow solid (172 mg).