Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:15][C@@H:14]3[C@H:16]([N:19]=[N+]=[N-])[CH2:17][CH2:18][N:13]3[C:12]2=[O:22])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>CO.O=[Pt]=O>[NH2:19][C@H:16]1[CH:14]2[N:13]([C:12](=[O:22])[N:11]([C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[CH2:15]2)[CH2:18][CH2:17]1
Reactant: Cc1c(N2C[C@@H]3[C@H](N=[N+]=[N-])CCN3C2=O)ccc(C#N)c1Cl
Agent: O=[Pt]=O
Solvent: CO
Product: Cc1c(N2CC3[C@H](N)CCN3C2=O)ccc(C#N)c1Cl
Yield: 68.2 %

Procedure:
A solution of compound 90B (20.5 mg, 0.06 mmol) in dry MeOH (1.0 mL) was treated with PtO2 (5.5 mg) and hydrogenated (balloon) at rt for 1.0 h. The reaction mixture was diluted with MeOH (1.0 mL) and filtered through a syringe filter, washing the syringe filter well with MeOH (3×1.0 mL). The clear filtrate was concentrated under reduced pressure and the residue was chromatographed (silica gel; CH2Cl2/CH3OH gradient) to yield the title compound (11.9 mg, 68.2%) as a white solid. HPLC: 100% at 1.38 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=18.98 min (99.6%); Conditions: OD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES+): m/z 291 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH:12]=[CH:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].[O:14]1CCCC1.B.[OH-].[Na+].OO>C1COCC1.O>[C:2]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC1CC=CC1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
In a dry round-bottomed flask, N-1-Boc-amino-3-cyclopentene (1.0 g, 5.46 mmol) was dissolved in THF (7 ml). The solution was cooled to 0° C. and borane tetrahydrofuran complex (1.0M in THF, 6.0 ml, 6.0 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h then warmed to room temperature overnight. The mixture was cooled back to 0° C. and water (2 ml) was added. Then 10% aqueous sodium hydroxide (8 ml, 20.0 mmol) was added dropwise followed by dropwise addition of hydrogen peroxide (30% solution in water, 5.0 ml, 49 mmol). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-60% EtOAc) to afford 330 mg (30%) of (cis-3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 5.12 (br. s., 1H), 4.39 (m, 1H), 4.03 (br. s., 1H), 1.95-2.17 (m, 2H), 1.78 (d, J=2.6 Hz, 3H), 1.64 (d, J=12.5 Hz, 1H), 1.44 (s, 9H). Also isolated 99 mg (9%) of (trans-3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 4.35-4.51 (m, 2H), 4.15 (br. s, 1H), 2.15-2.30 (m, 1H), 1.98-2.10 (m, 2H), 1.45 (s, 9H), 1.34-1.72 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:15][C:16]1[C:17]([O:28][CH3:29])([C:24]([O:26][CH3:27])=[O:25])[CH2:18][CH:19]([CH3:23])[C:20](=[O:22])[CH:21]=1.C(N(CC)CC)C.[C-]#N.[K+]>C(#N)C>[OH:15][C:16]1[C:17]([O:28][CH3:29])([C:24]([O:26][CH3:27])=[O:25])[CH2:18][CH:19]([CH3:23])[C:20](=[O:22])[C:21]=1[C:4]([C:3]1[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=1)=[O:5]
Reactant: COC(=O)C1(OC)CC(C)C(=O)C=C1O
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C1(OC)CC(C)C(=O)C(C(=O)c2ccc(C(F)(F)F)nc2C)=C1O
Reaction time: 0.5 h

Procedure:
2.23 g of fresh 2-methyl-6-trifluoromethylnicotinoyl chloride are added to a mixture of 2.14 g of methyl 2-hydroxy-1-methoxy-5-methyl-4-oxocyclohex-2-enecarboxylate and 2.02 g of triethylamine in 30 ml of acetonitrile. After approximately 30 minutes, 0.065 g of potassium cyanide is added and the mixture is stirred for 18 hours. At pH 2, the mixture is subsequently partitioned between water and ethyl acetate, dried over magnesium sulfate and evaporated. Filtration on silica gel (mobile phase ethyl acetate/methanoltriethylamine 85:10:5) gives the pure methyl 2-hydroxy-1-methoxy-methyl-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)-4-oxocyclohex-2-enecarboxylate as a viscous oil.
Reaction SMILES: [C:1]1([N:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17](B4OC(C)(C)C(C)(C)O4)=[CH:16][N:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:36]1[CH:37]=[CH:38][C:39]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=3[N:46]=2)=[N:40][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+].O>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(Cl)Cl.CC(C)=O.C(Cl)Cl.C1COCC1>[O:43]1[C:44]2[CH:50]=[CH:49][CH:48]=[CH:47][C:45]=2[N:46]=[C:42]1[C:39]1[N:40]=[CH:41][C:36]([C:17]2[CH:16]=[N:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:7]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)=[CH:19][CH:18]=2)=[CH:37][CH:38]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2nc3ccccc3o2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(-c5nc6ccccc6o5)nc4)cn3)cc2)cc1
Yield: 76.8 %

Procedure:
Following the procedure for 3, 2 (0.868 g, 1.94 mmol), 11 (0.533 g, 1.94 mmol), tetrakis(triphenylphosphine)palladium(0) (112 mg, 96.8 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) yielded 12 (0.77 g, 77% yield) as a bright yellow solid after flash chromatography (SiO2, 100% CH2Cl2 to 19:1 CH2Cl2-acetone).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:32][C:33]1[N:34]=[C:35]([CH3:38])[S:36][CH:37]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:22]1[CH:23]=[CH:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)[CH2:32][C:33]1[N:34]=[C:35]([CH3:38])[S:36][CH:37]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(CCl)cs1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Product: Cc1nc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cs1
Yield: 69.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.65 g) and 4-(chloromethyl)-2-methylthiazole (0.30 g) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.58 g) was obtained. By the reaction and treatment in the same manner as in Example 133 using this compound (0.51 g), 5-hydroxy-N-(4-isopropylphenyl)-N-[(2-methylthiazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.22 g) was obtained.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1
Reactant: O=C1Nc2ncccc2C12Cc1cc3ccc(O)nc3cc1C2
Reactant: O=P(Cl)(Cl)Cl
Product: O=C1Nc2ncccc2C12Cc1cc3ccc(Cl)nc3cc1C2

Procedure:
A solution of (±)-2-hydroxy-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step B (3.00 g, 9.89 mmol) in POCl3 (30 mL) was stirred at 80° C. for 2 h, then concentrated to dryness under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (200 mL) and CH2Cl2 (500 mL). The aqueous layer was extracted further with CH2Cl2 (200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=322 (M+1).
Reaction SMILES: [C:1](Br)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[O:11]=[C:12]([CH2:14][N:15]([C:17](=[NH:19])[NH2:18])[CH3:16])[OH:13].N1C=CC=CC=1.C(=O)=O>ClCCl.CC(C)=O>[CH3:16][N:15]([CH2:14][C:12]([OH:13])=[O:11])[C:17]([NH:19][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[NH:18]
Reactant: CCCCCCCC(=O)Br
Reactant: CN(CC(=O)O)C(=N)N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)NC(=N)N(C)CC(=O)O
Temperature: 25 °C

Procedure:
In a dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, a thermometer, a nitrogen inlet tube and the dropping funnel containing the octanoyl bromide solution, 7.08 g (54 mmol) of creatine is suspended, with stirring, in 50 ml of dry dichloromethane. To this suspension a catalytic amount (0.1 mmol) of pyridine is also added. The suspension is stirred in a dry ice and acetone bath to a temperature of between to about −10° C. and 0° C. When the target temperature is reached the drop wise addition of octanoyl bromide is commenced. Addition of octanoyl bromide continues, with cooling and stirring, until all of the octanoyl bromide is added, after which the reaction is allowed to warm to room temperature with constant stirring. The solution is then filtered to remove any remaining creatine and the volatile dichloromethane and pyridine are removed under reduced pressure yielding 2-(1-methyl-3-octanoylguanidino)acetic acid.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:18]2[CH:17]([OH:19])[CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:18]2[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c1C(O)CCC2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)NS(=O)(=O)c1cccc2c1C(=O)CCC2
Yield: 97.1 %

Procedure:
To a solution of 5.49 g (19.4 mmol) of material prepared in Example 11 in 250 mL of methylene chloride was added 8.35 g (39 mmol) of pyridiniumchlorochromate. After 3 hours the reaction mixture was diluted with ether and passed through a plug of fluorosil to give 5.3 g of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:26]2
Reactant: Brc1cccc2c1CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC1COc2c(N3Cc4cccc(Br)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 44.4 %

Procedure:
142 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7--oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 149 mg of 4-bromoisoindoline, 114 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 103 mg of the target compound.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Si:12]([O:19][C:20]1[CH:21]=[C:22]([CH:38]=[CH:39][CH:40]=1)[CH:23]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)[OH:24])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>ClCCl>[Si:12]([O:19][C:20]1[CH:21]=[C:22]([CH:38]=[CH:39][CH:40]=1)[C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:36][CH:37]=1)=[O:24])([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:14])[CH3:13]
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
Pyridinium chlorochromate (46.5 g, 0.216 mol) was added to a solution of 4-(3-(tert-butyldimethylsilyloxy)-α-hydroxybenzyl)-N,N-diethylbenzamide (44.6 g, 0.108 mol) from Example 11 in 600 mL dichloromethane at 0° C. The solution was stirred overnight at room temperature and filtered through Celite. The filtrate was concentrated to a volume of 150 mL and purified by chromatography on silica gel with ethyl acetate (5-40%) in hexane to give 29.4 g (66%) of 4-(3-((tert-butyldimethylsilyl)oxy)benzoyl)-N,N-diethylbenzamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>ClCCl>[Cl:1][C:2]1[C:3]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:15]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:8][CH2:7]2
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CNCC3)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(S(C)(=O)=O)CC3)cc1C(F)(F)F
Reaction time: 48 h

Procedure:
N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.193 g) in dichloromethane (10 ml) containing triethylamine (0.055 ml) was treated with methanesulfonyl chloride ((0.063 g) and the mixture stirred for 48 h. Water was added and the organic phase separated and solvent removed at reduced pressure. The residue was triturated with diethyl ether to give the title compound (0.19 g).
Reaction SMILES: [CH2:1]([N:8]([CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCOCC1>[CH2:1]([N:8]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(Cc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N(Cc1ccccc1)C1CCNCC1
Yield: 67.6 %

Procedure:
A solution of tert-butyl 4-(N-benzylacetamido)piperidine-1-carboxylate (9.3 g, 28.0 mmol) in dioxane (20 mL) and 4 M HCl/dioxane (14.0 mL, 56.0 mmol) was stirred at room temperature overnight and then concentrated in vacuo. The residue was basified with 2 N NaOH and extracted with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo, to afford N-benzyl-N-(piperidin-4-yl)acetamide (4.4 g, 67%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[C:13]2[C:17]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=3[O:15][N:14]=2)=[CH:3][CH:2]=1.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>N1C=CC=CC=1>[CH3:23][N:24]([CH3:28])[C:25](=[O:26])[O:22][C:20]1[CH:19]=[CH:18][C:17]2[C:13]([CH:8]3[CH2:9][NH:10][CH2:11][CH2:12][N:7]3[C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[N:14][O:15][C:16]=2[CH:21]=1
Reactant: Oc1ccc2c(C3CNCCN3c3ccncc3)noc2c1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)Oc1ccc2c(C3CNCCN3c3ccncc3)noc2c1
Temperature: 85 °C
Yield: 80.7 %

Procedure:
To a stirred solution of 3-[1-(4-pyridyl)piperazinyl]-1,2-benzisoxazol-6-ol (0.80 g) in pyridine (10 ml) was added dimethylcarbamyl chloride (0.70 g) under N2. The reaction was heated to 85° C. for 2 hours. TLC (silica gel 30% MeOH/CH2Cl2) showed no starting material was present. The solvent was removed in vacuo and the residue was flash chromatographed (silica gel) eluting with 7% MeOH/CH2Cl2 to afford 0.80 g of material. The material was further purified through recrystallization from CH2Cl2 /pet. ether to afford 0.70 g of the product, m.p. 171°-172° C.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][S:5][C:6]1[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=1.NN>C(Cl)Cl>[CH3:1][N:2]([C:12]([NH:11][C:9]1[S:10][C:6]([S:5][CH3:4])=[N:7][N:8]=1)=[O:13])[NH2:3]
Reactant: CNN
Reactant: CSc1nnc(N=C=O)s1
Agent: NN
Solvent: ClCCl
Product: CSc1nnc(NC(=O)N(C)N)s1

Procedure:
A solution of methylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Methylthio-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room tempertaure. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-methyl-4-(5-methylthio-1,3,4-thiadiazol-2-yl) semicarbazide as the residue.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][C:57]2([CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:49])[CH3:48].Br[C:66]1[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][C:57]2([CH2:64][CH2:63][N:62]([C:66]3[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=3)[CH2:61][CH2:60]2)[CH2:56][CH2:55]1)=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(F)cc1)CC2
Reaction time: 0.25 h
Yield: 43 %

Procedure:
BINAP (350 mg, 0.47 mmol) and Pd2 dba3 (317 mg, 1.57 mmol) was added to a mixture of 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (2 g, 7.87 mmol), 1-bromo-4-fluoro-benzene (1.3 g, 7.87 mmol) and sodium tert-butylate (2.26 g, 23.61 mmol) in toluene (25 ml) and the reaction mixture was degassed under argon for 20 minutes and heated under reflux for 4 h. The mixture was then diluted with ethyl acetate, stirred for 15 minutes and filtered over Celite. The reaction mixture was washed with water and sat. NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography. Yield: 43%
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:37])[C:26]=2[CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([Mg]Br)=[CH:41][CH:40]=1.Cl>C1COCC1>[CH2:1]([O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:42]3[CH:43]=[CH:44][C:39]([Cl:38])=[CH:40][CH:41]=3)([OH:37])[C:26]=2[CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(=O)c1ccccc1-2
Reactant: Clc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(O)(c1ccc(Cl)cc1)c1ccccc1-2
Temperature: 25 °C
Yield: 88 %

Procedure:
Under a nitrogen atmosphere, 2-docosyloxy-9-fluorenone (250 mg, 0.50 mmol) prepared in the above-mentioned 1-1 was suspended in THF (2.5 ml), and dissolved at 50° C. 4-Chlorophenylmagnesium bromide solution was added dropwise, and the mixture was stirred. After completion of the reaction, the reaction mixture was cooled to room temperature, 1N hydrochloric acid was added dropwise thereto in a water bath until foaming stopped to quench the reaction. The mixture was extracted with chloroform (15 ml), and washed 3 times with 1N hydrochloric acid (5 ml), 3 times with 5% NaHCO3 solution (5 ml), and once with 20% NaCl solution (5 ml). The organic layer was dried over Na2SO4, and the solvent of the filtrate was evaporated. The obtained residue was isolated and purified by silica gel column chromatography, and precipitated with methanol (3 ml) to give 2-docosyloxy-9-(4-chlorophenyl)-9-fluorenol (270 mg, 0.44 mmol, 88%).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[CH2:13][CH2:14][C@@:15]3([CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[CH2:17][O:16]3)[C@:9]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:10][C@H:11]2[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][C:59]([F:62])([F:61])[F:60])=[CH:54][C:53]=1I>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([N:8]1[C@H:12]2[CH2:13][CH2:14][C@@:15]3([CH:19]=[C:18]([C:53]4[CH:54]=[C:55]([O:58][C:59]([F:62])([F:61])[F:60])[CH:56]=[CH:57][C:52]=4[O:51][CH3:50])[CH2:17][O:16]3)[C@:9]1([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:10][C@H:11]2[S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)(=[O:34])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=C[C@@]2(CC[C@H]3[C@H](S(=O)(=O)c4ccccc4)C[C@]2(c2ccccc2)N3Cc2ccccc2)OC1
Reactant: COc1ccc(OC(F)(F)F)cc1I
Agent: [Cu]I
Agent: [Pd]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(OC(F)(F)F)cc1C1=C[C@@]2(CC[C@H]3[C@H](S(=O)(=O)c4ccccc4)C[C@]2(c2ccccc2)N3Cc2ccccc2)OC1
Yield: 86.9 %

Procedure:
Tetrakis(triphenylphosphine) palladium(0) (20 mg, 0,017 mmol) was added to a degassed suspension of (1R*,2R*,5S*,6R*)-8-Benzyl-2′,5′-dihydro-1-phenyl-6-phenylsulfonyl-4′-tributylstannylspiro[8-azabicyclo[3.2.1]octane-2,2′-furan](Description 18; 150 mg, 0.2 mmol), lithium chloride (50 mg, 1.2 mmol), 2-methoxy-5-trifluoromethoxyiodobenzene (100 mg, 0.3 mmol) and copper(I) iodide (10 mg, 0.05 mmol) in toluene (10 ml). The mixture was heated to reflux for 18 hours. On cooling the mixture was diluted with ethyl acetate (50 ml) and filtered through Celite™. The filtrate was washed with water (25 ml) then dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10, 20 and 30% ethyl acetate/iso-hexanes to give the title compound (115 mg, 87%).