Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[O:24])[CH:17]=1.CS(C)=O.C(O)(=O)C.O.[NH2:41][C:42]([NH2:44])=[NH:43]>>[NH:43]([C:3](=[O:2])[CH2:4][N:5]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:17]=[C:18]([NH:22][C:23]([C:25]2[CH:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[O:24])[CH:19]=[CH:20][CH:21]=1)[C:42]([NH2:44])=[NH:41]
Reactant: COC(=O)Cn1c(-c2ccccc2)ccc1-c1cccc(NC(=O)c2cc(C)on2)c1
Reactant: N=C(N)N
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)Nc2cccc(-c3ccc(-c4ccccc4)n3CC(=O)NC(=N)N)c2)no1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The residue from step 3 is dissolved in 300 μl guanidine in dimethylsulfoxide (500 μmoles) and agitated in a shaker at room temperature for 1-4 h. The reaction is quenched with excess acetic acid (ca. 1 mmole), DMSO (200 uL) and water (100 uL), and concentrated in vacuo. The residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL total) and purified by Gilson preparative HPLC system, Retention Time, 0.76 min., M+H 443.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])SC)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:30][OH:31]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[N:14]=[N:15][S:16][C:17]=2[CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:30][OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSC(=Nc1ccc(F)c(Cl)c1)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: NO
Solvent: CCO
Product: CC(C)[Si](OCc1snnc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Methyl N-(3-chloro-4-fluorophenyl)-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carbimidothioate (90 mg, 0.0002 mol) was dissolved in EtOH (2 mL) followed by addition of hydroxylamine (116 μL, 0.00190 mol) (50% by wt, 99.9% in water solution). The reaction was stirred at 60° C. for 4 h and overnight at room temperature. The reaction was evaporated and purified by flash chromatography to give the desired product (85 mg, 98%). 1H NMR (400 MHz, CDCl3): δ□ 7.32 (s, 1H), 7.25 (s, 1H), 6.90 (m, 2H), 6.62 (m, 2H), 5.17 (s, 2H), 1.05 (m, 21H). MF=C19H28ClFN4O2SSi; LCMS calculated for C19H29ClFN4O2SSi (M+H)+: m/z=459.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[C:7]1\[C:8](=[O:16])[NH:9][C:10]2[C:15]\1=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH2:17]=O.[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH2:24]>CCO.C(Cl)(Cl)Cl>[CH3:19][O:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:17][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7](=[CH:6][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[C:8]1=[O:16]
Reactant: C=O
Reactant: COCCCN
Reactant: O=C1Nc2ccccc2/C1=C/c1ccc[nH]1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COCCCNCN1C(=O)C(=Cc2ccc[nH]2)c2ccccc21
Temperature: 25 °C
Reaction time: 22 h
Yield: 0.8 %

Procedure:
A mixture of Z-(1H-Pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one (120.0 mg, 0.571 mmol), paraformaldehyde (17.1 mg, 0.571 mmol), and 3-methoxypropylamine (58.2 μL, 0.571 mmol) in 4.0 mL EtOH was heated at reflux for 6.5 h. The reaction mixture was cooled to room temperature and let stand for 22 h. The reaction mixture was filtered and the filter cake rinsed with 30% ethyl acetate in hexane. The filtrate was concentrated in vacuo and 4 mL of EtOH added. The reaction was refluxed an additional 19.5 h. The reaction mixture was cooled to room temperature and partitioned between 30 mL dilute HCl and 20 mL Ethyl acetate. The organic layer was removed and the aqueous layer washed with 15 mL ethyl acetate. The aqueous layer was made basic to pH 8 with saturated NaHCO3 and extracted with ethyl acetate. The ethyl acetate layer was washed with H2O, brine and dried over anhydrous Na2SO4. The ethyl acetate layer was filtered and then concentrated. The solid obtained (42.5 mg) was dissolved in CHCl3 and purified by chromatography (silica gel, 1:1/hexane:acetone) to give the title compound (1.5 mg, 1%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([CH:28]4[CH2:30][CH2:29]4)[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:36][OH:37].N1C=CC=CC=1.CO>>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:36][OH:37])=[C:24]([CH:28]4[CH2:29][CH2:30]4)[N:23]=[C:22]3[O:31][CH2:32][CH3:33])=[C:16]([F:34])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NO
Reactant: CCOc1nc(C2CC2)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CCOc1nc(C2CC2)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
Compound A (1.21 g, 2.60 mmol), hydroxylamine hydrochloride (181 mg, 2.6 mmol), pyridine (10 mL, 100 mmol), and MeOH (10 mL, 300 mmol) were combined and stirred at room temperature overnight. Additional hydroxylamine hydrochloride (20 mg) was added and the mixture evaporated to dryness. The solids were dissolved in DCM (50 mL), washed with water (2×20 mL) and saturated aqueous NaCl (10 mL), dried over Na2SO4, and evaporated to dryness to afford compound B as a white solid (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22].Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:15])[F:16])[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:24]4[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)cc4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.16) (168 mg, 0.5 mmol) and commercially available 4-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (110 mg, 46%). MS (ISN) 471.0 [(M−H)−]; mp 237° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N(OC(C)(C)C)=O.C(I)[I:22]>>[I:22][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: ICI
Reactant: Nc1cc(CO)cc(C(F)(F)F)c1
Agent: CC(C)(C)ON=O
Product: OCc1cc(I)cc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
[3-amino-5-(trifluoromethyl)phenyl]methanol (500 mg, 5.2 mmol) was suspended in CH2I2 (5 mL) and t-butyl nitrite (622 μL, 5.2 mmol) was added dropwise by syringe. The reaction was heated slowly to 100° C. and was maintained at this temperature for 30 minutes. The reaction was then cooled to room temperature, diluted with hexanes (50 mL), loaded on a silica gel column, and purified with 100% hexanes to 25% EtOAc/hexanes to afford [3-iodo-5-(trifluoromethyl)phenyl]methanol. Rf=0.19 (15% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.87 (s, 1H), 7.59 (s, 1H), 4.73 (d, J=4.9 Hz, 2H), 1.86 (t, J=5.6 Hz, 1H).
Reaction SMILES: S(Cl)(Cl)=O.CC1C=C(C)C=CC=1C(O)=O.CC1C=C(C)C=CC=1C(Cl)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.[CH3:49][C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[CH:52][C:51]=1[C:57]([N:59]=[C:60]=[S:61])=[O:58]>C1(C)C=CC=CC=1.C(O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:60]([NH:59][C:57](=[O:58])[C:51]2[CH:52]=[CH:53][C:54]([CH3:56])=[CH:55][C:50]=2[CH3:49])=[S:61])=[CH:44][CH:43]=1
Reactant: Cc1ccc(C(=O)N=C=S)c(C)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: Cc1ccc(C(=O)Cl)c(C)c1
Agent: Cc1ccc(C(=O)O)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4C)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,4-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,4-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,4-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 93%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[CH3:13][C:14]1[C:15](B(O)O)=[CH:16][S:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:15]1[C:14]([CH3:13])=[CH:18][S:17][CH:16]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: Cc1cscc1B(O)O
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2cscc2C)c(C)c1
Yield: 91.7 %

Procedure:
A suspension of methyl 4-bromo-3-methylbenzoate (ABCR AV19078; 3 g; 13.10 mmol; 1 eq.), 4-methyl-3-thiopheneboronic acid (Aldrich 542393; 2.05 g; 14.41 mmol; 1.10 eq.), potassium carbonate (9.05 g; 65.48 mmol; 5 eq.) and tetrakis(triphenylphosphine)palladium(0) (1.51 g; 1.31 mmol; 0.10 eq.) in toluene (15 mL) and water (15 mL) was refluxed for 3 hours. The resulting mixture was filtered through a short pad of Celite, which was further washed with toluene. After evaporation of the solvent, the residue taken up in ethyl acetate and washed successively with sat. aq. NaHCO3, water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (2.96 g, 92%) as a brown oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1)(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f33) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C(O)(C)C.[ClH:5].CNOC.Br[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C>[Cl:5][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]
Reactant: Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: CNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.7 %

Procedure:
To a suspension of 50 ml of isopropanol containing N,O-dimethylhydroxylamine hydrochloride (3.97 g, 40.0 mmol) was added dropwise 5.56 ml of triethylamine. The resulting mixture became homogeneous after 5 minutes. There were added 2.00 g (7.09 mmol) of N-(4-bromobutyl)phthalimide and the mixture was refluxed for 58 hours. This was cooled to room temperature, then poured into 200 ml of saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was separated, was washed with water and dried over magnesium sulfate. Chloroform was distilled off and the residue was purified by column chromatography on silica gel. Development with 30% hexane-chloroform resulted in elution of 0.719 g of N-(4-chlorobutyl)-phthalimide and further development with chloroform resulted in 0.964 g (yield: 41%) of N-[4-(N-methoxy-N-methylamino)-butyl]phthalimide as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:21][CH3:22])=[O:4].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:21]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[C:6]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:22]
Reactant: CCc1cccc2c(-c3ccccc3)c(C(=O)OC)c(Cl)nc12
Reactant: C1CCNC1
Product: CCc1cccc2c(-c3ccccc3)c(C(=O)O)c(N3CCCC3)nc12

Procedure:
The title compound was prepared in analogy to example 43 step E from 2-chloro-8-ethyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 43 step D) and pyrrolidine. Yellow solid. MS (ESI): 347.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(Cl)Cl.O>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:2]2[CH:15]=[CH:14][C:13]3[O:12][C:11]4[C:6](=[CH:7][C:8]([C:16]5[CH:17]=[N:18][CH:19]=[N:20][CH:21]=5)=[CH:9][CH:10]=4)[C@@:5]4([CH2:25][O:24][C:23]([NH2:26])=[N:22]4)[C:4]=3[CH:3]=2)[CH:28]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1=N[C@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 100 °C

Procedure:
0.5-2 ml Microwave vial was charged with (S)-2′-bromo-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (100 mg, 0.244 mmol), pyridin-3-ylboronic acid (38.7 mg, 0.315 mmol), dichlorobis(di-t-butyl-4-dimethylaminophenylphosphine)palladium (II) (7.44 mg, 10.51 μmol) and potassium carbonate (87 mg, 0.630 mmol), dioxane (1 ml) and water (0.12 ml) were added and the vial was sealed and heated at 100° C. in the microwave oven (Biotage) for 1 hr. The mixture was diluted with DCM, filtered through Celite, concentrated and purified by flash chromatography on silica gel (12 g column, 20-100% DCM/MeOH/NH4OH in DCM) to afford (R)-2′-(pyridin-3-yl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as yellowish solid.
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][SH:30])[CH2:23][CH2:22]2)=[CH:13][CH:12]=1>C(Cl)Cl>[ClH:10].[ClH:10].[CH2:1]([NH:7][C:8](=[SH:30][CH2:29][CH2:28][CH2:27][N:24]1[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)[CH2:22][CH2:23]1)[OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN=C=O
Reactant: SCCCN1CCN(CCCCc2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: CCCCCCNC(O)=[SH]CCCN1CCN(CCCCc2ccc(Cl)cc2)CC1
Product: Cl
Yield: 99.8 %

Procedure:
The procedure described in Example 2 was followed, using 1.0 g of n-hexyl isocyanate, 2.6 g of 3-{4-[4-(4-chlorophenyl)butyl]piperazin-1-yl}propanethiol and 25 ml of methylene chloride, to give 1.4 g (32% of theory) of N-(n-hexyl)-S-{3-[4-[4-(4-chlorophenyl)butyl]piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 235°-245° C. (dec.).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([OH:19])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:47][CH2:48][CH2:49][CH2:50][OH:51].O>CN(C=O)C>[OH:51][CH2:50][CH2:49][CH2:48][NH:47][C:17]([C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:15])[C:14]=2[CH:1]=1)=[O:19]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: NCCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCO)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred suspension of anthraquinone-2-carboxylic acid (Aldrich, 10.00 g, 39.64 mmol) in DMF (130 ml), was added (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (17.54 g, 39.66 mmol) and trethylamine (11.05 ml, 79.28 mmol). The resulting mixture (initially a clear green solution) was stirred at room temperature for 10 min. before dropwise addition of 3-amino-1-propanol (3.34 ml, 43.67 mmol). The reaction mixture (clear brown solution) was stirred at room temperature in the dark for 17 hours. The solution was poured in a thin stream into water (300 ml) containing some ice. The precipitated material was isolated by filtration and recrystallised from boiling 96% ethanol (ca. 200 ml) and gave the title compound 2 as a bright yew solid (6.93 g, 57% yield).
Reaction SMILES: C1(NCCC(NC)=O)CCC1.[Br:12][C:13]1[C:14]([N:20]([CH:27]([CH2:29][CH3:30])[CH3:28])[CH2:21][CH2:22][C:23]([NH:25][CH3:26])=[O:24])=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1>>[Br:12][C:13]1[C:14]([N:20]([CH:27]2[CH2:28][CH2:30][CH2:29]2)[CH2:21][CH2:22][C:23]([NH:25][CH3:26])=[O:24])=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1
Reactant: CCC(C)N(CCC(=O)NC)c1nc(Cl)ncc1Br
Agent: CNC(=O)CCNC1CCC1
Product: CNC(=O)CCN(c1nc(Cl)ncc1Br)C1CCC1

Procedure:
Using 3-(cyclobutylamino)-N-methyl-propanamide—Intermediate 92 and analogous conditions to Intermediate 88 the title compound was obtained as a white solid (609 mg)
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].Cl>O1CCCC1.O.CO>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1)#[N:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.2 %

Procedure:
A solution of 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (65.0 mg, 0.25 mmol) in tetrahydrofuran/water/methanol (2.5 mL, 3:1:1) was treated with a 1N aqueous lithium hydroxide solution (0.27 mL, 0.27 mmol). The reaction was stirred at 25° C. for 6 h. At this time, the reaction was acidified to pH=1 with a 1N aqueous hydrochloric acid solution and extracted with chloroform/methanol (9:1, 3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid (36.0 mg, 58.6%) as a white solid: mp 126-128° C.; EI-HRMS m/e calcd for C15H17NO2 (M+) 243.1259 found 243.1268.
Reaction SMILES: O([C@:3]12[CH2:20][C@@H:19]([OH:21])[CH2:18][CH2:17][C@:16]1([CH3:22])[C@@H:15]1[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]1)([CH3:12])[C:10](=[O:23])[CH2:9][CH2:8]3)[CH:5]=[CH:4]2)O.O[C@H:25]1CC[C@@]2(C)C(=C[C@@H](O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)[CH2:26]1>>[C:25]([C@@H:18]1[CH2:17][C@@:16]2([CH3:22])[C:3](=[CH:4][CH2:5][C@@H:6]3[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:23])[CH2:20][C@H:19]1[OH:21])#[CH:26]
Reactant: C[C@]12CC[C@H]3[C@@H](C=C[C@@]4(OO)C[C@@H](O)CC[C@]34C)[C@@H]1CCC2=O
Reactant: C[C@]12CC[C@H](O)CC1=C[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C#C[C@@H]1C[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C[C@H]1O

Procedure:
Reaction of the less hindered 3β-hydroxy-5α-androstan-17-one 1 with t-butyldimethylsilyl chloride yields the 3β-t-butyldimethylsilyl ether 2. Treatment of this first with catechol phosphochloridate followed by displacement with iodine yields 3β-hydroxy-11β-iodo-5α-androstan-17-one 3-dimethyl-t-butylsilyl ether 3. Protection of the C-17 ketone as the 1,3-dioxolane 4 followed by alkenylation using dialkenyl dilithio cyano cuprate, (RCH=CH)2Cu(CN)Li2 yields 11α-alkenyl-3β-hydroxy-5α-androstan-17-one-3-t-butyldimethylsilyl ether 5. Deprotection of the C-17 ketone and 3β alcohol affords 11α-alkenyl 3β-hydroxy-5α-androstan-17-one 6. If 6 has R=2'-tri-n-butylstannyl ethenyl, then lead tetraacetate oxidation affords 11α-alkynyl-3β-hydroxy-5α-androstan-17-one. 6, (R=C≡CH). ##STR58##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@@H:13]([CH3:17])[CH2:14][O:15][CH3:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:15][CH2:14][C@H:13]([CH3:17])[O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(F)cc2)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of methyl 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]benzoate (3.53 g, 14.7 mmol), p-fluoro-phenyl-boronic acid (16.2 mmol), copper(II) acetate (2.94 g, 16.2 mmol), triethylamine (10.3 ml, 73.5 mmol) and freshly activated 4 A molecular sieves (17.7 g) in dichloromethane was stirred at ambient temperature and under ambient atmosphere for 2 days. The reaction mixture was filtered, and the dichloromethane was removed in vacuo. The residual oil was partitioned between ethyl acetate and 2 mol/l hydrochloric acid. The ethyl acetate layer was separated, washed with aqueous sodium hydrogen carbonate and brine, dried over Na2SO4 and evaporated to give a residue, which was purified by column chromatograph on silica gel (20-60% ethyl acetate in iso-hexane, gradient) to give the desired ester.
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[CH:17]=O.Cl.[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27]C=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[CH:17]=[C:27]1[CH2:28][CH2:29][CH2:30][C:25]1=[O:9]
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: c1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cl
Product: COc1cc(C=C2CCCC2=O)cc(OC)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 3,5-dimethoxybenzaldehyde and 200 mL benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C. and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 79.9%.