Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)(O)=[O:2].[NH3:25]>C1(C)C=CC=CC=1.O=S(Cl)Cl.C1COCC1>[C:1]([C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1)(=[O:2])[NH2:25]
Reactant: N
Reactant: C[C@]12CCC(=O)CC1[C@@H](C(=O)O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@]12CCC(=O)CC1[C@@H](C(N)=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 85 °C
Reaction time: 5.5 h

Procedure:
To a stirred suspension of 6α-carboxyandrostane-3,17-dione (1.20 g) in dry toluene (12 mL), SOCl2 (1.2 mL) was added. After stirring 5.5 h at 85° C. the solution was cooled at 0° C. and 2M NH3 solution in THF (6 mL) was added. After stirring overnight at room temperature, the mixture was evaporated to dryness. The residue was treated with CH2Cl2 and H2O and extracted with CH2Cl2. The combined organic extracts were washed with 10% K2CO3 solution, brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 50/50) to give the title compound II-af (720 mg, 60%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.27 (1H, bs), 6.78 (1H, bs), 2.50-0.72 (21H, m), 1.00 (3H, s), 0.80 (3H, s).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.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>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:26][C:25]([F:28])([F:27])[C:22]1[CH:23]=[CH:24][C:19]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(C(F)(F)F)cc3)CC2)C1
Temperature: 120 °C
Yield: 37 %

Procedure:
Sodium t-butylate (6.24 mmol, 3.0 eq.) was added to a stirred mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.08 mmol, 1.0 eq.) and 1-bromo-4-(trifluoromethyl)benzene (2.08 mmol, 1.0 eq.) in toluene (15 ml) and the reaction mixture was degassed with N2. BINAP (0.12 mmol, 0.06 eq.) and Pd(OAc)2 (0.04 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated at 120° C. for 12 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 10% ethyl acetate in hexane), so that the desired product was achieved. Yield: 37%
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][NH:5][CH2:6]2.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:24][C:23]([C:25]([Cl:27])=[O:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]>COCCOC>[ClH:27].[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][N:5]([C:25]([C:23]1[O:24][C:20]([C:17]3[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=3)=[CH:21][CH:22]=1)=[O:26])[CH2:6]2
Reactant: O=C(Cl)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: CN1C2CCCC1CNC2
Solvent: COCCOC
Product: CN1C2CCCC1CN(C(=O)c1ccc(-c3ccc([N+](=O)[O-])cc3)o1)C2
Product: Cl

Procedure:
9-Methyl-3,9-diaza-bicyclo[3.3.1]nonane (2.0 g, 14.3 mmol), 5-(4-nitro-phenyl)-furan-2-carboxylic acid chloride (3.59 g, 14.3 mmol) and 1,2-dimethoxyethane (40 ml) was stirred at room temperature for 15 hours. The product was filtered and was purified by washing with 1,2-dimethoxyethane (100 ml). Yield 5.24 g (94%). Mp. 263° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][CH2:25][NH2:26])[O:21][N:20]=1)(=[O:12])=[O:11].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][CH2:25][NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:21][N:20]=1)(=[O:11])=[O:12]
Reactant: O=Cc1ccccc1
Reactant: NCCc1nc(C2CCCCN2S(=O)(=O)c2nc3ccccc3[nH]2)no1
Product: O=S(=O)(c1nc2ccccc2[nH]1)N1CCCCC1c1noc(CCNCc2ccccc2)n1

Procedure:
The title compound was prepared by a similar method to Example 13 from 2-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-yl)ethylamine [see Example 27] and benzaldehyde. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 99:1 changing to 98:2, by volume, dichloromethane:methanol to afford N-(2-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-yl)ethyl)-benzylamine.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][S:5][CH2:6][CH2:7][C:8]([OH:10])=O.[Cl:13][C:14]1(NCC)[CH:18]=[CH:17][N:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:15]1.[CH:28]([N:31](C(C)C)CC)(C)[CH3:29]>C(OCC)(=O)C>[Cl:13][C:14]1[C:18]([N:31]([CH2:28][CH3:29])[C:8](=[O:10])[CH2:7][CH2:6][S:5][CH2:4][CH2:3][C:2]([F:1])([F:12])[F:11])=[CH:17][N:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:15]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CCSCCC(F)(F)F
Reactant: CCNC1(Cl)C=CN(c2cccnc2)N1
Solvent: CCOC(C)=O
Product: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A solution of 3-((3,3,3-trifluoropropyl)thio)propanoic acid (2.18 g, 10.8 mmol) and 3-chloro-N-ethyl-1-(pyridine-3-yl)-1H-pyrazol-amine (2.00 g, 8.98 mmol) in ethyl acetate (16 mL) was cooled to 5° C. Diisopropylethylamine (5.15 mL, 29.6 mmol) was added dropwise at 0-5° C. over 30 minutes, followed by the addition of 2,4,6-tripropyl-trioxatriphosphinane-2,4,-trioxide (4.00 g, 12.6 mmol) over 30 minutes at 0-5° C. The reaction was allowed to warm to 25-30° C. and stirred for 2 h. Upon reaction completion, the reaction mixture was cooled to 0-5° C. and quenched with water (12 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were concentrated to afford the desired product as an oil (3.40 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7].[C:15](=S)=[S:16]>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH:6]1[N:8]=[N:9][C:15](=[S:16])[O:7]1
Reactant: NNC(=O)COc1ccc(Cl)cc1Cl
Reactant: S=C=S
Solvent: CN(C)C=O
Product: S=C1N=NC(COc2ccc(Cl)cc2Cl)O1

Procedure:
Following the procedure of Example IIA, 2,4-dichlorophenoxyacetic acid hydrazide (23.5 g) and carbon disulfide (38 g) in DMF (50 ml) were reacted and worked up to yield 2-(2,4-dichlorophenoxymethyl)-1,3,4-oxadiazol-5-thione (IIIA).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([CH:11]=[O:12])=[C:8]([CH3:13])[CH:7]=[C:6]([CH3:14])[C:5]=2[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.[CH3:25][Si:26]([CH3:46])([CH3:45])[CH2:27][CH2:28][O:29][CH2:30][N:31]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[N:32]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.C(Cl)Cl.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>[CH3:13][C:8]1[CH:7]=[C:6]([CH3:14])[C:5]2[N:4]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=3)(=[O:17])=[O:16])[CH:3]=[C:2]([C:35]3[N:31]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:46])([CH3:45])[CH3:25])[N:32]=[CH:33][CH:34]=3)[C:10]=2[C:9]=1[CH:11]=[O:12]
Reactant: CC1(C)OB(c2ccnn2COCC[Si](C)(C)C)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(C=O)c(C)cc(C)c32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccnn3COCC[Si](C)(C)C)c3c(C=O)c(C)cc(C)c32)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-bromo-5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (100 mg, 0.246 mmol), 1-(2-trimethylsilylethoxy)methyl-1H-pyrazole-5-boronic acid pinacol ester (CAS #: 903550-12-9) (239 mg, 0.738 mmol), and K3PO4 (157 mg, 0.738 mmol) in DME (1 mL)/H2O (0.5 mL) was added Pd(PPh3)4 (56.9 mg, 0.049 mmol), and then the mixture was stirred at 80° C. for 16 h. The reaction mixture was cooled down to room temperature. The mixture was diluted with CH2Cl2. The bi-phase layer was partitioned. The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography [heptane/(30% EtOAc in CH2Cl2)=1/0 to 4/6] to give the title compound. MS (ESI+) m/z 524.2 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Cl)=[N:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([NH:18][C:19]([C:21]2[CH:22]=[C:23]([F:31])[C:24]([CH3:30])=[C:25](B(O)O)[CH:26]=2)=[O:20])[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>CC(O)C.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>[CH:15]1([NH:18][C:19]([C:21]2[CH:22]=[C:23]([F:31])[C:24]([CH3:30])=[C:25]([C:10]3[N:9]=[CH:8][C:7]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14])=[CH:12][CH:11]=3)[CH:26]=2)=[O:20])[CH2:17][CH2:16]1
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(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: [Na+]
Solvent: CC(C)O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)cn1
Temperature: 90 °C

Procedure:
N-tertbutyl-6-Chloronicotinamide (100 mg), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 6, 100 mg), tetrakis(triphenylphosphine)palladium (10 mg) and aqueous sodium hydrogen carbonate (4 ml) were mixed in propan-2-ol (8 ml) and heated at 90° C. under nitrogen for 18 hrs. The solvents were evaporated from the cooled reaction under vacuum and the residue dissolved as far as possible in ethylacetate. The solution was applied to an SPE (SCX, 10 g) and washed with ethyl acetate. The product was eluted from the column with methanol/0.880 ammonia, and the solvents evaporated in vacuo. The residue was redissolved in ethyl acetate and filtered through an SPE (silica, 0.5 g). The filtrate was reduced to dryness under vacuum and triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-(1,1-dimethylethyl)-3-pyridinecarboxamide.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21]COC)=[CH:17][CH:16]=3)[CH:9]3[CH2:25][CH:26]([O:28][C:29](=[O:31])[CH3:30])[CH2:27][CH:8]3[C:7]=2[CH:6]=1.Cl.CCOC(C)=O.CCOC(C)=O.CCCCCC>C1COCC1>[OH:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][C@H:10]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)[C@@H:9]3[CH2:25][C@H:26]([O:28][C:29](=[O:31])[CH3:30])[CH2:27][C@@H:8]3[C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(OC(C)=O)CC32)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)O[C@H]1C[C@@H]2[C@H](C1)c1cc(O)ccc1O[C@@H]2c1ccc(O)cc1
Yield: 33.3 %

Procedure:
Dissolve acetate 42 (180 mg, 0.42 mmol) in THF (8 mL) and add 3M HCl (2 mL). Stir the reaction at room temperature overnight. Dilute the reaction with EtOAc and wash with saturated aqueous sodium bicarbonate and brine. Extract the aqueous solutions with EtOAc (1×). Combine, dry (Na2SO4), filter and concentrate the organic solutions in vacuo. Purify the product by flash chromatography (10 g SiO2, dry loading on 700 mg silica, 40 ml/min, 0-50% EtOAc/Hexane over 20 minutes and then 50% EtOAc/hexane for 13 minutes) to afford acetate 43 (47 mg, 0.14 mmol, 33%) as a white solid. The enantiomers were separated.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I:23]C1C=CC(N)=CC=1>C(O)C>[ClH:1].[I:23][C:6]1[CH:7]=[CH:8][C:3]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:4][CH:5]=1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: Nc1ccc(I)cc1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2ccc(I)cc2)c2c(ccc3nc[nH]c32)n1

Procedure:
A 500 ml., 3-neck, r.b. flask fitted with stirrer, condenser and thermometer was charged with the compound of Example I, C. (24.8 g., 0.114 mole), 4-iodoaniline (25 g., 0.114 mole) and ethanol (300 ml.). The mixture was stirred and heated overnight. The mixture was concentrated to dryness by rotary evaporator and the residue was collected and dried at 100°C to yield 49 g. (97.7%) brown crystals, m.p. 296°-305°C. Recrystallization from ethanol gave m.p. 313°-315°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:11])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:12]1[CH2:16]OC[CH2:13]1.[CH:17](=O)[CH2:18][CH3:19].[BH3-]C#N.[Na+]>CC#N.CC(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:11]([CH2:13][CH2:12][CH3:16])[CH2:17][CH2:18][CH3:19])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCC=O
Reactant: NC1(c2ccc(Br)cc2)CC1
Reactant: C1CCOC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCN(CCC)C1(c2ccc(Br)cc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-(4-bromophenyl)-cyclopropylamine (Intermediate 116) in CH3CN/HOAc (5 mL, 9:1, v/v) and THF 3 mL at 0° C. was added propionaldehyde (277.0 mg, 4.95 mmols) and NaCNBH3 (153.0 mg, 2.47 mmols). The reaction was warmed to room temperature and after 5 hours quenched with H2O. The pH of the solution was adjusted to 8-9 using aqueous NaOH and extracted with EtOAc. The combined extracts were washed with H2O and saturated aqueous NaCl, dried (MgSO4) and concentrated under reduced pressure. The title compound, 190.0 mg (56%), was isolated by column chromatography (2-5% EtOAc—hexanes).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].O[CH:12]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14]>CS(C)=O.C(Cl)Cl.O>[F:1][C:2]([F:10])([F:9])[C:3]1([C:5]([F:8])([F:7])[F:6])[O:15][C:13](=[O:14])[CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[O:4]1
Reactant: O=C(O)C(O)CC1CCCCC1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C1OC(C(F)(F)F)(C(F)(F)F)OC1CC1CCCCC1
Reaction time: 2 h

Procedure:
2-Hydroxy-3-cyclohexylpropionic acid prepared as described in Step 2 (2.24 g, 13.0 mmol) was treated as described in J.Org. Chem., 1995, 60, 7641-7645 to provide [2,2-Bis(trifluoromethyl)-4-oxo-1,3-dioxolan-5-yl]methyl cyclohexane. Thus, a solution of hexafluoroacetone (27.3 mmol) in DMSO (5 mL) was added to 2-hydroxy-3-cyclohexylpropionic acid and the mixture stirred for 2 hours under a dry ice condenser. The mixture was then diluted with 100 mL of 1:1 methylene chloride/water and the aqueous layer extracted twice with methylene chloride. The combined organic layers were dried and concentrated to provide the title compound. 1H-NMR (CDCl3): 4.7 ppm (m, 1H); 1.6-1.9 ppm (m, 5H); 1.3 ppm (m, 3H); 0.95 ppm (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:29])=[O:4].[OH-].[Li+].C1COCC1.Cl>O.CO>[OH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([O:20][C:15]2[C:14]([NH:13][C:12]3[C:7]4[C:6]([CH3:29])=[C:5]([C:3]([OH:4])=[O:2])[S:28][C:8]=4[N:9]=[CH:10][N:11]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:22][CH2:23]1
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 1.541 g 4-[2-(trans-4-hydroxy-cyclohexyloxy)-pyridine-3-ylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methylester, 2.00 g lithium hydroxide, 13.3 ml THF, 13.3 ml MeOH and 13.3 ml water was stirred at rt overnight. Then the mixture was acidified by addition of hydrochloric acid and extracted with DCM. The organic phase was dried, filtered and the filtrate was concentrated.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4].[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O>C1COCC1>[C:10]([C:9]1[CH:12]=[C:5]([C:3](=[O:4])[CH2:2][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@H:23]2[CH2:27][OH:28])[CH:6]=[CH:7][C:8]=1[F:13])#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: N#Cc1cc(C(=O)CBr)ccc1F
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)c(C#N)c2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-(Bromoacetyl)-2-fluorobenzonitrile (590 mg, 2.44 mmol) and (S)-4-N—BOC-2-hydroxymethyl-piperazine (527 mg, 2.44 mmol) were dissolved in THF (40 mL) at 0° C. then TEA (247 mg, 2.44 mmol) was added. The reaction mixture was stirred at RT for 16 h, then poured into water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The crude product was purified by MPLC through an 80 g Redi-sep column using 0-100% EtOAc/hexane to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[F:24])=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.CC(C)([O-:28])C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][NH-:39])[CH:33]=1>CN1CCCC1=O>[F:24][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:17]=1[NH:16][C:14]([C:11]1([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1)=[O:15])[O:23][C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]([NH2:39])=[O:28])[CH:33]=1
Reactant: CC(C)(C)[O-]
Reactant: [NH-]Cc1cc(Cl)ccn1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(O)cc2F)CC1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.8 %

Procedure:
N-(4-Fluorophenyl)-N′-(2-fluoro-4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (665 mg) was dissolved in N-methylpyrrolidone (10 ml) under a nitrogen atmosphere, and potassium tert-butoxide (247 mg) was added at room temperature, followed by stirring for 1.5 hr. After 4-chloropicolylamide (313 mg) was added, the reaction mixture was stirred under a nitrogen atmosphere at 110° C. overnight, then at 120° C. for 8 hr. The reaction mixture was allowed to cool down to room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:2, 1:3, then 1:4). Fractions containing the target compound were concentrated under reduced pressure. After ethyl acetate (3 ml)-heptane (6 ml) was added, crystals were allowed to precipitate under sonication. The solvent was removed and the crystals were dried under reduced pressure to provide the titled compound as pale brown crystals (261 mg, 29%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8](=[O:10])[CH3:9])=[C:5]([CH3:7])[N:6]=1.C1N=C[N:13]([C:16](N2C=NC=C2)=[O:17])C=1.N>CN(C=O)C.O1CCOCC1>[C:8]([C:4]1[S:3][C:2]([NH:1][C:16]([NH2:13])=[O:17])=[N:6][C:5]=1[CH3:7])(=[O:10])[CH3:9]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(=O)c1sc(NC(N)=O)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.2 %

Procedure:
2-Amino-4-methyl-5-acetylthiazole (3 g, 19.2 mmol) is dissolved in DMF (30 mL). CDI (3.5 g, 21.1 mmol) is added and the mixture is stirred at RT for 3 h. Ammonia 0.5 N in dioxane is added (60 mL, 30 mmol) is added and the mixture is stirred for 2 days in a closed system. The resulting precipitate is recovered by filtration, washed with petroleum ether and dried under vacuo, affording N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)urea as colorless solid (1.5 g, 39%).
Reaction SMILES: [CH:1]1[C:6]2[N:7]=[C:8]3[N:13]([CH2:14][C:5]=2[C:4](Cl)=[C:3](Cl)[CH:2]=1)CC(=O)[NH:9]3.O.Cl.C(N(CC1C(N)=CC=C(Cl)C=1Cl)CC(O)=O)C.N#CBr>C1(C)C=CC=CC=1>[NH:9]=[C:8]1[N:13]=[CH:14][C:5]2[C:6](=[CH:1][CH:2]=[CH:3][CH:4]=2)[NH:7]1
Reactant: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Agent: CCN(CC(=O)O)Cc1c(N)ccc(Cl)c1Cl
Agent: Cl
Agent: N#CBr
Solvent: Cc1ccccc1
Solvent: O
Product: N=c1ncc2ccccc2[nH]1

Procedure:
Commercially, as discussed in U.S. Pat. No. 5,801,245, and as shown in FIG. 1, anagrelide has been prepared as the hydrochloride monohydrate (compound IV) from the intermediate, ethyl-N-(6-amino-2,3-dichlorobenzyl)glycine (compound I) either by reaction with cyanogen bromide in hot alcoholic solution, or, preferentially, by reaction with cyanogen bromide in an aprotic solvent such as toluene to give the iminoquinazoline intermediate (compound II), which is isolated and then reacted with a base in a hot solution of alcohol to form anagrelide base (compound III).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][CH2:26][N:27]([CH:31]([CH3:33])C)[CH:28]([CH3:30])C.BrC/C=[CH:37]/[C:38](Cl)=[O:39].[Na+].[Cl-].C(NCC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([NH:20][C:38](=[O:39])[CH:37]=[CH:33][CH2:31][N:27]([CH2:26][CH3:25])[CH2:28][CH3:30])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)/C=C/CBr
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Br)c3)c2cc1N
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCNCC
Product: CCN(CC)CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Br)c3)c(C#N)cnc2cc1OC
Yield: 38.4 %

Procedure:
To a mixture of 0.77 g (1.98 mmol) of 4-[(3-bromo-4-fluorophenyl)amino]-7-methoxy-6-amino-quinoline-3-carbonitrile and 3.5 ml (20 mmol) of Hunig's base in 35 ml of dry THF at 0° C., with stirring, was added a THF solution containing 2.2 g (12 mmol) of 4-bromo crotonyl chloride dropwise. The mixture was stirred for additional 30 minutes at 0° C. 50 ml of saturated NaCl solution was added to the reaction mixture, then it was extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and then was added to a solution of 3.1 ml (30 mmol) of diethyl amine in 5 ml of THF at 0° C. dropwise. The solution was stirred an additional hour at 0° C. and 30 minutes at room temperature. The mixture was poured into diluted sodium bicarbonate solution. The organic layer was dried over sodium sulfate and solvent was removed under vacuum. The residue was chromatographed to give 0.4 g off-white solid: mass spectrum (electrospray, m/e): M+H 525.9 and 527.9.