Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH:3]=[O:4].[C:8]([Si](C)(C)C)([F:11])([F:10])[F:9]>>[F:9][C:8]([F:11])([F:10])[C@@H:3]([CH:2]1[CH2:5][CH2:6][CH2:7][NH:1]1)[OH:4]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C[C@H]1CCCN1
Product: O[C@H](C1CCCN1)C(F)(F)F

Procedure:
Compounds of Structures 2 and 4 are prepared from D-proline or D-pyroglutamic acid. For example, (R)-2,2,2-trifluoro-1-(pyrrolidin-2-yl)ethanol (Compound 2, Scheme I, R3=hydrogen) is prepared by oxidation of D-prolinol (Compound 4, Scheme I, R3=hydrogen) to afford D-prolinaldehyde (see e.g., Smith et al., March's Advanced Organic Chemistry, 6th ed., Wiley, N.J., 2007, p. 1715-1728). The resulting D-prolinaldehyde is reacted with CF3-TMS (trimethyl(trifluoromethyl)-silane) to afford the (R)-2,2,2-trifluoro-1-(pyrrolidin-2-yl)ethanol (see e.g., Prakash et al., J. Am. Chem. Soc. 111: 393, 1989).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[S:3])[NH:1]2)[CH:14]=[C:15]([C:18]#[N:19])[C:16]=1[OH:17]
Reactant: O=C1CNC(=S)N1
Reactant: N#Cc1cc(C=O)cc(O)c1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: N#Cc1cc(C=C2NC(=S)NC2=O)cc(O)c1O
Temperature: 100 °C

Procedure:
A solution containing 0.58 g of thiohydantoin, 0.82 g of 3,4-dihydroxy-5-cyanobenzaldehyde and 0.1 ml of piperidine in 10 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with ether. Yield 0.51 g, mp 210°-213° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH2:19])=O)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[H-]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][NH2:19])=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(CCC(N)=O)ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCCN)ccc1OCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 3-(4-benzyloxy-3-methoxy-phenyl)-propionamide (7.85 g, 27.53 mmol) in anhydrous THF (210 ml) was slowly added to a stirred, ice-cooled suspension of LiAlH4 (2.09 g, 55.07 mmol) in anhydrous THF (90 ml). Upon completion of the addition, the mixture was stirred at reflux for 1 h. After cooling to 0° C., H2O (15 ml) was added dropwise to decompose the excess of hydride, and the resulting suspension was then filtered. The residue after evaporation was partitioned between H2O (50 ml) and CH2Cl2 (100 ml). The organic layer was washed with NaHCO3 and brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give the crude. amine (6.03 g, 22.22 mmol, 81%) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18](O)=[O:19])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1>>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:18](=[O:19])[CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:8][CH:9]=2)=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]1
Reactant: CN1CCN(c2cc(N)ccc2Br)CC1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12
Product: CN1CCN(c2cc(NC(=O)Cc3ccc(-c4ccncc4)c4ccccc34)ccc2Br)CC1

Procedure:
The title compound was prepared from 4-(pyridin-4-yl)naphth-1-ylacetic acid (D2) and 4-bromo-3-(4-methylpiperazin-1-yl)aniline (Intermediate 44, EP 0533268A1) using a similar procedure to Example 20 (73%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[N:1]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCOC(=O)CBr
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cncn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
To a solution of 1H-1,2,4-triazol (2 g, 29.9 mmol, 1.0 eq) in DMF were added K2CO3 (12.3 g, 88.9 mmol, 3 eq.) and ethyl 2-bromoacetate (4.8 g, 29.9 mmol, 1 eq). The mixture was stirred at RT for 16 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to give the product in 65% yield (3 g). LC-MS (ESI): Calculated mass: 155.0; Observed mass: 156.1 [M+H]+ (rt: 0.113 min).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:13]([OH:15])=[O:14])=[CH:8][C:9]=2[CH2:11][CH3:12])[C:4](I)=[N:3]1.[C:17]([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:13]([OH:15])=[O:14])=[CH:8][C:9]=2[CH2:11][CH3:12])[C:4]([CH3:17])=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(C(=O)O)cc2c(I)nn(C)c12
Agent: [Na+]
Solvent: COCCOC
Product: CCc1cc(C(=O)O)cc2c(C)nn(C)c12
Temperature: 125 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
To a degassed solution of methyl 7-ethyl-3-iodo-1H-indazole-5-carboxylic acid (100 mg, 0.30 mmol) in DME (2.5 mL) was added degassed boroxine solution (50%, 0.28 mL) followed by palladium tetrakistriphenylphosphine (3.5 mg, 0.003 mmol) and 2 M Na2CO3 (0.57 mL). The mixture was heated in a microwave reactor (very high absorption setting) at 125° C. for 10 minutes and then at 165° C. for 10 minutes. The reaction was extracted with EtOAc and washed with saturated aqueous NaCl. The organic extract was reduced and the crude material was purified by silica gel chromatography (40 g column) using 0-40% EtOAc/heptane to afford methyl 7-ethyl-3-methyl-1H-indazole-5-carboxylic acid (18 mg, 27%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32](O)[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38].C(O)C(C)(C)C.[CH:46]12[CH2:51][CH:50]1[C:49](=[O:52])[NH:48][C:47]2=[O:53]>O1CCCC1>[CH2:32]([N:48]1[C:49](=[O:52])[CH:50]2[CH:46]([CH2:51]2)[C:47]1=[O:53])[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38]
Reactant: O=C1NC(=O)C2CC12
Reactant: C=CCCCCCO
Agent: CC(C)(C)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCCCCN1C(=O)C2CC2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.5 g) was added dropwise over 1 minute to a stirred solution of triphenylphosphine (0.75 g) in tetrahydrofuran (20 ml) at -78° C. under a nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and then 6-hepten-1-ol (0.36 g) was added dropwise over 1 minute, followed by stirring at -78° C. for a further 5 minutes. Neopentanol (0.12 g) was added to the reaction mixture, followed by 3-azabicyclo[3.1.0]hexane-2,4dione (0.32 g) and stirring was continued for a further 5 minutes at -78° C. The reaction mixture was warmed to room temperature and stirred overnight. The volatiles were removed by evaporation in vacuo and the residue was triturated with hexane/dichloromethane and then filtered. The filtrate was evaporated in vacuo and then purified by chromatography on silica gel using 20% ethyl acetate/hexane as eluant. The title compound was obtained as a colourless oil (boiling point 150-160° C. @ 1 mmHg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>C1C=CC=CC=1.O1CCCC1.CN(C)C1C=CN=CC=1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([N:13]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:19]3[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:12]2)=[O:29])=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COc1ccc(-c2cn(C(=O)Nc3ccc(Cl)cc3)c3ncccc23)cc1OC
Temperature: 200 °C
Yield: 39.8 %

Procedure:
3-(3,4-Dimethoxy-phenyl)-1H-pyrrolo-[2,3-b]pyridine 1 (40 mg, 0.16 mmol) was dissolved in benzene and 4-chlorophenyl isocyanate (36 mg, 0.24 mol) dissolved in tetrahydrofuran (4 mL) was added. 4-Dimethylaminopyridine (20 mg, polymer bound) was added. The reaction was heated in a CEM Discover microwave at 200° C. for 10 minutes. The mixture was filtered and concentrated. The resulting solid was washed with a minimum of methanol, filtered, and then washed with dichloromethane to provide 26, (26 mg, 40%). MS(ESI) [M+H+]+=408.4.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:24])[C:20]([CH3:23])([CH3:22])[CH3:21].O>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:24][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: CC(C)(C)CN
Solvent: CC#N
Solvent: O
Product: C=CCNc1nc(NCC(C)(C)C)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
In 0.5 ml of acetonitrile were dissolved 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 740 mg (8.49 mmol) of neopentylamine, and the resulting solution was stirred at room temperature for 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 215 mg (yield: 72.2%) of the title compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([N:9]1[CH:13]=[C:12]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:11]=[N:10]1)[CH2:6][C:7]#[N:8].[OH:23]O.C(#N)C>>[CH3:1][S:2]([CH2:3][CH2:4][CH:5]([N:9]1[CH:13]=[C:12]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:11]=[N:10]1)[CH2:6][C:7]#[N:8])=[O:23]
Reactant: OO
Reactant: CSCCC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Solvent: CC#N
Product: CS(=O)CCC(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Yield: 30.5 %

Procedure:
A solution of 5-(methylthio)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentane-nitrile (0.065 g, 0.00021 mol) and hydrogen peroxide (0.022 mL, 0.00023 mol) in ACN (1 mL, 0.02 mol) was stirred overnight. The reaction was concentrated and purified by HPLC to give 21 mg of a solid. The solid was triturated with MTBE (1 mL)/DCM (10 drops). The solid was filtered and washed to give 13 mg of a white solid (20% yield) which was dried rt to 50° C. for 2 h.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][NH:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][N:24]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Brc1cccc2c1CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(Br)cccc21
Yield: 72.3 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 402 mg of 4-bromoindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 303 mg of 2-[2-(4-bromo-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 71 (379 mg, 1 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 361 mg (76%) of white solids. M.P. 221° C. 1H NMR. (DMSO-d6): δ 3.70 (m, 4H), 3.97 (m, 4H), 5.48 (s, 2H), 6.67 (dd, J=2.0, 3.6 Hz, 1H), 7.10 (d, J=3.6 Hz, 1H), 7.20 (m, 2H), 7.25 (m, 1H), 7.27 (m, 2H), 7.42 (d, J=9.2 Hz, 1H), 7.70 (dd, J=2.4, 9.2 Hz), 7.90 (s, 1H). EIMS m/z 496 (M+23). Anal. (C26H21ClN4O3) C, H, N.
Reaction SMILES: C([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([F:19])=[CH:11][C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]1=2)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:19][C:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:8][C:9]2[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=2[CH:11]=1
Reactant: [H][H]
Reactant: FC1=Cc2ccccc2N(Cc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: FC1=Cc2ccccc2Nc2ccccc21

Procedure:
A solution of 6.03 g (0.02 mole) of 5-benzyl-10-fluoro-5H-dibenz[b,f]azepine in 100 ml of methanol is hydrogenated at 25° C in the presence of 0.6 of palladium on charcoal catalyst (5% Pd) until the uptake of hydrogen has ceased (app. 15 hours). The catalyst is filtered off and the filtrate is concentrated in vacuo. The residual colourless oil is chromatographed over 50 times the amount of silica gel (particle size: 0.063-0.2 mm) with benzene/petroleum ether (1:1) as eluant. The homogeneous fractions are combined, concentrated by rotary evaporation and the residue is crystallised from ether/hexane to yield 10-fluoro-5H-dibenz[b,f]azepine of m.p. 69°-72° C.
Reaction SMILES: BrCC(=O)C[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:18]CCCCCC(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].C1C=CC=CC=1.C([SiH](CC)CC)C>ClCCl>[Br:18][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CBr)CCCCCCCc1ccccc1
Reactant: O=C(Cl)CCCCCBr
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: ClCCl
Product: BrCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
1-Bromo-9-phenylnonan-2-one--A solution of 6-bromohexanoyl chloride (49.7 g, 0.233mol) in dry dichloromethane (40 ml) was added dropwise over 5 minutes to a suspension of aluminium chloride (31.0 g, 0.233 mol) in dry dichloromethane (100 ml), keeping the temperature between 20° C.-23° C. The mixture was stirred for 30 minutes at room temperature to give a yellow solution. Benzene (18.2 g, 0.233 mol) in dry dichloromethane (30 ml) was added and stirred for 20 hours at room temperature. Triethylsilane (59.9 g, 0.515 mol) was added over 10 minutes, maintaining the temperature between 25° C.-35° C. The solution was stirred for 60 minutes at room temperature. This was then poured onto ice/water (200g). A partial separation was achieved and the organic layer was washed with brine and water several times until the pH of the solution was neutral. The organic solution was dried (MgSO4) and evaporated under reduced pressure to a yellow oil. This was distilled under reduced pressure at 90° C.-110° C./0.5 mbar to give colourless oils. The relevant fractions were combined and purified by flash chromatography on silica gel using hexane to give 6-bromo-1-phenylhexane as a colourless oil (18.33 g, 33%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5](#[N:8])[CH:6]=[CH2:7].Cl>CO>[CH2:1]([O:4][CH2:7][CH2:6][C:5]#[N:8])[CH2:2][O:3][CH2:7][CH2:6][C:5]#[N:8]
Reactant: C=CC#N
Reactant: OCCO
Agent: Cl
Solvent: CO
Product: N#CCCOCCOCCC#N
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.9 %

Procedure:
Small scale: Ethylene glycol (1 g, 16.1 mmol) was mixed with Triton B (40% in MeOH, 0.22 g, 0.53 mmol) and cooled in an ice-bath while acrylonitrile (1.71 g, 32.2 mmol) was added. The mixture was stirred at room temperature for 60 hours after which it was neutralized with 0.1M HCl (0.6 cm3) and extracted with CH2Cl2 (80 cm3). The extracts were concentrated under reduced pressure and the residue was Kugelrohr-distilled to give 3,3′-(ethane-1,2-diylbis(oxy))dipropanenitrile (1.08 g, 39.9%) as a light coloured oil, by 150-170° C./20 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:19]3[N:26]=[CH:27][C:28]([CH:29]=O)=[C:18]3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].N1CCCCC1.[NH:37]1[CH2:43][C:41](=[O:42])[NH:40][C:38]1=[O:39]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[CH:21]=[C:20]([NH:22][CH:23]3[CH2:25][CH2:24]3)[N:19]3[N:26]=[CH:27][C:28](/[CH:29]=[C:43]4/[C:41](=[O:42])[NH:40][C:38](=[O:39])[NH:37]/4)=[C:18]3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13]
Reactant: O=C1CNC(=O)N1
Reactant: CN(C)CCCOc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)cc1Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)CCCOc1ccc(Nc2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)cc1Cl
Temperature: 85 °C
Reaction time: 6 h
Yield: 65.9 %

Procedure:
To 5-(3-chloro-4-(3-(dimethylamino)propoxy)phenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (79 mg, 0.184 mmol) in EtOH (3 mL) was added piperidine (22 uL 0.221 mmol) followed by hydantoin (21 mg, 0.202 mmol). The reaction mixture was stirred at 85° C. for 6 h. The solvent was removed by rotary evaporation and the residue was diluted with 3 mL of water. The suspension was sonicated and the resulting solid was filtered off and washed with water followed by a 1:1 mixture of EtOH/water. The material was Dried under vacuum to provide 62 mg of (Z)-5-((5-(3-chloro-4-(3-(dimethylamino)propoxy)phenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione LCMS (ES): m/z 511 [M+1]+.
Reaction SMILES: Cl.Cl.Cl.C[CH:5]([C:24](=[O:26])[OH:25])[CH2:6][C@H:7]([C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[NH2:8].[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37](O)=[O:38])=[CH:31]2.[Li+].[OH-].Cl>>[ClH:27].[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32]([C:37]([NH:8][C@@H:7]([C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[CH2:15][CH2:16]1)=[O:10])[CH2:6][CH2:5][C:24](=[O:26])[OH:25])=[O:38])=[CH:31]2
Reactant: CC(C[C@@H](N)C(=O)N1CCC(C2CCN(C)CC2)CC1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CN1CCC(C2CCN(C(=O)[C@@H](CCC(=O)O)NC(=O)c3cc4cc(Cl)ccc4[nH]3)CC2)CC1

Procedure:
Prepared from 1-[(γ-methyl)-D-glutamyl]-4-(1-methylpiperidin-4-yl)piperidine dihydrochloride hydrochloride and 5-chloroindole-2-carboxylic acid using methods substantially equivalent to General Coupling Method 1. Ester deprotection with 2 eq LiOH and final purification and HCl salt formation via prep HPLC.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH3:8])=[C:5]([C:9](O)=[O:10])[C:4]([CH3:12])=[N:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][CH3:33]>CN(C)C=O.O1CCCC1>[CH2:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[CH2:26][NH:25][C:9]([C:5]1[C:4]([CH3:12])=[N:3][N:2]([CH3:1])[C:6]=1[O:7][CH3:8])=[O:10])[CH3:33]
Reactant: CCN1CCCC1CN
Reactant: COc1c(C(=O)O)c(C)nn1C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN1CCCC1CNC(=O)c1c(C)nn(C)c1OC
Reaction time: 1 h
Yield: 90 %

Procedure:
3.1 g (0.0178 mole) of 1,3-dimethyl-5-methoxy-4-pyrazole carboxylic acid was dissolved in 15 ml of dry N,N-dimethylformamide. Then 3.18 g (0.0196 mole) of 1,1'-carbonyl-diimidazole was added. The reaction mixture was stirred for one hour. A solution of 2.28 g (0.0178 mole) of 2-(aminomethyl)-1-ethylpyrrolidine in 10 ml of dry tetrahydrofuran was added dropwise with stirring over 1/2 hour. The reaction was then stirred overnight at room temperature and the solvent evaporated under vacuum (1 mm) and a water bath (60° C.). The resultant oil was then taken up in chloroform, washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated. 4.5 g of amber colored oil (90% yield) was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=4)[CH2:24][CH2:25]3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc2c(c1)CCO2
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(c3)CCO4)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2,3-dihydro-1-benzofuran-5-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 379.1 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.[C:13]([OH:20])(=[O:19])[CH2:14][CH2:15][C:16]([CH3:18])=O.B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:18][C:16]1([CH2:15][CH2:14][C:13]([OH:20])=[O:19])[C:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[CH2:10][CH2:11][O:12]1
Reactant: CC(=O)CCC(=O)O
Reactant: OCCC1=CCc2ccccc21
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1(CCC(=O)O)OCCC2=C1Cc1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of indene-3-ethanol (15 g), dry benzene (300 ml), levulinic acid (22.6 g), boron trifluoride etherate (3 ml) and hydrated alkali-aluminum silicate (Molecular Sieves No. 4) is stirred at ambient temperature for 2 hr.
Reaction SMILES: C([N:8]1[CH2:15][C@@H:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])(OC(C)(C)C)=O.O=S(Cl)Cl.[CH3:29]O>>[CH3:29][O:12][C:10](=[O:11])[C@@H:9]1[CH2:13][C@H:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:15][NH:8]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1C[C@@H](SCc2ccc(Br)cc2)C[C@H]1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1C[C@H](SCc2ccc(Br)cc2)CN1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Na (0.25 g) (0.011 mol) in 3 mL of MeOH was added 4-bromobenzyl mercaptan (2.2 g) (0.011 mol). The reaction mixture was stirred for 1 h. Trans-N-Boc-4-methanesulfonyloxy-L-proline methyl ester (1.2 g) (0.0037 mol) (Preparation 9) was added and the mixture refluxed for 18 hrs. Upon cooling to RT, 40 mL of water was added and the mixture was extracted with EtOAc. The aqueous layer was acidified with 1 N HCl and extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4, and the solvent evaporated in vacuo to afford cis-N-Boc-4-(4-bromobenzyl thio)-L-proline (1.08 g). NMR (CDCl3, 200 MHz): 10.65 (1H, COOH), 7.4 (2H, d), 7.15 (2H, d), 4.15-4.35 (1H, m), 3.65 (2H, s), 2.95-3.35 (2H, m), 2.4-2.6 (1H, m), 1.85-2.2 (1H, m), 1.3-1.5 (9H). To a solution of cis-N-Boc-4-(4-bromobenzyl thio)-L-proline (1.08 g) in 10 mL of MeOH was added dropwise SOCl2 (0.2 mL), and the mixture was stirred for 72 hrs at RT. The solvent was evaporated under reduced pressure and the residue dissolved in DCM. The organic layer was washed with dilute aqueous NaHCO3, water, and dried over MgSO4. The solvent was evaporated in vacuo to afford cis-4-(4-bromo-benzylthio)-L-proline methyl ester (0.6 g).