Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([N+:4]1([CH2:17][CH3:18])[CH2:12][C:11]2[CH:10]=[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]3=[CH:7][C:6]=2[CH2:5]1)[CH3:3].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:2]([N:4]([CH2:5][C:6]1[C:11]([CH2:12][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:10][C:9]2[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1)[CH2:17][CH3:18])[CH3:3]
Reactant: C1COCCN1
Reactant: CC[N+]1(CC)Cc2cc3ccccc3cc2C1
Agent: [Br-]
Product: CCN(CC)Cc1cc2ccccc2cc1CN1CCOCC1

Procedure:
2,2-Diethylbenz[f]isoindolinium bromide (13 g) was refluxed with morpholine (150 ml) for 30 hr. Morpholine was evaporated and the residue was partitioned between sodium hydroxide solution and ether; the ether layer was evaporated to dryness and the residue purified by chromatography [eluent, diethylamine:cyclohexane = 1:4, silica (250 g)] and distillation to give 2-diethylaminomethyl-3-morpholinomethylnaphthalene, b.p. 160°/0.015 mm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:18]1([CH:24]2[CH2:26][O:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[OH:25][CH:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:26][N:15]1[CH2:16][CH2:17][CH:12]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([CH3:11])[N:7]=2)[CH2:13][CH2:14]1
Reactant: Cn1nc(C2CCNCC2)c2ccc(F)cc21
Reactant: c1ccc(C2CO2)cc1
Solvent: CC#N
Product: Cn1nc(C2CCN(CC(O)c3ccccc3)CC2)c2ccc(F)cc21
Yield: 32.9 %

Procedure:
A mixture of 4-(6-fluoro-1-methyl-1H-indazol-3-yl)piperidine (1 g; 4.3 mmol) and phenyloxirane (0.6 g; 5 mmol) in 10 ml acetonitrile was refluxed for 16 h. The cooled reaction mixture was concentrated in vacuo and purified by chromatography on silica gel 60 with ethyl acetate: methanol (9:1, v/v) as eluent. Concentration of the appropriate fractions gave 500 mg (33%) of 1-(2-hydroxy-2-phenyl-ethyl)-4-(6-fluoro-1-methyl-1H -indazol-3-yl)-piperidine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Rh]>[CH3:1][CH:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)O)o1
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CC1CCC(C(=O)O)O1
Yield: 97.3 %

Procedure:
A solution of 5-methyl-2-furoic acid (3.65g, 28.97mmol) in ethyl acetate (60ml) was hydrogenated over 5% rhodium on carbon (250mg) until hydrogen uptake ceased. The catalyst was filtered off and washed with ethyl acetate. The combined filtrates were concentrated in vacuo to yield the title compound as a pale yellow oil (3.67g, 97%); vmax (CH2Cl2) 3384, 3359, 1775, 1724 and 1355cm-1 ; δH (CDCl3, 250MHz) 1.35 (3H, d, J 6.1Hz), 1.53 (1H, m), 2.09 (1H, m), 2.17-2.40 (2H, m), 4.21 (1H, m) and 4.46 (1H, dd, J 8.9, 4.7Hz). [Mass spectrum: +ve ion (ammonia) MNH4+ (148)].
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].B(O)O>>[C:26]([O:25][C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:34][CH:33]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Agent: OBO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and [4-(N-Boc-aminomethyl)phenyl]boronic acid as a boronic acid, 4-(4-tert-butoxycarbonylaminomethyl-phenyl)-2-(morpholin-4-yl)-7-(pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained. This was dissolved in 1N hydrochloric acid-acetic acid, followed by stirring at room temperature for 40 minutes, and diethyl ether was added to the reaction mixture, to filter off a solid, whereby the desired compound was obtained.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[F:20])[CH2:5][CH2:4]1.[Cl:24][C:25]1[C:38]([N:39]=[C:40]=S)=[C:37]([Cl:42])[CH:36]=[CH:35][C:26]=1[CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].CC(C)N=C=NC(C)C>>[F:23][C:2]([F:1])([F:22])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10]([C:11]2[C:12]([F:20])=[CH:13][C:14]3[N:18]([CH3:19])[C:40]([NH:39][C:38]4[C:37]([Cl:42])=[CH:36][CH:35]=[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]=4[Cl:24])=[N:17][C:15]=3[CH:16]=2)=[O:21])[CH2:7][CH2:8]1
Reactant: CNc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(F)cc21

Procedure:
The title compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-fluoro-4-methylamino-5-amino-benzoic acid amide and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide with DIC in analogy to example 1g.
Reaction SMILES: [CH2:1]([CH:3]([C:26]([OH:28])=[O:27])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2].CO.[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([CH:3]([C:26]([OH:28])=[O:27])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2]
Reactant: CCC(C(=O)O)N(CCCCc1ccc([N+](=O)[O-])cc1)c1cccc(C#N)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C(=O)O)N(CCCCc1ccc(N)cc1)c1cccc(C#N)c1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Part D. A solution of ethyl N-[4-[4-nitrophenyl]butyl]-N-[3-cyanophenyl]glycine (0.31 gm, 0.81 mmol) and 20 mL methanol:ethyl acetate (v:v, 50:50) was degassed with nitrogen in a Parr shaker bottle, then 10% palladium on carbon was added. The reaction was charged to 50 PSI hydrogen and shaken for 1/2 hr. The catalyst was filtered off over celite, the filtrate concentrated and the product purifed by flash chropmatography on silica gel eluting ethyl acetate:methylene chloride (v:v, 10:90) to give ethyl N-[4-[4-aminophenyl]butyl]-N-[3-cyanophenyl]glycine as a semisolid 0.27 gm (94%). MS 352(M+H)+ 1 H NMR (CDCl3): 7.2(m, 1H), 7.0(m, 3H), 6.8(m, 2H), 6.6(d, 2H), 4.2(q, 2H), 4.0(s, 2H), 3.6(bs, 2H), 3.4(m, 2H), 2.6(m, 2H), 1.6(m, 4H), 1.2(t, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2>C1COCC1.O>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccn2)=CCC3(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccccn2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of 80.0 mg (0.196 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 10) and 20.6 mg (0.491 mmol) of LiOH--H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 8.64 (1H, m), 7.94 (2H, d, J=8.3 Hz), 7.87 (1H, dt, J=1.7, 7.8 Hz), 7.58 (2H, d, J=8.3 Hz), 7.50 (1H, d, J=8.2 Hz), 7.47 (2H, s), 7.37 (1H, m), 7.25 (1H, s), 6.30 (1H, t, J=4.6 Hz), 2.39 (2H, d, J=4.6 Hz), 1.31 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]1[OH:15])=[O:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][CH2:12][C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]1[O:15][S:24]([CH3:23])(=[O:26])=[O:25])=[O:4]
Reactant: COC(=O)C1CCCC2(CCCC2)C1O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CCCC2(CCCC2)C1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-hydroxy-spiro[4.5]decane-7-carboxylic acid methyl ester (10.1 g) obtained in Step 3 and triethylamine (19.9 mL) in chloroform (100 mL) was added dropwise methanesulfonyl chloride (5.2 mL) under ice-cooling, followed by stirring the reaction mixture at room temperature for 2 hours. Then, after addition of triethylamine (10 mL), the reaction mixture was stirred at room temperature for 30 minutes. After ice-cooling, ice-cold water (30 mL) and saturated aqueous sodium bicarbonate solution (50 mL) were added to the reaction mixture, followed by separation of the organic layer. The organic layer was washed with saturated brine, dried and concentrated to give a crude 6-methanesulfonyloxy-spiro[4.5]decane-7-carboxylic acid methyl ester (22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]2[C:18](=[O:23])[C:19]([F:22])([F:21])[CH2:20][C:15]2=[N:14]1.[CH3:24][Mg]Br.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]2[C:18]([CH3:24])([OH:23])[C:19]([F:22])([F:21])[CH2:20][C:15]2=[N:14]1
Reactant: C[Mg]Br
Reactant: O=C1c2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2CC1(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(O)c2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of (91) (3.6 mg, 9.7 mmol) in 300 mL THF was added methyl magnesium bromide (50 mL, 3.0 M) at 0° C. The solution was then stirred at room temperature for 30 min. The mixture was poured into 5 mL of saturated NaHCO3 solution and extracted with dichlormethane (5 mL×3). The organic layers were combined, washed with brine, and dried with anhydrous sodium sulfate. The mixture was then chromatographed on a silica gel TLC plate using hexane/ethyl acetate (3:1) to give (93): yield 98%; 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 2H), 7.47 (s, 1H), 3.65-3.31 (m, 2H), 2.46 (br s, 1H), 1.67 (s, 3H).
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=O.P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C(Cl)(Cl)Cl>[Cl:14][C:5]1[CH:6]2[CH:2]([CH:1]3[O:10][CH:7]2[CH2:8][CH2:9]3)[C:3](=[O:12])[CH:4]=1
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1C=C(Cl)C2C3CCC(O3)C12
Yield: 139.7 %

Procedure:
To a solution of 10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (1.66 g, 10 mmol) in chloroform (20 ml) is added PCl5 (1.04 g, 5 mmol) in one portion. The reaction mixture is stirred and heated at reflux for 5 hours. The reaction mixture is evaporated to dryness. The crude product is purified by flash chromatography to give 5-chloro-10-oxa-tricyclo[5.2.1.0*2,6*]dec-4-en-3-one (1.29 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:26]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH:25]=1)=[O:23])[CH2:9][CH2:10][NH:11][C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO.[Cl-].[Na+]>CC(O)C>[C:38]([O:37][C:26]1[CH:25]=[C:24]([CH:22]([OH:23])[CH2:21][N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:29]=[CH:28][C:27]=1[O:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])(=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42]
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: CC(C)(C)C(=O)Oc1ccc(C(O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Temperature: -10 °C
Yield: 82.2 %

Procedure:
A suspension of 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-bis(pivaloyloxy)acetophenone (2.0 g.) in 2-propanol (20 ml.) was cooled to -10° C. and sodium borohydride (0.34 g.) added in two portions interspersed by a portion of methanol (4 ml.). After 30 minutes at -10° C. a saturated aqueous solution (150 ml.) of sodium chloride (brine) was added and the mixture was extracted with ether (3×80 ml.). Evaporation of the dried (MgSO4) ethereal extracts gave 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)-N-benzyl-ethylamino]ethanol (1.65 g.) which was dissolved without purification in ethanol (40 ml.). To this solution was added benzyl bromide (0.37 ml., 0.0031 mole) and the mixture was then hydrogenated in the presence of 10% palladium-carbon (0.4 g.) at atmospheric pressure and room temperature during 2 hours. The catalyst was separated, washed with ethanol (10 ml.) and the ethanol washings and reaction solution was evaporated together. The residue was triturated with ether (20 ml.) containing several drops of ethanol to give 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)ethylamino]ethanol hydrobromide, (1.2 g.), m.p. 110°-115° C., identical with that obtained in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([N:13]2[C:17]3=[CH:18][CH:19]=[CH:20][C:21](=[O:22])[N:16]3[C@H:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@@H:14]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:12])=[O:11])[CH:5]=1.C1C(=O)N([I:45])C(=O)C1>>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([N:13]2[C:17]3=[CH:18][CH:19]=[C:20]([I:45])[C:21](=[O:22])[N:16]3[C@H:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@@H:14]2[C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)(=[O:11])=[O:12])[CH:5]=1
Reactant: COC(=O)c1cccc(S(=O)(=O)N2c3cccc(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1
Reactant: O=C1CCC(=O)N1I
Product: COC(=O)c1cccc(S(=O)(=O)N2c3ccc(I)c(=O)n3[C@H](c3ccc(Cl)cc3)[C@@H]2c2ccc(Cl)cc2)c1

Procedure:
The titled compound was prepared according to general method B by reaction of rac-3-[cis-2,3-bis-(4-chloro-phenyl)-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-sulfonyl]-benzoic acid methyl ester with NIS.
Reaction SMILES: C([N:11]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Br:28])(OCC1C=CC=CC=1)=O.[CH2:38]([N:40](CC)[CH2:41][CH3:42])[CH3:39].N1CCCC1>CCOCC>[Br:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:29]1[CH:30]=[CH:31][C:32]([C:33]([N:40]2[CH2:41][CH2:42][CH2:39][CH2:38]2)=[O:34])=[CH:36][CH:37]=1
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCCBr)C(=O)OCc2ccccc2)cc1
Reactant: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCNC1
Product: O=C(c1ccc(NCCCCCCCCCCCCCCCCBr)cc1)N1CCCC1

Procedure:
A solution of 6.0 g. of 4-[N-carbobenzyloxy-N-(16-bromohexadecyl)amino]benzoyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 1.1 g. of pyrrolidine. After 1 hour at reflux, the precipitate is filtered off and washed with warm ether. After evaporation in dryness, the intermediate is dissolved in 50 ml. 30% hydrobromic/acetic acid and warmed at 50° for 2 hours. The solvents are evaporated and the product is partitioned between methylene chloride and water. The layers are separated and the methylene chloride is evaporated. The residue is crystallized from acetone to yield colorless crystals.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH:14]([CH3:19])[CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:13][CH:14]([CH3:19])[CH2:15][C:16]2=[O:17]
Reactant: COc1ccccc1CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cccc2c1CC(C)CC2=O
Temperature: 0 °C
Yield: 36.1 %

Procedure:
A mixture of AlCl3 (6.4 g) and CH2Cl2 (100 mL) was cooled to 0° C. To the mixture was added 4-(2-methoxyphenyl)-3-methylbutyryl chloride (24 mmol, crude from previous reaction). The reaction was allowed to warm slowly to room temperature and then quenched by slowly pouring over ice. The mixture was extracted with dichloromethane (3×) and the combined organics were washed with 1 M HCl, water, dried over sodium sulfate, and concentrated. Purification by flash column chromatography yielded the desired product (1.65 g, 36% yield from 4-(2-methoxy-phenyl)-3-methyl-but-2-enoic acid ethyl ester). LCMS-ESr (m/z): [M+H]+ calcd for C12H15O2: 191.11. Found: 191.19.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[CH2:22][C:23]([NH:25][O:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[C:22]1[C:23](=[O:24])[N:25]([O:26][CH3:27])[C:2]2[N:3]=[C:4]([S:10][CH3:11])[N:5]=[CH:6][C:7]=2[CH:8]=1
Reactant: CONC(=O)Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CSc1ncc(C=O)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COn1c(=O)c(-c2cc([N+](=O)[O-])ccc2Cl)cc2cnc(SC)nc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
4-Chloro-2-(methylthio)pyrimidine-5-carbaldehyde (90 mmol) and 2-(2-chloro-5-nitrophenyl)-N-methoxyacetamide (98 mmol) were dissolved in DMF (1 L) to give a brown solution. The reaction mixture was cooled to 0° C. Potassium carbonate (197 mmol) was added. The mixture was stirred at 0° C. for 2 h and then allowed to warm to room temperature over night. Potassium carbonate was filtered off and the filtrate was concentrated to approximately 100 mL. The residue was diluted with water (1 L) and filtered. The filter cake was washed with 350 mL of EtOH to give a brown solid that was dried in vacuum. The by-product (Z)-6-(2-chloro-5-nitrophenyl)-2-(methylthio)-7H-pyrano[2,3-d]pyrimidin-7-one O-methyl oxime was separated by reflux of the mixture for 4 h in EtOH and hot filtration of the suspension through a sintered glass funnel. Evaporation of the filtrate and drying gave 6-(2-chloro-5-nitrophenyl)-8-methoxy-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as a solid (52%).
Reaction SMILES: [C:1]12([C:11]3[CH:31]=[CH:30][C:14]([C:15]([NH:17][C:18]4[CH:29]=[CH:28][C:21]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[CH:20][CH:19]=4)=O)=[CH:13][C:12]=3[O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:55])=CC=1>O>[C:1]12([C:11]3[CH:31]=[CH:30][C:14]([C:15]([NH:17][C:18]4[CH:29]=[CH:28][C:21]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[CH:20][CH:19]=4)=[S:55])=[CH:13][C:12]=3[O:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C=CCOC(=O)c1ccc(NC(=O)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OCOCCOC)c2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC(=O)c1ccc(NC(=S)c2ccc(C34CC5CC(CC(C5)C3)C4)c(OCOCCOC)c2)cc1

Procedure:
2.9 g (5.6 mmol) of allyl 4-[4-(1-adamantyl)-3-methoxyethoxymethoxybenzamido]benzoate and 30 ml of toluene were introduced into a round-bottomed flask and 1.14 g (2.8 mmol) of Lawesson's reagent were added. The reaction medium was heated at reflux for three hours and was then evaporated to dryness. The residue obtained was taken up in water and dichloromethane and the organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with a mixture of heptane and ethyl acetate (80/20). After evaporation of the solvents, 1 g (33%) of the expected allylic ester was collected in the form of an orange-coloured oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1.[H-].[Na+].[O:25]([CH2:32][CH2:33]Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]([CH2:33][CH2:32][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(Cc1ccc(OCOC)cc1)C(=O)OCC
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(CCOc1ccccc1)(Cc1ccc(OCOC)cc1)C(=O)OCC
Yield: 78.5 %

Procedure:
In a similar manner to that described in Reference example 2(a), a reaction was carried out using diethyl 2-(4-methoxymethoxybenzyl)malonate (1.58 g), which is the product of Reference example 3(b), sodium hydride (55% suspension in oil, 0.24 g) and 2-phenoxyethyl bromide (1.23 g) and the reaction mixture was treated to afford the desired compound (1.72 g) as a syrup.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][CH:7]1[CH2:12][NH:11][CH2:10][CH:9]([CH3:13])[NH:8]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:6][CH:7]1[NH:8][CH:9]([CH3:13])[CH2:10][N:11]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12]1
Reactant: CC1CNCC(C)N1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN(S(C)(=O)=O)CC(C)N1
Reaction time: 0.5 h

Procedure:
A solution of methanesulfonyl chloride (1.42 mL, 18.4 mmol) in DCM (10 mL) was added dropwise to a solution of 2,6-dimethylpiperazine (2 g, 17.5 mmol) and triethylamine (2.56 mL, 18.4 mmol) in DCM (10 mL) under nitrogen. The mixture was stirred for 30 min. The solvent was removed and the residue was applied to a 5 g aminopropyl SPE cartridge to give the product as a yellow solid (2.3 g), ˜10:1 mixture of cis and trans isomers by NMR.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:6][CH2:5]1)[CH3:3].Br[C:18]1[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=1>>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][CH:23]=3)[CH2:15][CH2:16]2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: FC(F)(F)c1ncc(Br)cn1
Reactant: CC(C)N1CCC(CC2CCNCC2)CC1
Product: CC(C)N1CCC(CC2CCN(c3cnc(C(F)(F)F)nc3)CC2)CC1

Procedure:
Example 36 was prepared using an analogous process to that described in Example 35 from 1-(1-methylethyl)-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 4) and 5-bromo-2-trifluoromethylpyrimidine (may be prepared as described in F. Cottet and M. Schlosser, Eur. J. Org. Chem., 2002, 327). 1H-NMR and mass spectral data were consistent with structure. MS electrospray (+ion) 371 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)#[N:4].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].O>C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2)#[N:4]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C#N)ccc32)cc1
Reaction time: 0.17 h
Yield: 89.7 %

Procedure:
In a 100 mL round-bottom flask was placed NaH (0.4 g, 60% dipersion in mineral oil, 10 mmol) and anhydrous THF (10 mL) was added. To the suspension was added a solution of 5-cyanoindole (1.0 g, 7 mmol) in anhydrous THF (10 mL) by syringe at 0° C. The mixture was stirred for 10 min, and tosyl chloride (1.6 g, 8.4 mmol) was added. After stirring at room temperature for 2 h, water (100 mL) was added. The mixture was extracted with ethyl acetate (3×50 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography using hexane: ethyl acetate=2:1 as eluent to yield 1.86 g (92%) of the desired product.