Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:8][CH:7]=3)(=[O:10])=[O:11])[CH2:13][CH2:14]2)=[O:28])[CH:22]=1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: O=C(O)c1cc(Br)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)ccn1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Yield: 52.6 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (200 mg, 0.680 mmol) in DMF (10 ml) was added 4-bromo-2-pyridinecarboxylic acid (137 mg, 0.680 mmol), HOBT.H2O (104 mg, 0.680 mmol), HBTU (258 mg, 0.680 mmol) and DIPEA (0.356 ml, 2.039 mmol) and the reaction mixture was stirred at room temperature for 2.5 hours. The DMF was evaporated under vacuo then 10 ml of DCM were added and washed with 2M aq. HCl solution (10 ml) saturated aq. NaHCO3 solution (10 ml) and brine (10 ml), dried on a phase separation cartridge and evaporated in vacuo. The crude material was purified by silica chromatography using a gradient isohexane/EtOAc [100/0] to [50/50] then to [0/100]). The desired fractions were then collected and concentrated to dryness to give 1-[(4-bromo-2-pyridinyl)carbonyl]-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (171 mg, 0.358 mmol, 52.6% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.CCN(C(C)C)C(C)C.[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)n1
Reaction time: 8 h

Procedure:
To a solution of 2,6-dichloropyrimidine-4-carbonyl chloride (1.026 g, 4.85 mmol) in DCM (25 mL) was added iPr2NEt (1.01 mL, 5.80 mmol) and t-butanol (0.51 mL, 5.3 mmol). The mixture was stirred overnight then pyridine (0.39 mL, 4.8 mmol) was added and the stirring continued over another night. The reaction mixture was evaporated in vacuo and the resulting residue was chromatographed over silica gel with 0-40% EtOAc in hexanes. The product fractions were evaporated in vacuo to give tert-butyl 2,6-dichloropyrimidine-4-carboxylate as a yellow-orange waxy solid (0.310 g, 1.24 mmol, 26% yield). 1H NMR (400 MHz, DMSO-d6): 8.15 (1H, s), 1.56 (9H, s). LC/MS: m/z=271.1 [M+Na]+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][N:30]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:19][C:20]5([CH2:21][CH2:22][N:23]([C:29]6[N:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][N:30]=6)[CH2:24][CH2:25]5)[CH2:26]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CCCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Product: CCCc1cnc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)nc1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2-chloro-5-n-propyl-pyrimidine following a procedure analogous to that described for Example 15. LC (method 3): tR=0.88 min; Mass spectrum (ESI+): m/z=510 [M+H]+.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=[O:20])C>>[C:12]1([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[C:1](=[O:11])[CH2:2][C:3]3=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1Cc2ccccc2C1=O
Reactant: CCOC(C)=O
Reactant: c1ccccc1
Product: O=C1CC(=O)c2cc(-c3ccccc3)ccc21

Procedure:
A solution of dimethyl 4-phenyl phthalate (bp 0.1 170°-80°C) in ethyl acetate was cyclised to the indane dione as described in Example 16(b), m.p. (benzene, petroleum [40°-60°]) 116°C. (Found: C, 80.96; H, 4.70; C15H10O2 requires: C, 81.07; H, 4.54%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:13]2[O:12][CH2:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][C:5]=1[C:14]([OH:16])=O)#[N:2].[NH2:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][N:19]=1>>[CH3:23][C:21]1[NH:20][N:19]=[C:18]([NH:17][C:1]2[NH:2][C:14](=[O:16])[C:5]3[C:4](=[C:13]4[C:8](=[CH:7][CH:6]=3)[O:9][CH2:10][CH2:11][O:12]4)[CH:3]=2)[CH:22]=1
Reactant: N#CCc1c(C(=O)O)ccc2c1OCCO2
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(Nc2cc3c4c(ccc3c(=O)[nH]2)OCCO4)n[nH]1

Procedure:
Similar procedure as described in example 2c was used, starting from 5-Cyanomethyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid and 3-amino-5-methylpyrazole to give 6-(5-Methyl-1H-pyrazol-3-ylamino)-2,3-dihydro-7H-1,4-dioxa-7-aza-phenanthren-8-one. LC-MS: m/e 299 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)[C:3]#[N:4].[C:13]([CH2:16][CH:17]=O)(=[O:15])[CH3:14]>>[C:13]([C:16]1[C:3]([NH2:4])=[C:2]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[NH:1][CH:17]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)CC=O
Reactant: COc1ccc(C(N)C#N)cc1
Product: COc1ccc(-c2[nH]cc(C(C)=O)c2N)cc1

Procedure:
Starting from 2-amino-2-(p-methoxyphenyl)acetonitrile and acetylacetaldehyde, the open-chain intermediate product is prepared, boiling at 180° C./0.03 mm Hg. Overall yield of the title compound: 44%, m.p. 198°-200° C. (from diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](O)=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-:24].[K+].[K+]>C1C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:24][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(COc1cc(Cl)c2ccccc2c1)c1ccccc1

Procedure:
The product of step A is reacted with α-bromoacetophenone in benzene in the presence of potassium carbonate using the method of Example 1, step A, to provide white crystals of α-(4-chloro-2-naphthoxy)acetophenone after recrystallization from a dichloromethane-petroleum ether mixture.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11](=[O:20])[N:12]2[CH3:19])[C:3]([OH:5])=O.[NH2:21][C:22](N)=[S:23].C([O-])(=[O:27])C.[Na+]>COC(O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:7]([CH2:6][CH:2]2[S:23][C:22](=[O:27])[NH:21][C:3]2=[O:5])=[C:8]2[C:13]=1[N:12]([CH3:19])[C:11](=[O:20])[CH:10]=[CH:9]2
Reactant: COc1ccc(CC(Cl)C(=O)O)c2ccc(=O)n(C)c12
Reactant: CC(=O)[O-]
Reactant: NC(N)=S
Agent: COC(C)O
Agent: [Na+]
Product: COc1ccc(CC2SC(=O)NC2=O)c2ccc(=O)n(C)c12
Temperature: 110 °C
Reaction time: 7.5 h
Yield: 38.1 %

Procedure:
1.0 g of 2-chloro-3-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-yl)propionic acid, 0.45 g of thiourea, and 0.4 g of sodium acetate were added to 20 ml of methoxy ethanol, and the mixture was stirred at 110° C. for 7.5 hours. The reaction mixture was concentrated under reduced pressure, an aqueous sodium hydrogencarbonate solution was added to the residue to precipitate a solid, and the precipitated solid was collected by filtration. The filtrate was extracted with dichloromethane, and the extract was dried over anhydrous sodium sulfate and concentrated. The concentrated residue and the solid collected by filtration were combined and added to a mixed solvent of 10% hydrochloric acid and ethanol, followed by heating and refluxing overnight. The solvent was distilled off under reduced pressure, and the residue was recrystallized from an aqueous DMF, giving 0.41 g of 5-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)thiazolidine-2,4-dione as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[NH:34][CH:35]=[CH:36][N:37]=1.CC(O)=O.CCO>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][N:34]4[CH:35]=[CH:36][N:37]=[C:33]4[N:32]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Reactant: Nc1ncc[nH]1
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4nccn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Compound 1 (1.2 g, 2.9 mmol) and 2-aminoimidazole (0.77 g 4.3 mmol) were added into a solution of AcOH (2 mL) and EtOH (10 mL). The mixture was heated to reflux and stirred overnight. The solution was cooled to r.t. and diluted with 30 mL of DCM. The organic phase was washed with 0.1N HCl(aq) and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give 1.2 g of 4-1 as a yellow solid. MS (ESI) m/e (M+H+): 441.3
Reaction SMILES: [Cl:1][C:2]1[N:7]=C(Cl)[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH3:14])[N:3]=1.COCCOC.B(O)(O)[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1.C(N(C(C)C)CC)(C)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:28]([C:25]2[CH:24]=[CH:23][CH:22]=[CH:27][CH:26]=2)[N:7]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccccc1
Yield: 81.1 %

Procedure:
To a suspension of methyl 2-(2,4-dichloro-6-methylpyrimidin-5-yl)acetate (4 g; 17.02 mmol) in a mixture of degassed DME (75 mL) and water (25 mL) was added p-tolylboronic acid (4.63 g; 34 mmol), Tetrakis(triphenylphosphine) palladium(0) (2 g; 1.731 mmol) and diisopropyl ethylamine (11.73 mL; 68.1 mmol). The reaction was stirred under reflux for 3.5 h. The reaction mixture was then partitioned between brine and ethyl acetate. The phases were separated and the water layer was extracted with ethyl acetate. The combined organic layers were dried with magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (5-40%) in heptane to give 3.82 g (61%) of the title compound as a white solid (purity: 80%). ESI/APCI(+): 291 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:13]([CH:15]=[C:16](OCC)[NH:17][C:18]#[C:19][CH3:20])#[N:14].C(N)C#C.C(C=C(OCC)OCC)#N>>[C:13]([CH:15]=[C:16]([NH:17][CH2:18][C:19]#[CH:20])[NH:12][CH2:11][CH2:10][S:9][CH2:8][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:14]
Reactant: NCCSCc1ncccc1Cl
Reactant: CC#CNC(=CC#N)OCC
Agent: C#CCN
Agent: CCOC(=CC#N)OCC
Product: C#CCNC(=CC#N)NCCSCc1ncccc1Cl

Procedure:
When 2-[(3-chloro-2-pyridyl)methylthio]ethylamine is reacted with 1-cyano-2-ethoxy-2-propynylaminoethylene [prepared from propargylamine and 1-cyano-2,2-bis(ethoxy)-ethylene, which is itself prepared according to the procedure described in J. Am.. Chem. Soc., 71, 47 (1949)], the title product is produced.
Reaction SMILES: O1CCCC1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1>CO>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1
Reactant: O=C(CN1CCCC1)Nc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Brc1ccc(NCCN2CCCC2)cc1
Reaction time: 8 h

Procedure:
A 1M solution of BH3 in tetrahydrofuran (7.7 ml, 7.7 mmol) was added dropwise to N-(4-bromo-phenyl)-2-pyrrolidin-1-yl-acetamide (0.22 g, 0.77 mmol) and the solution was stirred overnight at reflux then subsequently hydrolysed by slow addition of excess of methanol and refluxing for a further 2 hours. The solvent was removed under reduced pressure and aqueous ammonium chloride was added. The aqueous was extracted twice with ethyl acetate and the organics were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the desired product. Yield 0.18 g, 86%. LCMS method: 2, RT: 4.62 min; MI: 267-269 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]([NH2:8])=[O:7])[CH2:5][CH2:4]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:20]([O:22][C:23]([CH3:25])=[CH2:24])=[O:21]>C1COCC1>[CH3:1][O:2][C:3]1([C:6]([NH:8][C:20](=[O:21])[O:22][C:23]([CH3:25])=[CH2:24])=[O:7])[CH2:5][CH2:4]1
Reactant: COC1(C(N)=O)CC1
Reactant: C=C(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C1(OC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
A −78° C. solution of 1-methoxycyclopropane-1-carboxamide (0.23 g, 1.998 mmol) in THF (6 mL) was treated drop-wise with lithium bis(trimethylsilyl)amide (1M THF, 2.80 mL, 2.80 mmol), stirred for 0.5 h, treated drop-wise with a solution of isopropenyl chloroformate (0.262 mL, 2.397 mmol) in dry THF (1 mL), stirred for 1 h at −78° C., allowed to slowly warm to RT and stirred for 1 h. The mixture was quenched with satd. NaHCO3), extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl (1-methoxycyclopropane-1-carbonyl)carbamate (0.423 g, 106%). MS (ESI) m/z: 222.1 (M+Na+).
Reaction SMILES: COC[CH2:4][CH2:5][O:6][C:7]1[N:12]=[C:11]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]([NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31]([OH:33])=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)=[CH:9][CH:8]=1.[CH3:34][O:35]CCO>>[CH3:34][O:35][CH2:4][CH2:5][O:6][C:7]1[N:12]=[C:11]([O:13][CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:10]([NH:20][C:21]2[C:22]3[C:29]([CH3:30])=[C:28]([C:31]([OH:33])=[O:32])[S:27][C:23]=3[N:24]=[CH:25][N:26]=2)=[CH:9][CH:8]=1
Reactant: COCCO
Reactant: COCCCOc1ccc(Nc2ncnc3sc(C(=O)O)c(C)c23)c(OC2CCOCC2)n1
Product: COCCOc1ccc(Nc2ncnc3sc(C(=O)O)c(C)c23)c(OC2CCOCC2)n1

Procedure:
Prepared as described for 4-(6-(3-methoxypropoxy)-2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid except that 2-methoxyethanol was used in place of 3-methoxypropan-1-ol in the first step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[CH:12]1([C:10]2[N:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]3=[N:8][N:9]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(NNc1ccc(F)cn1)C1CCCCC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2nnc(C3CCCCC3)n2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.2 %

Procedure:
To a solution of Intermediate 34a (1.15 g, 4.83 mmol), triphenylphosphine (2.54 g, 9.67 mmol), and triethylamine (2.68 mL, 19.3 mmol) in dry THF (17 mL) at 0° C. under N2 was added hexachloroethane (2.28 g, 9.67 mmol), and the mixture stirred at 0° C. for 15 min, and at RT for 6 h. Water was added, then the organics washed with brine, dried (MgSO4) and concentrated in vacuo. Flash chromatography (silica gel, 0-100% EtOAc in cyclohexane) gave the title compound as an off-white solid (330 mg, 31%). 1H NMR (400 MHz, CDCl3): 1.36-1.55 (3H, m), 1.78-2.00 (5H, m), 2.05-2.14 (2H, m), 2.97 (1H, tt, J=11.5, 3.5 Hz), 7.16 (1H, ddd, J=10.0, 7.5, 2.3 Hz), 7.76 (1H, dd, J=10.0, 4.9, 0.9 Hz), 7.85 (1H, ddd, J=3.5, 2.2, 0.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH3:25])[C:15]3[S:19][C:18]([C:20]([O:22]CC)=[O:21])=[CH:17][CH:16]=3)[CH:8]=2)[N:3]=1.CCO.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH3:25])[C:15]3[S:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][CH:16]=3)[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc(N(C)Cc2ccc3nc(C)[nH]c(=O)c3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1nc2ccc(CN(C)c3ccc(C(=O)O)s3)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 62.9 %

Procedure:
A 25 mL 3-necked flask equipped with a condenser, a thermometer, and a magnetic stirrer was charged with 0.20 g of ethyl 5-(((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)methylamino)-2-thiophene-carboxylate, 6 mL of EtOH, and 6 mL of 1N aqueous NaOH. The resulting solution was stirred under nitrogen and RT for 25 min and then at 55° C. for 2 h. Analysis by tlc (SiO2, 95:5 CH2Cl2) indicated no remaining starting material and a new component at Rf =0.06. The solution was cooled to RT and subjected to rotary evaporation to remove EtOH. The remaining solution was diluted with 10 mL of water and acidified to pH=3.5 by addition of 1N aqueous HCl. A tan precipitate formed which was collected by centrifugation, washed with four cycles of aqueous suspension-centrifugation-decantation, and lyophilized to afford 0.116 g (63%) of 5-(((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)methylamino)-2-thiophene-carboxylic acid as a white powder, m.p. 195° C. (dec).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].N1C=CC=CC=1.[C:13](Cl)(=[O:31])[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][CH2:28][CH2:29][CH3:30].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:13]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])(=[O:31])[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][CH2:28][CH2:29][CH3:30]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
To a mixture of glycerol (30 g, 326 mmol) and pyridine (25 ml) dissolved in DMF (300 ml) was added dropwise stearoyl chloride (10 g, 33 mmol) dissolved in DMF 100 ml 9. The mixture was cooled on an ice bath until addition was complete, whereupon the reaction was maintained under an N2 atmosphere overnight. After 15 hours CH2CL2 (300 ml) and saturated NaHCO3 (aq) was added. The phases were separated and the organic phase washed with water (50 ml) and dried with Na2SO4. The solvent and any pyridine were evaporated under vacuum. The crude product was chromatographed on a silica column (CH2Cl2-MeOH, 20:1) and recrystallised (CH2Cl2-ether) to yield around 7 grams.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1(CC)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CC)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-ethyl-cyclopentane carboxylate (4.90 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.22 ml) was slowly added, then benzoyl chloride (4.68 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours; Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed in turn using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 8.86 g of yellow liquid. MS: m/e 290(M+″), 261, 216, 185, 168, 139, 105(base), 77.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=2[O:21][CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C(O)(=O)C.[N+:30]([CH3:33])([O-:32])=[O:31]>CO>[CH3:33][NH2:30].[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[CH:33][N+:30]([O-:32])=[O:31])=[CH:15][C:14]=2[O:21][CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C=O)ccc1OCCCCCc1ccccc1
Reactant: C[N+](=O)[O-]
Solvent: CCO
Solvent: CO
Solvent: CC(=O)O
Product: CN
Product: COc1cc(C=C[N+](=O)[O-])ccc1OCCCCCc1ccccc1

Procedure:
Operating analogously to example 2 using 4-(5-phenylpentyloxy)-3-methoxy-benzaldehyde (21 g, 73.4 mmoles), obtained as described in example 21, in methanol (86 ml), 8.03M methylamine in ethanol (1.92 ml, 15.4 mmoles), acetic acid (0.88 ml, 15.4 mmoles) and nitromethane (4.34 ml, 80.7 mmoles) 20 g of the title product were obtained (yield: 80%).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[C:5]([CH:10]2[C:19]([CH3:21])([CH3:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:22]([OH:24])=O)[CH:16]=3)[NH:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1.Cl.CN(C)CCCN=C=NCC.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:25][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:10]2[C:19]([CH3:21])([CH3:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:22]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:24])[CH:16]=3)[NH:11]2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CN(C)c1cc(F)cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(C)c1cc(F)cc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)c1
Yield: 39.7 %

Procedure:
A mixture of 2-(3-dimethylamino-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (10 mg, 0.03 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.4 mg, 0.044 mmol), 4-dimethylaminopyridine (5.4 mg, 0.044 mmol), methane sulfonamide (8.3 mg, 0.09 mmol) in dichloromethane (3 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(3-dimethylamino-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (5 mg, 42%) as a light yellow solid: LC/MS m/e calcd for C21H26FN3O3S (M+H)+: 420.5, observed: 420.1.