Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[N:25]1([CH2:30][CH:31]([OH:33])[CH3:32])[CH:29]=[CH:28][N:27]=[CH:26]1.CN(C)C=O>C1(C)C=CC=CC=1>[C:1]([O:33][CH:31]([CH3:32])[CH2:30][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(O)Cn1ccnc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OC(C)Cn1ccnc1
Yield: 92.2 %

Procedure:
With ice cooling and stirring, 35.9 g of behenic chloride (16) was added to a mixture of 12.6 g of 1-(1H-imidazol-1-yl)-2-propanol (15) and 50 g of dimethylformamide. Then the mixture was stirred at room temperature for 2 hours. Toluene was added to the solution, followed by neutralization. Subsequent standard aqueous work-up and purification by column chromatography gave 41.3 g of [2-(1H-imidazol-1-yl)-1-methylethyl] behenate (Quencher 1). Yield 92%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22])(=[O:11])=[O:10].[CH2:23](O)[CH2:24][CH2:25][OH:26]>C1C=CC=CC=1>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[S:9]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]12[O:26][CH2:25][CH2:24][CH2:23][O:22]1)(=[O:11])=[O:10]
Reactant: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: OCCCO
Solvent: c1ccccc1
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCCO1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of 5-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione (13.41 g, 41.3 mmol), 1,3 propanediol (12.1 mL, 165 mmol, 4eq) and p-tolune sulfonic acid (3.14 g, 16.5 mmol, 0.4 mole %) in benzene (800 mL) was heated to reflux under a Dean Stark Trap for 5 hours and stirred overnight at room temperature. The mixture was washed with saturated aqueous NaHCO3 (3×300 mL), water (3×300 mL) and brine (3×300 mL), dried over sodium sulfate, filtered, and concentrated to give 10.7 g of crude product that was flash chromatographed (Biotage KP silica gel, step gradient 60/40-50/50 Pet Ether/EtOAc) to give the title compound as a white solid (7.1 g, 45% yield). Anal: Calc'd for C17H22N2O6S: C, 53.39; H, 5.80; N, 7.32; Found: C, 53.08; H,5.82; N, 6.92; NMR (400 MHz, DMSO-d6): consistent. IR: consistent. MS: (ES−) m/z 381 [M−H]. m.p: 127-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[CH:5][CH:4]=1.[Br:18]N1C(=O)CCC1=O>CO>[Br:18][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[C:7]([CH3:9])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2cccc(C#N)c2)c(C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: COc1nc(C)c(-c2cccc(C#N)c2)cc1Br
Temperature: 25 °C
Reaction time: 66 h
Yield: 29.5 %

Procedure:
A mixture of 3-(6-methoxy-2-methylpyridin-3-yl)benzonitrile (3.00 g, 13.4 mmol), N-bromosuccinimide (2.89 g, 16.08 mmol) and methanol (150 mL) is stirred 66 hr at room temperature. The solids are collected by filtration to give 3-(5-bromo-6-methoxy-2-methylpyridin-3-yl)benzonitrile (1.20 g, 30%) as a white solid. LC/MS RT 4.19 min; MS m/e=303/305 (M); NMR (CDCl3) 7.65 (2H, m), 7.60 (1H, s), 7.56 (2H, m), 4.02 (3H, s), 2.37 (3H, s).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[CH3:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O>[Br-:1].[CH3:29][N+:30]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH2:13]3)=[O:11])=[CH:5][CH:4]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CN1CCCCC1
Reactant: Cc1ccc(-c2ccc3c(c2)CN(C(=O)Cc2ccc(CBr)cc2)CC3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)CN(C(=O)Cc2ccc(C[N+]4(C)CCCCC4)cc2)CC3)cc1
Product: [Br-]

Procedure:
A solution of 2-(4-bromomethylphenylacetyl)-7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (0.2 g) and 1-methylpiperidine (0.17 ml) in dimethylformamide (5 ml) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was evaporated to remove the solvent and was mixed with ethyl acetate, and the precipitate was collected by filtration. The precipitate was dissolved in ethanol, and the solvent was evaporated to obtain 1-methyl-1-(4-((7-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)carbonylmethyl)benzyl)piperidinium bromide (compound 31) (0.24 g) as a colorless amorphous substance.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][CH2:3]1.[Cl:23][C:24]1[C:33]([CH:34]=O)=[N:32][C:31]2[NH:30][C:29](=[O:36])[CH2:28][O:27][C:26]=2[CH:25]=1>>[ClH:22].[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:33]5[C:24]([Cl:23])=[CH:25][C:26]6[O:27][CH2:28][C:29](=[O:36])[NH:30][C:31]=6[N:32]=5)[CH2:3][CH2:4]4)[C:13]=1[C:12]=23
Reactant: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)CC1
Product: Cl
Product: O=C1COc2cc(Cl)c(CNC3CCN(CC4Cn5c(=O)ccc6ncc(Cl)c4c65)CC3)nc2N1
Yield: 84 %

Procedure:
The free base of the title compound was prepared from 4-[(4-amino-1-piperidinyl)methyl]-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (75 mg) and 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003064421, Example 15(c)) (50 mg) according to the general method of Example 2(h) in 84% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[NH:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][C:14]=1[CH3:21])=O>>[CH3:21][C:14]1[CH:15]=[C:16]([C:18]([OH:20])=[O:19])[NH:17][C:13]=1[CH:11]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: O=C1Cc2ccccc2N1
Product: Cc1cc(C(=O)O)[nH]c1C=C1C(=O)Nc2ccccc21
Yield: 100 %

Procedure:
Oxindole (133 mg, 1 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (153 mg) using method D to give 268 mg (100%) of the title compound as an orange-red solid.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]1[CH2:25][C:23](=O)[C:22]2[C:17](=[CH:18][CH:19]=CC=2)[CH2:16]1.[C:26]1(=[O:32])[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]1.FC(F)(F)S(O)(=O)=O.[CH3:41][CH2:42]N(CC)CC>>[O:32]=[C:26]1[CH:31]2[CH2:41][CH2:42][CH:28]([C:29]3[CH2:19][CH2:18][C:17]4[C:22]([C:30]=32)=[CH:23][CH:25]=[CH:15][CH:16]=4)[CH2:27]1
Reactant: O=C1CCCc2ccccc21
Reactant: O=C1C=CCCC1
Reactant: CCN(CC)CC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1CC2CCC1C1=C2CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 1.9 g of phosphorous pentoxide in 50 mL DCManh. were added 4.5 mL of alpha tetralone followed by 9.9 mL of 2-cyclohexen-1-one at rt. The suspension was cooled to 0° C. with an ice bath before 9.0 mL of trifluoromethanesulfonic acid was carefully added. The reaction mixture was warmed to rt and then heated at 40° C. overnight. 18.5 mL of NEt3 were dropwise added at 0° C., the mixture was stirred at rt for 10 min and then evaporated to dryness. Purification by CC with EtOAc-Hept (2:8) yielded 3.9 g of rac-(1R*,4R*)-1,2,3,4,9,10-hexahydro-3-oxo-1,4-ethanophenanthrene as yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[CH:16]=[C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:9]([C:10]([O:12]CC)=O)=[CH:8][N:7]=1)[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C[Al](C)C>C1COCC1>[CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[CH:16]=[C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:9]([C:10]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:12])=[CH:8][N:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(Nc2cccnc2)c(C(=O)OCC)cn1
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(Nc2cccnc2)c(C(=O)Nc2ccccc2)cn1
Temperature: 125 °C
Yield: 40.9 %

Procedure:
A solution of ethyl 6-(3-ethylureido)-4-(pyridin-3-ylamino)nicotinate (0.60 g, 1.82 mmol) and aniline (250 μL, 2.73 mmol) in THF (10 mL) was purged with nitrogen for 15 minutes. To this solution was added trimethylaluminium (2M in toluene, 5.40 mL, 10.80 mmol) dropwise over 10-15 min. The reaction mixture was heated at 125° C. for 30 min in a microwave reactor. The reaction mass was then quenched with water and extracted with EtOAc (3×1000 mL). The organics were combined, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue thus obtained was purified by preparative HPLC to afford Compound 13 (0.28 g, 41%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.89 (s, 1H), 9.15 (s, 1H), 8.59 (s, 1H), 8.54 (s, 1H), 8.35 (d, J=4.8 Hz, 1H), 7.93 (br s, 1H), 7.73 (t, J=8.0 Hz, 3H), 7.45-7.41 (m, 1H), 7.37 (t, J=7.6 Hz, 2H), 7.23 (s, 1H), 7.13 (t, J=7.6 Hz, 1H), 3.16-3.13 (m, 2H), 1.08 (t, J=7.2 Hz, 3H). [M+H]+ m/z=377.22.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:23])[C:3]([OH:24])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 0.08 h
Yield: 43.7 %

Procedure:
A solution of 4-[(2-quinolinyl)methoxy]-alpha-oxobenzeneacetic acid methyl ester (0.34 g) in methanol (2 mL) and tetrahydrofuran (8 mL) was treated with 1N sodium hydroxide (1.1 mL) and a white precipitate formed. After 5 minutes, the reaction mixture was concentrated and the residue was acidified with excess hydrochloric acid. The residue was triturated with water (25 mL) and dichloromethane-tetrahydrofuran (150 mL, 9:1) and the solids were crystallized twice from dimethylsulfoxide-acetonitrile-water to give 0.142 g of 4-[(2-quinolinyl)methoxy]-alpha-oxo-benzeneacetic acid, mp 225°-228° C.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CN(C)C=O.C(N(CC)C(C)C)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>>[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][N:22]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(S(C)(=O)=O)CC3)cc1
Reaction time: 2 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea hydrochloride (0.1000 g, 0.2310 mmol) in dry N,N-Dimethylformamide (1.60 mL, 20.7 mmol) was added N,N-Diisopropylethylamine (0.161 mL, 0.924 mmol) followed by Methanesulfonyl chloride (0.0268 mL, 0.346 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.69 (s, 1H), 8.19 (d, J=8.7, 2H), 7.49 (d, J=8.8, 2H), 6.18 (t, J=5.5, 1H), 4.23 (dd, J=31.8, 14.8, 2H), 3.97-3.91 (m, 1H), 3.88 (d, J=11.3, 1H), 3.72 (dd, J=11.4, 2.7, 1H), 3.62 (dd, J=10.0, 7.5, 3H), 3.49-3.38 (m, 3H), 3.16-3.08 (m, 2H), 3.03 (s, 3H), 2.99 (t, J=6.3, 2H), 1.22 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+475.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH:17]1[N:23]=[N+]=[N-])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:4].Cl.[H][H].N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>CO.[Pd].ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH:17]1[NH:23][C:41](=[O:43])[CH3:42])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1N=[N+]=[N-])C(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1NC(C)=O)C(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 46.5 %

Procedure:
To 3-[(2-Azido-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (17.5 mg, 0.04 mmol) in methanol (400 ul) was added concentrated hydrochloric acid (15 ul) followed by 10% palladium on charcoal (4 mg, 0.004 mmol). The reaction vessel was introduced with 20 psi of hydrogen and then stirred at room temperature for 17 hours. The residue was then filtered off through celite, washed with methanol and evaporated to give the crude product. To the crude product in dichloromethane (400 ul) was added pyridine (19 ul, 0.24 mmol), followed by acetic anhydride (15 ul, 0.16 mmol) and a catalytic amount of DMAP. The resulting solution was stirred for 24 hours at room temperature and then quenched with a saturated solution of NaHCO3 (5 ml). The aqueous phase was separated and washed with dichloromethane (2×5 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was then purified by preparative chromatography (60% EtOAc/Hexane) to obtain 8.5 mg (47% for two steps) of 3-[(2-Acetylamino-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17]([C@:27]([C:44]([OH:46])=[O:45])([OH:43])[C@:28]([C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)([OH:32])[C:29]([OH:31])=[O:30])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>CC(=O)CC>[C:33]([C@:28]([C:29]([OH:31])=[O:30])([OH:32])[C@:27]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([OH:43])[C:44]([OH:46])=[O:45])(=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Solvent: CCC(C)=O
Product: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.0 g, 38.5 mmol) and butanone. Add a solution of (R,R)-di-p-anisoyltartaric acid (1.6 g, 38.0 mmol) in butanone (80 mL). Heat to reflux. After 15 minutes, cool to ambient temperature and then cool further in an salt-ice bath. Filter the solid that forms and rinse with butanone. Recrystallize the solid from water/methanol to give (S)-(−)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt: mp; 201-204° C. (dec). [α]2D0=18.9° (c=0.60, dimethylsulfoxide). X-ray diffraction analysis of a single crystal confirms the (S)-configuration. Analysis on HPLC, on an analytical sample of the free amine obtained by extraction, using a CHIRALPAK AD 25 cm×0.46 cm column eluting with pentane/methanol/triethylamine (80/10/0.1) with a flow rate of 1.0 mL/minute indicates an enantiomeric excess of 96%, (96% ee), retention time of the (S)-isomer 11.2 minutes, retention time of the (R)-isomer 14.5 minutes.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8](S(C)(=O)=O)[N:7]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][NH:25][C:24]1=[O:28].C(N(CC)CC)C>COC(O)C>[S:1]1[C:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][NH:25][C:24]3=[O:28])[N:7]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: CS(=O)(=O)c1nccc(-c2cc3ccccc3s2)n1
Reactant: NCCN1CCNC1=O
Agent: COC(C)O
Solvent: CCN(CC)CC
Product: O=C1NCCN1CCNc1nccc(-c2cc3ccccc3s2)n1
Temperature: 100 °C

Procedure:
A mixture of 4-(benzo[b]thiophen-2-yl)-2-(methylsulfonyl)pyrimidine (75 mg, 0.26 mmol)), 1-(2-aminoethyl)imidazolidin-2-one (33 mg, 0.26 mmol) and triethylamine (32 mg, 0.31 mmol) in methoxyethanol (3 mL) was heated at 100° C. overnight. After cooling to rt the solvent was removed in vacuo and the product was purified by chromatography eluting with methanol/dichloromethane (1:20) to give the title compound as a slightly yellow solid (56 mg, 64%). MS (M+H)+ 340.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].C(Cl)(=O)C(Cl)=O.[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[O:15])[C:5](=[O:12])[N:6]([CH:9]([CH3:10])[CH3:11])[C:7]=1[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Cc1c(Cl)cc(C(=O)O)c(=O)n1C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(Cl)cc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)c(=O)n1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid as prepared in Example 1(7) (2.66 g, 11.6 mmol) in dichloromethane (30 mL) were added oxalyl chloride (4.41 g, 34.8 mmol) and a drop of N,N-dimethylformamide at room temperature, and the mixture was stirred at room temperature for 2 h. The solvent and excess amounts of oxalyl chloride were removed in vacuo. The residue was dissolved in dichloromethane (80 mL). To the resulting solution were added tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (3.72 g, 17.4 mmol, prepared according to Carceller, Elena et al., J. Med. Chem., 1996, 39, 487), N,N-diisopropylethylamine (2.25 g, 17.4 mmol) at room temperature, and the mixture was stirred at room temperature for 18 h. Then, the mixture was quenched with saturated sodium hydrogencarbonate aqueous solution (100 mL), and extracted with dichloromethane (100 mL×4). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (v/v=1/1) to give 5.27 g (99%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([O:15]C)[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].B(Br)(Br)Br.CO.O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11]
Reactant: COc1ccc(NC(=O)C(F)(F)F)c(C)c1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1c(NC(=O)C(F)(F)F)ccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of 3-methyl-2-nitro4-trifluoroacetamidoanisole (5.37 g, 19.3 mmol) in dry methylene chloride (250 mL) at -78° C. under nitrogen atmosphere is treated dropwise with a solution of boron tribromide (9.16 mL, 96.9 mmol) in dry methylene chloride (50 mL). After complete addition, the mixture is allowed to warm to room temperature and stirring is maintained for one hour. The mixture is cooled to -78° C. and methanol (100 mL) is added dropwise. After complete addition, the solution is allowed to warm to room temperature. The reaction mixture is distributed between water (100 mL) and methylene chloride (200 mL). The methylene chloride layer is dried over magnesium sulfate and concentrated under reduced pressure to yield 4.81 g of 3-methyl-2-nitro-4-trifluoroacetamidophenol.
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[Cl:12][C:13]1[N:14]=[CH:15][C:16]2[CH2:17][CH2:18][CH2:19][C:20](=[O:23])[C:21]=2[CH:22]=1.Cl>CCO>[CH2:10]([O:9][C:2](=[O:8])[C:3]([CH:19]1[CH2:18][CH2:17][C:16]2[CH:15]=[N:14][C:13]([Cl:12])=[CH:22][C:21]=2[C:20]1=[O:23])=[O:5])[CH3:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CCCc2cnc(Cl)cc21
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCc2cnc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium (253 mg; 11 mmol) is added portion-wise to EtOH (6 ml). After complete dissolution, diethyl oxalate (800 mg; 5.5 mmol) is introduced at room temperature, followed by 3-chloro-7,8-dihydro-6H-isoquinolin-5-one (1 g; 5.5 mmol) in EtOH (30 ml). The reaction mixture is stirred for 3 h at room temperature, poured on 1 N HCl and extracted with TBME three times. The organic phases are combined, dried over Na2SO4 and evaporated to dryness, yielding the desired product as orange oil. 1H-NMR (400 MHz; DMSO-d6): 8.47 (s, 1H); 7.68 (s, 1H); 4.29 (q, 2H); 3.42 (bs, 1H); 2.86 (bt, 2H); 2.63 (bt, 2H); 1.29 (t, 3H).
Reaction SMILES: [C:1]1([S:7][C:8]([CH3:18])([CH3:17])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:21])C.C(OC(=O)C)(=O)C.OO>C(OCC)C>[C:1]1([S:7]([C:8]([CH3:18])([CH3:17])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(Sc1ccccc1)C(=O)c1ccccc1
Reactant: CC(=O)O
Agent: OO
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(C)(C(=O)c1ccccc1)S(=O)c1ccccc1
Reaction time: 48 h

Procedure:
68 g of 2-phenylthio-2-methylpropiophenone (1a) are added at 0° C. to a solution prepared from 500 ml of glacial acetic acid, 47 g of acetic anhydride and 45.5 g of 33% hydrogen peroxide. After 48 hours of agitation at ambient temperature, it is taken up in ethyl ether, washed with water and neutralised with sodium bicarbonate.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17](Cl)=[N:18][CH:19]=[C:14]2[CH2:13][N:12]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=2)[C:11]1=[O:29])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1>CC(O)C.ClCCl>[C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH2:7][C@H:8]([N:10]1[C:15]2=[N:16][C:17]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([F:32])=[CH:34][CH:35]=3)=[N:18][CH:19]=[C:14]2[CH2:13][N:12]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=2)[C:11]1=[O:29])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(N2Cc3cnc(Cl)nc3N([C@H](C)CO[Si](C)(C)C(C)(C)C)C2=O)cc1
Reactant: Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CC(C)O
Product: CCc1ccc(N2Cc3cnc(Nc4ccc(F)cc4)nc3N([C@H](C)CO[Si](C)(C)C(C)(C)C)C2=O)cc1
Temperature: 160 °C

Procedure:
(R)-1-[2-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-7-chloro-3-(4-ethyl-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (100 mg, 0.21 mmol) (from Example 38e supra) was suspended in 2-propanol (2 mL) (Fisher). 4-Fluoroaniline (0.03 mL, 0.32 mmol) (Aldrich) was added and the mixture was heated to 160° C. in a microwave synthesizer (SmithSynthesizer™) for 30 minutes. After cooling to room temperature, the heterogeneous reaction mixture was diluted with dichloromethane. The resulting solution was washed with 1 N aqueous hydrochloric acid. The layers were separated and the organic phase was dried over anhydrous sodium sulfate, filtered and then concentrated under reduce pressure to give (R)-1-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-3-(4-ethyl-phenyl)-7-(4-fluoro-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a pale yellow solid. (Yield 107 mg, 91%).