Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Br:21][C:22]1[CH:23]=[N:24][C:25](Cl)=[N:26][CH:27]=1>O>[Br:21][C:22]1[CH:23]=[N:24][C:25]([O:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])=[N:26][CH:27]=1
Reactant: CCOC(CO)OCC
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1ncc(Br)cn1)OCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.2 %

Procedure:
2,2-Diethoxyethanol (1.6 g) and cesium carbonate (5.8 g) were added to DMF solution (10 mL) of 5-bromo-2-chloropyrimidine (1.15 g), and stirred at room temperature for 12 hours. After addition of water, the reaction liquid was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (C-200; ethyl acetate:hexane=1:9-1:4) to provide the title compound (1.63 g, 94%).
Reaction SMILES: [CH3:1][NH2:2].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:26][C@@:24]2([CH3:25])[C@@H:20]([CH2:21][CH2:22][C@@H:23]2[OH:27])[C@@:19]2([CH:28]=[CH2:29])[C@H:10]1[C:11]1[CH:12]=[CH:13][C:14]([OH:30])=[CH:15][C:16]=1[CH2:17][CH2:18]2>>[CH3:1][NH:2][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]1[CH2:26][C@@:24]2([CH3:25])[C@@H:20]([CH2:21][CH2:22][C@@H:23]2[OH:27])[C@@:19]2([CH:28]=[CH2:29])[C@H:10]1[C:11]1[CH:12]=[CH:13][C:14]([OH:30])=[CH:15][C:16]=1[CH2:17][CH2:18]2
Reactant: CN
Reactant: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCBr)C[C@@]1(C)[C@H]2CC[C@@H]1O
Product: C=C[C@@]12CCc3cc(O)ccc3[C@H]1[C@@H](CCCCCNC)C[C@@]1(C)[C@H]2CC[C@@H]1O

Procedure:
In the reaction with methylamine (40% in water, 2 ml/mmol) analogously to instructions 17.2, 258 mg of bromide 30a yields 161 mg of amine 31a as a colorless solid (GC-MS: m/z theor.: 397, pract.: 397).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]([O-])(=O)[CH3:11].[Na+].[BH4-].[Na+].[OH-].[Na+].[C:19](O)(=O)C>CC(C)=O.C(O)C.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([CH3:11])[CH3:19])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: CC(=O)[O-]
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1cc(NC(C)C)ccc1Br
Reaction time: 0.08 h
Yield: 92 %

Procedure:
A solution of 4-bromo-3-methylaniline (5.05 g, 27 mmol) in acetic acid (6.0 mL), acetone (7.0 mL), ethanol (25.0 mL) and water (16.0 mL) was cooled to 0° C. and treated with sodium acetate (7.16 g, mmol). The reaction was stirred 5 minutes and then treated slowly and in several small portions with sodium borohydride (5.15 g, 136 mmol) and the resulting reaction mixture was stirred at 0° C. for 3 hours. The solution was neutralized with NaOH pellets and extracted with ether (2×). The combined organic extracts were washed with brine and dried (Na2SO4). The filtered solution was concentrated under reduced pressure to give the title compound (5.68 g, 92%) as an oil.
Reaction SMILES: [F:1][CH2:2][C:3]1([C:6]2[CH:7]=[C:8]([NH2:18])[N:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH2:5][CH2:4]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20].[NH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([O:42][CH:43]2[CH2:48][CH2:47][N:46]([C:49]([C:51]3([CH3:54])[CH2:53][CH2:52]3)=[O:50])[CH2:45][CH2:44]2)=[N:34][CH:33]=1>C(Cl)Cl>[F:1][CH2:2][C:3]1([C:6]2[CH:7]=[C:8]([NH:18][C:19]([NH:31][C:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:35]([O:42][CH:43]4[CH2:48][CH2:47][N:46]([C:49]([C:51]5([CH3:54])[CH2:53][CH2:52]5)=[O:50])[CH2:45][CH2:44]4)=[N:34][CH:33]=3)=[O:20])[N:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=2)[CH2:4][CH2:5]1
Reactant: Cc1ccc(-n2nc(C3(CF)CC3)cc2N)cc1
Reactant: CC1(C(=O)N2CCC(Oc3ncc(N)c4ccccc34)CC2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C3(CF)CC3)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)C4(C)CC4)CC3)c3ccccc23)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 4.9 %

Procedure:
Add 5-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-ylamine (160.00 mg; 652.26 μmoles) dissolved in 1 L of DCM slowly to a solution of 1,1′-carbonyldiimidazole (158.65 mg, 978.39 μmoles) in DCM. Stir mixture at 40° C. for 7 hours. Then add a solution of [4-(4-Amino-isoquinolin-1-yloxy)-piperidin-1-yl]-(1-methyl-cyclopropyl)-methanone (Preparation 23, 212.25 mg, 652.26 μmoles, 1.00 equiv) in 1 mL of DCM. Stir mixture overnight. Evaporate solvent under N2. Purify first by HLB cartridge (6 g) using NH4CO3/MeOH (100:0 to 0:100) and then finally by HPLC (Kromasil C18 column (100×21.2 mm, 5 □m (Hi-Chrom). The mobile phase is water (solvent A) and acetonitrile (solvent B), both containing 0.05% trifluoroacetic acid (TFA). Gradient mode: 2 min at 40% of B, from 40 to 60% of B in 6 min. Finally, 2 min at 95% of B. Flow rate: 25 mL/min) affording 1-[5-(1-fluoromethyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-3-{1-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yloxy]-isoquinolin-4-yl}-urea as a solid (19 mg, 5% yield). ES+ (m/z):597[M+1].
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](B(O)O)[CH:12]=2)[NH:7][C:6](=[O:17])[CH2:5]1)([CH3:3])[CH3:2].Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:26][C:21]1[CH:20]=[C:19]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:17])[CH2:5][N:4]3[CH:1]([CH3:3])[CH3:2])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CC(C)N1CC(=O)Nc2ccc(B(O)O)cc21
Reactant: Fc1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC(C)N1CC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21
Temperature: 25 °C

Procedure:
A mixture of (3,4-dihydro-4-isopropyl-2-oxoquinoxalin-6-yl)boronic acid (2.4 g, 10 mmol), 4-bromo-2-chlorofluorobenzene (2 g, 10 mmol), potassium carbonate (4 g, 30 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.46 g, 0.4 mmol) in dimethoxyethane (100 ml), ethanol (25 ml) and water (25 mol) was heated to reflux for 6 hrs. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water, then brine, dried (MgSO4) and evaporated to obtain crude product (2.9 g, 91%). Recrystallization from EtOAc/hexane afforded the title compound, mp 208-213° C.: 1H-NMR (DMSO-d6) δ1.16 (d, J=6.59 Hz, 6H), 3.56 (s, 2H), 4.22 (septet, J=6.59 Hz, 1H), 6.86 (d, J=7.91 Hz, 1H), 6.96 (dd, J=7.91, 1.76 Hz, 1H), 7.01 (d, J=1.76 Hz, 1H), 7.43 (t, J=9.01 Hz, 1H), 7.61 (m, 1H), 7.82 (dd, J=7.14, 2.31 Hz, 1H), 10.47 (s, 1H). MS (EI) m/z 318 [M]++1 chlorine.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 250 mL 3 neck flask with mechanical stirring and condenser, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle and under nitrogen atmosphere, the following was added: 7.61 g of methyl 4-hydroxybenzoate, 11.05 g of β-chloroethylpiperidine hydrochloride, 16.59 g of powdered potassium carbonate and 60 mL of ethyl acetate. The mixture was heated slowly to reflux. After overnight reflux, the mixture was cooled to ambient temperature, after which 60 mL of deionized water was added. The aqueous layer was separated and discarded. The organic layer was extracted with 4N hydrochloride (3 aliquots of 20 mL). The combined acid extracts were heated to reflux. After 1 hour at reflux, HPLC indicated the saponification to be 60% complete. After 4 hours, the reaction was near 100% complete. The mixture was cooled to 0° C.-5° C. and stirred. The resulting crystals were filtered, rinsed with acetone and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]=[N+]=[N-])=[CH:7][CH:6]=[CH:5][N:4]=1.[C:13](OC([O-])=O)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][NH:10][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: COc1ncccc1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ncccc1CNC(=O)OC(C)(C)C
Yield: 49.6 %

Procedure:
9.5 g of [(2-methoxy-3-pyridyl)methyl]azide was dissolved in 100 ml ethyl acetate, and 13 g of tertiary butyl dicarbonate and 3 g of 10% palladium-carbon were added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated, and the residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1→44:1), 6.84 g of tertiary butyl N-[(2-methoxy-3-pyridyl)methyl]carbamate was obtained. 2.916 g of this crude product was dissolved in 30 ml acetonitrile, and 2.19 g of N-bromosuccimide was added. After stirring at room temperature for 3 days, the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was washed with a mixed solvent of diethyl ether, ethyl acetate and hexane, to give 1.185 g of N-[(5-bromo-2-methoxy-3-pyridyl)methyl]carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[S:18][C:17]([I:19])=[CH:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:23]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:20])[C:12]3[S:18][C:17]([I:19])=[CH:16][C:13]=3[N:14]([CH3:23])[CH:15]=2)=[O:9])=[CH:21][CH:22]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(I)sc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(I)cc21
Temperature: 90 °C
Yield: 74 %

Procedure:
To a stirring mixture of N-(4-chlorobenzyl)-7-hydroxy-2-iodothieno[3,2-b]pyridine-6-carboxamide (0.50 g, 1.12 mmol) in DMF (20 mL) in a pressure tube was added K2CO3 (0.31 g, 2.25 mmol). To the resulting suspension was added CH3I (0.335g, 2.36 mmol), the vessel capped and heated at 90° C. for 16 h. The resulting dark suspension was cooled to ambient temperature and poured into H2O (100 mL). The aqueous solution was extracted with CH2Cl2 (3×100 mL). The organic layers were combined, dried over MgSO4 and solvent removed to afford 0.38 g title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:29][CH3:30])=[CH:9][C:10]3[C:11]4[N:19]([C@@H:20]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH3:21])[C:18](=O)[NH:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:31])[O:4][N:3]=1.O=P(Cl)(Cl)Cl.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CN1C(=O)CCC1.CS(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:29][CH3:30])=[CH:9][C:10]3[C:11]4[N:19]([C@@H:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH3:21])[C:18]([N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1[nH]c(=O)n([C@H](C)c3ccccc3)c12
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(N3CCOCC3)n([C@H](C)c3ccccc3)c12
Temperature: 100 °C
Yield: 0.75 %

Procedure:
7-(3,5-Dimethyl-4-isoxazolyl)-8-(methyloxy)-1-[(1R)-1-phenylethyl]-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (for a preparation see Intermediate 11) (0.16 g, 0.386 mmol) was dissolved in POCl3 (1 ml, 10.73 mmol) and heated at 100° C. for 3 days. The reaction mixture was evaporated in vacuo to give a black gum. The residue was dissolved in NMP (2 ml) and morpholine (2 ml, 22.96 mmol) was added, then the solution was heated in the microwave at 150° C. for 1 h. The reaction mixture was loaded onto a 20 g SCX-2 cartridge and washed through with methanol (40 ml), then eluted with 2M methanolic ammonia and the eluant evaporated in vacuo to give an amber oil. This was dissolved in DMSO (1 ml) and purified by MDAP (HpH) to give 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-2-(4-morpholinyl)-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinoline (1.4 mg, 2.90 μmol, 0.750% yield). LCMS (formate) Rt 0.86 min, MH+ 484
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[Br:13][CH2:14][CH2:15][CH2:16]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:16][CH2:15][CH2:14][Br:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: OCCCBr
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1cccc(OCCCBr)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
A solution of 3-hydroxyphenyl acetic acid methyl ester (1) (5.28 g, 0.032 mol), 3-bromo-1-propanol (6.95 g, 0.05 mol), and Ph3P in CH2Cl2 (100 mL) was treated with diisopropyl azodicarboxylate (6.67 g, 0.033 mol) dropwise. The reaction mixture stirred at room temperature for 12 hours and was concentrated to an oil, which was purified by flash chromatography (gradient elution, 9:1 to 7:3 Hexanes/EtOAc to give the desired product as oil 7.90 g in 86% yield. 1H NMR (CDCl3) δ 7.25 (t, 1H), 6.88 (d, 1H), 6.84 (m, 2H), 4.11 (t, 2H), 3.70 (s, 3H), 3.61 (m, 4H), 2.34 (m, 2H). 13C NMR (CDCl3) δ 169.0, 155.9, 132.5, 126.7, 119.0, 112.7, 110.3, 62.3, 49.2, 38.3, 29.5, 27.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:33].[C:34](Cl)(=O)[O:35]C1C=CC([N+]([O-])=O)=CC=1.[C:47]([C:51]1[O:55][N:54]=[C:53]([NH2:56])[CH:52]=1)([CH3:50])([CH3:49])[CH3:48]>O1CCCC1>[C:47]([C:51]1[O:55][N:54]=[C:53]([NH:56][C:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:19][CH:18]=4)[CH2:14][CH2:15]3)=[O:9])=[CH:4][C:3]=2[F:33])=[O:35])[CH:52]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1cc(N)no1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(C(=O)N3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2F)no1
Temperature: 120 °C
Yield: 5.2 %

Procedure:
(4-Amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.417 mmol, 0.2 g) and 4-nitrophenyl carbono-chloridate (0.417 mmol, 0.084 g) were combined and stirred in tetrahydrofuran (2 mL) at room temperature for 1 hour. 5-tert-Butylisoxazol-3-amine (1.252 mmol, 0.175 g) was added and the reaction heated in the microwave to 120° C. for 10 minutes. The solvent was removed at reduced pressure and the resulting residue purified by silica column chromatography (eluant dichloromethane/methanol 0% to 5%) to afford the title compound (14 mg). MS (ESI) m/z 646.5 [M+H]+
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3]C=1.SCC[C:11]([OH:13])=[O:12].[CH3:14]C1C=CC2C(=CC=C(C)C=2)C=1>C(Cl)Cl>[CH3:14][O:13][C:11]([CH:5]1[CH2:4][CH2:3][O:7][CH2:1][CH2:6]1)=[O:12]
Reactant: Cc1ccc2cc(C)ccc2c1
Reactant: O=C(O)CCS
Reactant: Oc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1CCOCC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of 94 grams (1.0 mol) of phenol, 5.31 g (0.0500 mol) of 3-mercaptopropionic acid, 10 g of LEWATIT BE ion exchange resin and 1.0 g of 2,6-dimethylnaphthalene (internal standard for liquid chromatography analysis) was heated to about 65° C. in a round bottom flask equipped with a condenser, an internal thermometer and a mechanical stirrer. The solution was held under a static nitrogen atmosphere and stirred at about 65° C. for about 8 hrs. after which the THPE was isolated by precipitation with methylene chloride (4 mL/1 g of reaction mixture). The yield is given in Table III.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:33])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][CH:10]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26](Cl)[C:27](OCC)=[O:28])=[CH:21][CH:20]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[NH2:34][C:35]([NH2:37])=[S:36].S1(CCCC1)(=O)=O>>[C:1]([O:4][C:5]1[C:6]([CH3:33])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][CH:10]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]3[S:36][C:35](=[NH:34])[NH:37][C:27]3=[O:28])=[CH:21][CH:20]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Reactant: NC(N)=S
Solvent: O=S1(=O)CCCC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(COc1ccc(CC3SC(=N)NC3=O)cc1)O2

Procedure:
The procedure described in Example 1(a) was repeated, except that 490 mg of ethyl 3-[4-(6-acetoxy-5,7,8-trimethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate, 100 mg of thiourea and 2 ml of sulfolane were heated at 110°-120° C. for 5 hours. The product was then treated as described in Example 1(a), except that the crude product (in the form of crystals) was washed with ethyl acetate, to give the title compound, softening at 228°-236° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@:13]3([CH3:21])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:22]>>[NH2:22][C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@@:13]3([CH3:21])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)c2ncnc(Cl)c12
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@]2(C)O)c2ncnc(N)c12

Procedure:
To the compound from Step B (0.2 g, 0.64 mmol) was added methanolic ammonia (saturated at 0° C.; 40 mL). The mixture was heated in a stainless steel autoclave at 100° C. for 14 h, then cooled and evaporated in vacuo. The crude mixture was purified on a silica gel column (5×5 cm) with CH2Cl2/MeOH (50/1, 30/1, 20/1) gradient as eluent to give the title compound as a white solid (0.12 g).
Reaction SMILES: C[O-].[Na+].CO.C1(S([CH2:15][CH2:16][CH2:17][CH:18]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]2=O)(=O)=O)C=CC=CC=1.CS(C)=O>C1(C)C=CC=CC=1>[C:18]12[CH2:17][CH2:16][CH:15]=[C:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CS(C)=O
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 75.8 %

Procedure:
2.37 ml of a 30% solution of sodium methoxide in methyl alcohol (10.2 mmole) were added dropwise to a solution of 0.728 g (2.0 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone in 10 ml of toluene as indicated sub letter (b). After 90 min. of heating, 0.57 ml (8.0 mmole) of dimethylsulfoxide (DMSO) were added to the reaction mixture which was then heated to reflux for 4 further hours. After extraction and distillation, there were isolated 0.310 g (76% yield) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[Cu](C#N)[C:12]#[N:13].N1C=CC=CC=1.N>CN(C=O)C.O>[Br:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=1)[C:12]#[N:13]
Reactant: N#C[Cu]C#N
Reactant: CCc1cc(Br)cc(Br)c1
Agent: N
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCc1cc(Br)cc(C#N)c1
Temperature: 150 °C

Procedure:
A mixture of 1,3-dibromo-5-ethylbenzene (2.7 g, 10.2 mmol), copper cyanide (0.916 g, 10.2 mmol), pyridine (1.65 mL, 20.5 mmol) in DMF (15 mL) was heated at 150° C. for 3 h. After cooling to r.t., the mixture was poured into a solution of H2O (30 mL) and ammonia (25% aq. Solution, 20 mL) and extracted with EtOAc. The combined organic layer was dried (MgSO4), filtered and concentrated in vacuo. The product was purified using flash chromatography on silica gel, gradient elution of 0-60% EtOAc in n-heptane. GCMS (CI) m/z 210 [M+1]+.
Reaction SMILES: [Cl-].[CH3:2]/[C:3](=[C:9](/[CH3:13])\[C:10]([O-:12])=[O:11])/[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:14][C:15]([CH3:22])([CH:19]([CH3:21])[CH3:20])[C:16]([NH2:18])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([O:6][C:4](=[O:5])/[C:3](/[CH3:2])=[C:9](\[CH3:13])/[C:10]([O-:12])=[O:11])[CH3:8].[NH2:18][C:16]([C:15]([NH-:14])([CH3:22])[CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)C(C)(N)C(N)=O
Agent: CCOC(=O)/C(C)=C(\C)C(=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(C)([NH-])C(N)=O

Procedure:
A solution of 13 g of monoethyl 2,3-dimethylfumarate chloride in 20 ml of methylene chloride was added dropwise, while stirring and cooling with ice, to a solution of 12 g of 2-amino-2,3-dimethyl-butyric acid amide and 12 ml of triethylamine in 80 ml of methylene chloride. The mixture was stirred for 2 hours at room temperature, the resulting solution was extracted with water, with 2N hydrochloric acid and again with water, then dried and evaporated. The residue was triturated with diethyl ether, suction-filtered and recrystallized from a little ethanol. 8.0 g (41% of theory) of monoethyl-2,3-dimethylfumarate-N-(1-aminocarbonyl-1-methylisobutyl)-amide were obtained, m.p. 122°-125° C.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.CCCCCC.[CH2:19]([O:21][C:22]([CH:24]1[CH2:29][CH2:28][CH:27]([O:30][Si:31]([C:44]([CH3:47])([CH3:46])[CH3:45])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20].C(I)C=C>C1COCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:19]([O:21][C:22]([C:24]1([CH2:7][CH:5]=[CH2:6])[CH2:29][CH2:28][CH:27]([O:30][Si:31]([C:44]([CH3:45])([CH3:47])[CH3:46])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:26][CH2:25]1)=[O:23])[CH3:20]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: C=CCI
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
Diisopropylamine (3.14 g, 4.38 mL, 31 mmol) was dissolved in THF (100 mL) and cooled to −78° C. To this solution was added 2.5 M n-butyl lithium in hexane (12.4 mL, 31 mmol) and stirred for 15 min, warmed up to 0° C. and stirred for an additional min, then re-cooled to −78° C. 4-(tert-Butyl-diphenyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (10.5 g, 25.6 mmol) in THF (15 mL) was then added and the reaction mixture was allowed to stir at −78° C. for 1 h followed by the addition of a mixture of hexamethyl-phosphoramide (HMPA) (7 mL) and allyl iodide (5.59 g, 33.3.0 mmol). This mixture was stirred at −78° C. for 20 min. Then, the dry ice bath was removed and the stirring was continued to allow the reaction mixture to warm to room temperature over 1 h. The reaction mixture was poured into ice-water (100 mL) and ether (50 mL). The two layers were separated; the aqueous layer was extracted with ether (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to afford 11.4 g (99%) of the title compound.