Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:32][CH2:33][NH2:34])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:32][CH2:33][NH:34][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCCCC1CN1CCCC1
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCCC2CN2CCCC2)c2ccccc21
Yield: 44 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(pyrrolidin-1-yl)methyl]-piperidin-1-yl]ethanamine in a yield of 44% of theory. Colourless crystals, m.p. 198° C. (from acetonitrile using fuller's earth).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[F:28])[NH:24][N:23]=[CH:22]3)=[O:17])=[CH:4][C:3]=1[N+:29]([O-])=O.Cl[Sn]Cl.O.[OH-].[Na+]>CCOC(C)=O>[NH2:29][C:3]1[CH:4]=[C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[F:28])[NH:24][N:23]=[CH:22]3)=[O:17])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(Cl)c([N+](=O)[O-])c2)CC(=O)N1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(Cl)c(N)c2)CC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
The product (222 mg, 0.5 mmol, 1.0 equiv.) from Example 76, Step 3 was dissolved in EtOAc (50 mL) and SnCl2 (380 mg, 2.0 mmol, 4 equiv.) and H2O (0.5 mL) were added. The mixture was refluxed for 3 h. After the reaction was cooled to room temperature, 2N NaOH was added and the mixture was stirred for 30 min. The biphasic solution was filtered through the Celite, and the phases were separated. The organic phase was washed twice with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give the title compound in 64% yield. MS (ES+) m/e 414 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[OH:4].C(=O)([O-])[O-].[K+].[K+].F[C:26]1[CH:40]=[CH:39][C:29]([C:30]([C:32]2[CH:37]=[CH:36][C:35](F)=[CH:34][CH:33]=2)=[O:31])=[CH:28][CH:27]=1.C1(C)C=CC=CC=1>CN(C)C(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[OH:4].[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])[C:29]1[CH:39]=[CH:40][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1cc(C(C)(C)c2ccc(O)cc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Polymerization was carried out similar to the P(BPZ-BNZPH) polymerization, except methylbisphenol-A (10.0000 g, 39.00 mmol), potassium carbonate (10.782 g, 78.00 mmol), 4,4′-difluorobenzophenone (8.5102 g, 39.00 mmol), toluene (50 g) and N,N-dimethylacetamide (85 g) were used. The yield was about 15.34 g. The number average molecular weight of the polymer was about 8.2 K.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1.Cl.[O:28]([CH2:35][CH2:36][CH2:37][NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:28]([CH2:35][CH2:36][CH2:37][NH:38][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCCCOc1ccccc1
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: Cl
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(NCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A flask containing 1-(4-bromophenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide (EXAMPLE C2, 100 mg, 0.25 mmol) and 3-phenoxypropylamine hydrochloride (54 mg, 0.29 mmol) was evacuated and refilled with N2 (2×). To this was added BINAP (112 mg, 0.18 mmol), Pd2 dba3 (55 mg, 0.06 mmol) and t-BuONa (68 mg, 0.7 mmol) in one portion as a mixture, with minimum exposure to air. The flask was again evacuated and refilled with N2 (3×). Degassed, anhydrous dioxane (2 mL) was added via syringe and the solution was stirred under N2 for 10 min at rt and then at 80° C. for 18 h. Later, the reaction was cooled to rt, filtered through Celite (using MeOH and CH2Cl2 to rinse the Celite), concentrated under reduced pressure and purified using the Waters mass-directed HPLC purification system to provide 1-{4-[(3-phenoxypropyl)amino]phenyl}-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide as a white solid. MS (ES+): m/z 478 (100) [MH+].
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]1[CH2:9][CH:8]([OH:10])[CH2:7][N:6]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])C.[BH4-].[Li+].Cl>O1CCCC1>[OH:10][CH:8]1[CH2:7][N:6]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C@@H:5]([CH2:4][OH:3])[CH2:9]1
Reactant: CCOC(=O)[C@H]1CC(O)CN1S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2CO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
To an ice-cold solution of 286.4 g (0.914 mole) of 4-hydroxy-(4-toluenesulfonyl)-D-proline ethyl ester (5) in 2.8 L of tetrahydrofuran was added 20 g (0.918 mole) of lithium borohydride in one portion. The mixture was stirred at 0° C. for 1 hour and then kept at a temperature below 25° C. overnight. The mixture was cooled to 0° C. and the pH adjusted to 3 with 6N hydrochloric acid (180 ml). The volume was reduced to 500 ml by rotary evaporation, and 1.5 L of water was added. The white precipitate was filtered, washed with cold water (500 ml) dried under reduce pressure to give 223.8 g (90%) of the title compound. M.P.=127° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][O:10][C:11]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:24])[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:24][C:16]([C:7]1[CH:8]=[C:1]([OH:2])[CH:3]=[CH:4][C:5]=1[OH:6])([CH2:15][CH2:14][CH2:13][C:11]([O:10][CH3:9])=[O:12])[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: Oc1ccc(O)cc1
Reactant: COC(=O)CCC=C(C)CCCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)CCCC(C)(CCCC(=O)OC)c1cc(O)ccc1O

Procedure:
5.5 Parts of hydroquinone, 22.8 parts of 1,7-di-methoxycarbonyl-4-methylhept-3-ene and 1.0 parts of p-toluene sulphonic acid, are heated on a steam-bath for 3 days. After dilution with ether the reaction mixture is washed with sodium bicarbonate solution, water, evaporated and distilled to give dimethyl 5-methyl-5-(2',5'-dihydroxyphenyl)-azelate, b0.1 260°-9° C. with the following percentage composition by weight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1/[CH:17]=[CH:18]/[CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH2:21]1.C(O)(C(F)(F)F)=O>>[NH2:26][CH:23]1[CH2:22][CH2:21][N:20]([CH2:19]/[CH:18]=[CH:17]/[C:4]2[C:5]3[C:6]4[CH:16]=[CH:15][S:14][C:7]=4[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH2:25][CH2:24]1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1/C=C/CN1CCC(NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1/C=C/CN1CCC(N)CC1
Yield: 47.8 %

Procedure:
Following General Procedure C, (E)-tert-butyl 1-[3-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)allyl]piperidin-4-ylcarbamate (40 mg, 0.085 mmol) was reacted with TFA (1 mL) to afford the desired product (15 mg, 86%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.94 (d, J=5.3 Hz, 1H), 7.86 (d, J=5.3 Hz, 1H), 7.34 (d, J=9.1 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 7.06 (d, J=16.0 Hz, 1H), 6.14-6.08 (m, 1H), 4.12 (d, J=7.1 Hz, 2H), 3.84 (br s, 2H), 3.55 (br s, 1H), 3.26 (br s, 3H), 2.38 (d, J=13.3 Hz, 2H), 2.12-2.07 (m, 2H), 1.35-1.31 (m, 1H), 0.96-0.90 (m, 1H); ESI MS m/z 370 [C20H23N3O2S+H]+; HPLC 95.6% (AUC), tR=6.78 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:16]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(O)c1

Procedure:
3-hydroxybenzoic acid (30.0 g, 0.22 mol), methanol (101 ml) and concentrated sulphuric acid (2.7 ml) were added together and heated under reflux for 4 h. The reaction mixture was allowed to cool and the methanol was removed. The crude product was dried in vacuo and used without further purification.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([C:14]3[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=3)=[C:10]([Cl:13])[CH:11]=2)[N:6]=[C:5]1[O:21][C@@H:22]1[CH2:26][O:25][C@@H:24]2[C@H:27]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:28][O:29][C@H:23]12)[CH:2]=[CH2:3].[N:38]1[NH:39][CH:40]=[C:41]2[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:43][C:42]=12.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CCOC(C)=O.CCCCCC.O1CCOCC1>[Si:31]([O:30][C@H:27]1[C@H:24]2[O:25][CH2:26][C@@H:22]([O:21][C:5]3[N:4]([CH2:1][CH:2]=[CH2:3])[C:12]4[C:7]([N:6]=3)=[N:8][C:9]([C:14]3[CH:15]=[CH:16][C:17]([N:39]5[CH:40]=[C:41]6[CH2:45][N:44]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:43][C:42]6=[N:38]5)=[CH:18][CH:19]=3)=[C:10]([Cl:13])[CH:11]=4)[C@H:23]2[O:29][CH2:28]1)([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: C=CCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O[Si](C)(C)C(C)(C)C)nc2nc(-c3ccc(-n4cc5c(n4)CN(C(=O)OC(C)(C)C)C5)cc3)c(Cl)cc21
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A vial was charged with [(3R,3aR,6R,6aS)-3-[1-allyl-5-(4-bromophenyl)-6-chloro-imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy-tert-butyl-dimethyl-silane (508.1 mg, 0.837 mmol), tert-butyl 4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate (213.1 mg, 1.018 mmol), tripotassium phosphate (603.1 mg, 2.84 mmol), and copper(I) iodide (33.2 mg, 0.174 mmol). The vial was evacuated and backfilled with nitrogen (3×). Trans-N,N′-dimethylcyclohexane-1,2-diamine (53 μl, 0.335 mmol) and dioxane (1.6 ml) were added to the vial to give a pale blue suspension that was heated at 100° C. with stirring for 24 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (100 ml) and water (100 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a light green residue. Flash chromatography of the residue utilizing an 40 g silica RediSep Rf® column and employing a 0-40% EtOAc/hexane gradient followed by 40% EtOAc/hexane afforded the desired product as a white foam. LC-MS: calculated for C37H47ClN6O6Si 734.3 observed m/e: 735.34 (M+H)+ (Rt 1.47/2 min)
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:14][CH2:15][C:16]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:26]([NH:1][C:2]1[C:3]([NH:14][CH2:15][C:16]([N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C(=O)CNc1nc(-c2ccccc2)ncc1N)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cnc(-c2ccccc2)nc1NCC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(5-amino-2-phenyl-4-pyrimidinylamino)-N-methyl-N-phenylacetamide (3.6 g) obtained in Example 124, acetic anhydride (10 ml) and pyridine (7 ml) is stirred at room temperature for four hours. To the reaction mixture is added chloroform, and the mixture is washed with 1N hydrochloric acid, then washed with a saturated aqueous sodium hydrogen carbonate solution. The chloroform layer is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from ethanol to give the desired compound (4.0 g), m.p. 200-201° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[C:12]([O:19][CH3:20])=[CH:11][C:9]=2[N:10]=1)=O)C.[BH4-].[Na+]>CO>[OH:3][CH2:4][C:6]1[S:7][C:8]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[C:12]([O:19][CH3:20])=[CH:11][C:9]=2[N:10]=1
Reactant: CCOC(=O)c1nc2cc(OC)c(OC)c(OC)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2nc(CO)sc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Ethoxycarbonyl-5,6,7-trimethoxybenzothiazole (1.04 g) was dissolved in methanol (30 mL), sodium borohydride (331 mg) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 2 hours. Sodium borohydride (100 mg) was additionally added to the reaction mixture to conduct stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:29])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]2[O:15][CH:16]([CH2:18][NH:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:17][C:13]=2[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37].C(N=C=NCCCN(C)C)C>ClCCl>[O:37]=[C:32]1[CH2:33][CH2:34][C:35](=[O:36])[N:31]1[O:24][C:23](=[O:25])[CH2:22][CH2:21][C:20]([NH:19][CH2:18][CH:16]1[O:15][C:14]2[CH:27]=[CH:28][C:11]([CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:29])=[CH:12][C:13]=2[O:17]1)=[O:26]
Reactant: CC(Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)O)O2)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(Cc1ccc2c(c1)OC(CNC(=O)CCC(=O)ON1C(=O)CCC1=O)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 32 mg (0.078 mmol) of 3G was added 4 mL of dichloromethane (distilled over CaH2) followed by 14 mg (0.12 mmol) of N-hydroxysuccinimide and 30 mg (0.152 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide. The reaction mixture was allowed to stir at room temperature under argon atmosphere 18 hours. The reaction mixture was diluted with additional 25 mL of dichloromethane and washed with 2×20 mL of water, 2×20 mL of saturated sodium bicarbonate and 1×20 mL of water. The organic layer was dried (Na2SO4) and concentrated to give 36 mg (0.071 mmol) of 3H as a colorless gum.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH3:40][C:41]([CH3:43])=O>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][N:35]4[CH:41]([CH3:43])[CH3:40])=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4)ncn3)cccc2s1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)C4CCCCN4C(C)C)ncn3)cccc2s1

Procedure:
N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-piperidine-2-carboxamide, Example 49(a), (0.40 g, 0.72 mmol) was reacted with acetone under the conditions of Example 3(d) to give the title compound. MS (ESI, pos. ion.) m/z: 599 (M+1). Mp: 260° C. (with dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:28][CH:27]=3)[S:30][C:31]=2[CH3:37])=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Reactant: Cc1sc(-c2ccc(C(C)(C)C)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(C)(C)C)cc3)sc2C)c(C)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (example 4 c]) was reacted with 2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethanol (example 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-(4-{2-[2-(4-tert-butyl-phenyl)-5-methyl-thiazol-4-yl]-ethoxy}-3-methyl-phenyl)-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][CH2:18]CS([O-])(=O)=O)(=[O:4])=[O:3].[I-].[K+].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[C:38]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[N:39][CH:40]=[N:41][CH:42]=1>C(#N)C.C(Cl)Cl>[CH3:35][O:36][C:37]1[C:38]([N:43]2[CH2:48][CH2:47][N:46]([CH2:18][CH2:17][CH2:16][C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:8]=4)[NH:12][CH:11]=3)[CH2:45][CH2:44]2)=[N:39][CH:40]=[N:41][CH:42]=1
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CCCCS(=O)(=O)[O-])c2c1
Reactant: COc1cncnc1N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(CNS(C)(=O)=O)cc23)CC1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
To a solution of crude 3-[5-[[(methylsulfonyl)amino]methyl]-1H-indol-3-yl]propylmethanesulfonate (15.1 mmol, 1.0 equiv.) in 200 mL of anhydrous acetonitrile were added 2.51 g (15.1 mmol, 1.0 equiv.) of potassium iodide, 3.15 mL of N,N-diisopropylethylamine and 3.23 g of 1-(5-methoxy-4-pyrimidinyl)piperazine. The mixture was heated to reflux for 48 hours. The reaction mixture was cooled to room temperature, filtered and concentrated. The residue was dissolved in 250 mL of chloroform, washed with 50 mL portions of 10% aqueous potassium carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield an oil. Chromatography on silica gel using 7.5% methanol in methylene chloride containing 0.75% concentrated aqueous ammonium hydroxide gave 3.93 g (57%) of 4-(5-methoxy-4-pyrimidinyl)-1-[[5-[[(methylsulfonyl)amino]methyl]-1H-indol-3-yl]propyl]piperazine. The hydrochloride was prepared by addition of 3N ethanolic HCl to an ethanolic solution of the base. Recrystallization from ethanol followed by drying in vacuo at 65° C. gave 0.268 g (53%) of the hydrochloride ethanolate: C22H30N6O3S/2.4 HCl/0.4 C2H6O, m.p. 204°-206° C. Elemental analysis calculated C., 48.51; H, 6.21; N, 14.89; found: C., 48.59; H, 6.21; N, 14.95.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][OH:8])[N:3]=1.[CH3:9][C:10](=O)[CH2:11][C:12](=O)[CH3:13]>C(O)(=O)C>[CH3:9][C:10]1[CH:11]=[C:12]([CH3:13])[N:6]2[N:5]=[C:4]([CH2:7][OH:8])[N:3]=[C:2]2[N:1]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1nc(CO)n[nH]1
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (9.5 g, 50 mmol) from step 6 above in acetic acid (200 mL) was added 2,4-pentanedione (5.13 mL, 50 mmol). The mixture was heated to reflux for 4 hours, and then cooled to room temperature. The product was isolated by removing the solvent by rotary evaporation (8.5 g, 95% yield). MS (ESI): 179 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(N(CC)C(C)C)(C)C.[O:21]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[O:24][CH2:23][CH2:22]1>C(#N)C>[O:21]1[C:25]2([CH2:30][CH2:29][N:28]([C:7]3[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=3[F:1])[CH2:27][CH2:26]2)[O:24][CH2:23][CH2:22]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)c(F)c1

Procedure:
3,4-Difluoronitrobenzene (15.53 g, 0.098 M) was dissolved in acetonitrile (150 ml), and treated with N,N-diisopropylethylamine (31.5 g, 0.244 M) and 1,4-dioxa-8-aza-spiro[4,5]decane (15.36 g, 0.107 M). The mixture was stirred and heated to reflux for 18 hours. After cooling, product precipitated as a yellow solid, and was filtered off (16.1 g); further product could be obtained by concentrating the residues (8.43 g).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[NH2:6][C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>N1C=CC=CC=1>[S:1]([NH:6][C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:4])(=[O:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1NS(C)(=O)=O
Yield: 24.2 %

Procedure:
A solution of mesyl chloride (0.95 g) in pyridine (3 ml) was added to a solution of ethyl 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate (2.3 g) in pyridine (10 ml), and the mixture was stirred for an hour. The reaction mixture was poured into water (100 ml) and extracted with diethyl ether (80 ml×2). The extract was washed with 5% hydrochloric acid (50 ml×2) and saline, dried over magnesium sulfate and then evaporated in vacuo. The oily residue (2.5 g) was crystallized by treating with ethanol and the resultant solid substance was recrystallized from ethanol to give ethyl 2-[2-mesylamino-3-(2-chlorophenoxy)phenyl]acetate (0.7 g). mp 145°-149° C.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[K+]>[Pd].O>[C:4]1([CH2:3][CH2:2][CH:1]=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=CCCc1ccccc1

Procedure:
hydrogenating cinnamaldehyde using a Pd-containing catalyst, said hydrogenation being carried out in the presence of potassium acetate, and in the presence of 1-wt. % water, and said hydrogenation being carried out in the absence of a solvent, whereby 3-phenylpropanal is obtained;