Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH2:21])[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].[Cl:23][CH:24]([Cl:39])[C:25]([O:27][N:28]=[C:29]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:30](Cl)=[O:31])=[O:26]>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:20]([NH:21][C:30](=[O:31])[C:29](=[N:28][O:27][C:25](=[O:26])[CH:24]([Cl:39])[Cl:23])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:19](=[O:22])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=NOC(=O)C(Cl)Cl)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)C(Cl)Cl)c3ccccc3)[C@H]2SC1
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of t-butyl 3-acetoxymethyl-7β-aminoceph-3-em-4-carboxylate (3.28 g) in ethyl acetate (25 ml.) was added a solution of 2-dichloroacetoxyimino-2-phenylacetyl chloride (syn-isomer) in ethyl acetate (25 ml.) dropwise with stirring. The solution became warm and a precipitate formed. After two hours, the solution was filtered, washed successively with 2 N-hydrochloric acid, water, and saturated sodium bicarbonate solution, dried, and evaporated to give a yellow foam which solidified on standing, and was triturated with petroleum spirit giving t-butyl 3-acetoxymethyl-7β-(2-dichloroacetoxyimino-2-phenylacetamido)-ceph-3-em-4-carboxylate (4.0 g; 70%), νmax. (CHBr3) 3420 (NH), 1796 (β-lactam), 1730 and 1230 (acetate), 1700 and 1512 cm-1 (CONH), τ (DMSO-d6) values include 2.1-2.5 (multiplet; aromatic protons), 2.98 (singlet; CHCl2), 7.6 (singlet; CH3CO), 8.5 (singlet; t-butyl ester).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[CH:16][NH:1][C:2]1[O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10](=[O:12])[CH:11]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc(=O)c2ccccc2o1
Product: CCOC(=O)C(=CNc1cc(=O)c2ccccc2o1)C(=O)OCC
Temperature: 130 °C
Yield: 90.7 %

Procedure:
A mixture of 2-aminochromone (3.22 g, 0.02 mole) and diethyl ethoxymethylenemalonate (8.64 g, 0.04 mole) is heated at 130° C. under nitrogen until an homogeneous solution forms (16 hrs.). The reaction mixture is cooled. The product, which precipitated, is filtered off and washed with hexane. Recrystallization from ethylacetate gives pale yellow crystals (6.01 g, 91%), mp 138°-140° C.
Reaction SMILES: [C:1]([O:16][CH2:17][CH:18]1[O:20][CH2:19]1)(=[O:15])[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[O:7])=[CH:4][CH:3]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>COCCOC>[OH:12][CH:10]([CH2:11][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[CH2:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])=[O:15])=[CH:14][CH:13]=1
Reactant: CCNCC
Reactant: O=C(OCC1CO1)c1ccc(C(=O)OCC2CO2)cc1
Solvent: COCCOC
Product: CCN(CC)CC(O)COC(=O)c1ccc(C(=O)OCC(O)CN(CC)CC)cc1
Temperature: 60 °C

Procedure:
Diglycidyl terephthalate (145 parts, 1.0 epoxy equivalent) was dissolved in 1,2-dimethoxyethane (145 parts). Diethyl amine (73 parts, 1 mol.) was added at room temperature. The mixture was heated at 60° C. for 20 hours and part of the solvent (75 parts) was stripped off in vacuo. The product, a light-brown viscous solution, had a solids content of 4.45 meq./g theory: 4.59). 2-hydroxy-3-diethylaminiopropyl groups per molecule: 2; molecular weight: 436 (calculated).
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([F:13])[C:7]([OH:12])=[C:8]([CH:11]=1)C=O.OO>S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:3][C:4]1[CH:11]=[C:8]([OH:1])[C:7]([OH:12])=[C:6]([F:13])[CH:5]=1
Reactant: O=Cc1cc(Br)cc(F)c1O
Reactant: [OH-]
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Product: Oc1cc(Br)cc(F)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a 1 N aqueous solution of sodium hydroxide (230 mL, 0.23 mol), 5-bromo-3-fluoro-2-hydroxybenzaldehyde (45.0 g, 0.21 mol) was added at room temperature, and a 6% hydrogen peroxide solution (225 mL) was added dropwise over five minutes at room temperature. After the reaction mixture was stirred at room temperature for two hours, a saturated aqueous solution of sodium thiosulfate (150 mL) was added thereto at room temperature. The mixture was extracted three times with ethyl acetate (450 mL), the organic layer was washed sequentially with a 1 N aqueous solution of hydrochloric acid (150 mL) and saturated saline, dried over anhydrous magnesium sulfate, and filtered through silica gel. The solvent was distilled off from the resultant filtrate under reduced pressure to give 39.0 g of the title compound (yield: 92%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[C:22]4[CH3:28])[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(#N)C>[CH2:45]([N:24]1[C:25]2[C:21](=[CH:20][C:19]([C:17]3[S:18][C:14]4[C:13]([C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)=[C:12]([C@H:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:30]([CH3:31])=[CH:29][C:15]=4[N:16]=3)=[CH:27][CH:26]=2)[C:22]([CH3:28])=[N:23]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4[nH]nc(C)c4c3)sc2c1-c1ccc(Cl)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(C)nn4Cc3ccccc3)sc2c1-c1ccc(Cl)cc1
Temperature: 75 °C

Procedure:
To a stirring solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-methyl-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetate (219 mg, 0.4 mmol) in ACN (5 mL) was added K2CO3 (166 mg, 1.2 mmol) and benzyl bromide (71 μL, 0.6 mmol). The reaction was then heated to 75° C. for 27 hours. After cooling to room temperature, the solids were filtered off, the crude reaction was concentrated and purified by column chromatography (gradient 0 to 20% EtOAc in hexanes) to give (S)-ethyl 2-(2-(1-benzyl-3-methyl-1H-indazol-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.05 (d, J=8.9 Hz, 1H), 7.92 (s, 1H), 7.60-7.45 (m, 4H), 7.35-7.27 (m, 4H), 7.22-7.18 (m, 2H), 5.54 (s, 2H), 5.16 (s, 1H), 4.21 (dtt, J=10.9, 7.4, 3.7 Hz, 2H), 2.63 (s, 3H), 2.60 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 0.98 (s, 9H).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)C=O.[OH:15][C:16]1C=CC(C=O)=CC=1>>[CH3:14][O:13][CH2:12][O:11][C:6]1[CH:7]=[CH:10][C:3]([CH:16]=[O:15])=[CH:4][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCOc1ccc(OC)cc1C=O
Product: COCOc1ccc(C=O)cc1

Procedure:
4-methoxymethoxybenzaldehyde (F3) was prepared in a similar manner for the preparation of 5-methoxy-2-methoxymethoxybenzaldehyde (F1) by using 4-hydroxybenzaldehyde (4.48 g, 40 mmol) instead of 2-hydroxy-5-methoxybenzaldehyde in 96% (6.40 g): 1H-NMR (500 MHz, CDCl3) δ3.53 (s, 1H), 5.24 (s, 2H), 7.17 (d, 1H, J=9.0 Hz), 7.35 (d, 1H, J=9.0 Hz), 10.52 (s, 1H).
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([Mg:22][Cl:23])CCCCCCC>>[CH2:1]([Mg:22][Cl:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCCl
Reactant: CCCCCCCC[Mg]Cl
Product: CCCCCCCCCCCC[Mg]Cl
Yield: 92.5 %

Procedure:
The compound n-C12H25MgCl was prepared from Mg and n-C12H25Cl by operating according to the modalities described in Example 1(a) for the compound n-C8H17MgCl.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]4[C:22](=[O:23])[C:21]5=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]5[C:19]4=[O:28])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:29]=1.[BH4-].[Na+].CCCCCCC.CCOC(C)=O>CCO.ClCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]4[CH:22]([OH:23])[C:21]5[C:20](=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:19]4=[O:28])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(c2csc3cc(F)ccc23)CC1
Agent: ClCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCCCCCC
Product: O=C1c2ccccc2C(O)N1CCN1CCN(c2csc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of N-[2-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]-ethyl]phthalimide (2.7 g, 6.6 mmol) in a mixture of 200 ml absolute EtOH and 50 ml CH2 Cl2 under N2 was added Sodium Borohydride (0.56 g, 14.8 mmol) in one portion. The mixture was stirred at room temperature for 15 minutes, during which time the solids dissolved. At the end of 15 minutes, TLC [silica, 1:1 heptane:EtOAc] showed no starting material remained and a major, lower Rf spot had appeared.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1([OH:16])[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)CCC.FC(F)(F)C(O)=O.[NH2:25][NH2:26]>C(Cl)Cl.CO>[OH:16][C:8]1([CH2:7][C:6]([NH:25][NH2:26])=[O:5])[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1
Reactant: CCCCOC(=O)CC1(O)CN2CCC1CC2
Reactant: NN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: NNC(=O)CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.5 g of the compound of step (a) in 15 ml of methylene chloride was added trifluoroacetic acid (39 ml) and the mixture was stirred at ambient temperature for three hours. The mixture was then concentrated in vacuo. The residue was dissolved in methanol (30 ml) and 18M H2SO4 (3 ml) was added and the mixture was stirred overnight. The mixture was then poured into a solution of sodium carbonate in water, extracted three times with chloroform, dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid. The solid was dissolved in methanol (10 ml) and hydrazine (2 ml) was added to this solution and the mixture was heated to reflux for one hour. The mixture was then concentrated in vacuo. The resulting solid was suspended in toluene (50 ml) and heated to reflux in an apparatus equipped with a Dean-Stark trap for two hours. The reaction mixture was then allowed to cool, and the product was filtered off to give 1.82 g of the subtitle compound as a tan solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]([OH:18])[CH:12]([CH3:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][C:7]=1[OH:8].[Br:19]Br>C(O)(=O)C>[Br:19][C:5]1[CH:6]=[C:7]([OH:8])[C:2]([OH:1])=[CH:3][C:4]=1[CH2:9][CH2:10][CH:11]([OH:18])[CH:12]([CH3:17])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: BrBr
Reactant: CCCCC(C)C(O)CCc1ccc(O)c(O)c1
Solvent: CC(=O)O
Product: CCCCC(C)C(O)CCc1cc(O)c(O)cc1Br
Yield: 76.2 %

Procedure:
To a solution of 0.5 g of 1-(3,4-dihydroxyphenyl)-4-methyl-3-octanol obtained in Example 1 in 20 ml of acetic acid was added dropwise a mixture of 0.37 g of bromine and 2 ml of acetic acid and after the color of bromine disappeared, the solvent was distilled off under reduced pressure. The residue thus formed was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was applied to silica gel column chromatography and eluted with a mixture of toluene and ethyl acetate (2:1) to provide 0.5 g of 1-(2-bromo-4,5-dihydroxyphenyl)-4-methyl-3-octanol.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][O:21][C:20]3=[O:25])[CH2:13][CH2:12]2)[N:2]=1.[CH3:26][NH2:27]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([N:11]2[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][NH:19][C:20](=[O:25])[O:21][CH2:22][C:23]([NH:27][CH3:26])=[O:24])[CH2:15][CH2:16]2)[N:2]=1
Reactant: O=C1COC(=O)N1CCC1CCN(c2cc3ccccc3cn2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCC1CCN(c2cc3ccccc3cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.5). Starting with 0.24 g (0.71 mmol) of 3-{2-[1-(3-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 11.3, and 1.8 ml (3.53 mmol) of a solution (2M) of methylamine in tetrahydrofuran, and after chromatography on silica gel, eluting with a 98/2 and then 96/4 mixture of dichloromethane and methanol, followed by crystallization from diisopropyl ether, 0.16 g of pure product is obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1.COC(=O)CN.[CH2:27]([N:29](CC)[CH2:30]C)C>CN(C=O)C>[CH3:27][N:29]([CH3:30])[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([I:20])[CH:15]=2)[N:3]=1
Reactant: CCN(CC)CC
Reactant: Cn1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Agent: COC(=O)CN
Solvent: CN(C)C=O
Product: CN(C)c1nc(NCc2cccc(I)c2)c2ncn(C)c2n1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
A mixture of compound 6 (40 mg, 0.1 mmol), glycine methyl ester (310 mg, 2.47 mmol), and triethylamine (0.7 mL, 5.0 mmol) in DMF (2 mL) was heated for 22 h at room temperature. After cooling, the mixture was evaporated to dryness and purified on a silica gel column (chloroform-methanol, 20:1) to give compound 12 (25 mg, 53.5%) as a colorless solid. 1H NMR (DMSO-d6) δ 3.06 (s, 6 H, N(CH3)2), 3.58 (s, 3 H, 9-CH3), 4.55 (br s, 2 H, CH2), 7.10 (pseudo t, J=8.0 and 7.6 Hz, 1 H, H-16), 7.38 (d, J=7.7 Hz, 1 H, H-17), 7.56 (d, J=8.0 Hz, 1 H, H-15), 7.70 (s, 1 H, H-13), 7.77 (s, 1 H, H-8), 7.92 (br s, 1 H, exchangeable with D2O, NH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([O:20][CH3:21])[NH:17][N:16]=2)[C:11]([F:22])=[C:10](Cl)[N:9]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([O:20][CH3:21])[NH:17][N:16]=2)[C:11]([F:22])=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: COc1cc(Nc2nc(Cl)nc(Cl)c2F)n[nH]1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(Nc2nc(Cl)nc(N3CCOCC3)c2F)n[nH]1
Temperature: 90 °C

Procedure:
To a solution of 2,4,6-trichloro-5-fluoropyrimidine (2.01 g) in absolute ethanol (50 mL) was added DIEPA (4.4 mL) and 5-methoxy-1H-pyrazol-3-amine (2.24 g). The resulting solution was stirred at room temperature for over night. The solvent was removed by reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound 2,6-dichloro-5-fluoro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine as solid (0.776 g). m/z 278. A mixture of morpholine (0.256 mL), 2,6-dichloro-5-fluoro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (776 mg) and DIPEA (0.742 ml) in n-butanol (14.0 ml) was heated at 90° C. for 5 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (310 mg). 1H NMR 9.80 (s, 1H) 5.66 (s, 1H) 3.77 (s, 3H) 3.64-3.71 (m, 4H) 3.53-3.64 (m, 4H); m/z 329.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>C(=S)=S>[C:19]([CH2:18][CH2:17][C:16]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:2][CH:3]=1)=[O:22])([OH:21])=[O:20]
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)Cc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 18 g. of methyl phenylacetate, 26 g. of aluminum chloride and 150 ml. of carbon disulfide, 20 g. of succinic anhydride are added. The reaction mixture is allowed to stand for two hours at 35° C; then it is added to a liter of ice water and extracted with methylene chloride. The extracts are combined, washed, dried, and evaporated to give methyl p-(3'-carboxy-1'-oxopropyl)-phenylacetate. This derivative is reduced with sodium borohydride and dehydroxylated with palladium charcoal catalyst by the procedures described in Part A of Example 2 to afford methyl p-(3'-carboxypropyl)-phenylacetate. This derivative is refluxed in 50 ml. of thionyl chloride for three hours and then it is evaporated. The residue, containing methyl p-(3'-chlorocrabonylpropyl)-phenylacetate, is taken up in 175 ml. of benzene containing 40 g. of aluminum chloride. The resulting mixture is stirred for two hours at 20° C; then it is added to a liter of ice and water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, and evaporated to give 7-(methoxycarbonylmethyl)-1-tetralone.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][NH:18]C(=O)OCC)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+]>CC(O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)NCCCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1ccc2[nH]c3c(c2c1)CN(CCCN)CC3
Yield: 45.7 %

Procedure:
A mixture of intermediate (10) (0.063 mol) and KOH (35 g) in 2-propanol (300 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was stirred in water and this mixture was extracted with methyl isobutyl ketone. The separated organic layer was dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 85/15). The pure fractions were collected and the solvent was evaporated, yielding 7 g (46%) of 1,3,4,5-tetrahydro-8-methyl-2H-pyrido[4,3-b]indole-2-propanamine (intermediate 11).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[C:9]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:10]=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>CC(C)=O.O>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6](=[O:26])[C:7]3[CH:8]=[C:9]([C:16]4[NH:20][N:19]=[N:18][N:17]=4)[CH:10]=[CH:11][C:12]=3[CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc2c(c1)Cc1ccc(-c3nnn[nH]3)cc1S2
Solvent: CC(C)=O
Solvent: O
Product: O=S1c2ccc(Cl)cc2Cc2ccc(-c3nnn[nH]3)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-Chloro-3(5-tetrazolyl)thioxanthene (100g.) was suspended in a mixture of acetone (40 ml.) and water (10 ml.) and 85% m-chloroperoxybenzoic acid (0.61g.) was added in portions. After 1.5 hr. stirring at 25° C. the mixture was diluted with water and allowed to stand overnight. The solid product was filtered off and dried, then boiled under refulx with ether (50 ml.), filtered, washed with ether, and dried, yielding 7-chloro-3(5-tetrazolyl)thioxanthene-10-oxide which had no defined melting point.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)[CH:16]=[CH:15]2)[CH2:4][CH2:5][OH:6])[CH3:2]>CO.[Pd]>[CH2:1]([N:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1)[CH:16]=[CH:15]2)[CH2:4][CH2:5][OH:6])[CH3:2]
Reactant: C#Cc1ccc(-n2ccc3cc(C#CCCCN(CC)CCO)ccc32)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(-n2ccc3cc(CCCCCN(CC)CCO)ccc32)cc1
Yield: 13.2 %

Procedure:
60 mg (0.16 mmol) 2-(Ethyl-{5-[1-(4-ethynyl-phenyl)-1H-indol-5-yl]-pent-4-ynyl}-amino)-ethanol in 10 ml MeOH were hydrogenated in the presence of 20 mg Pd/C, filtered and concentrated. Purification by column chromatography on silica gel with CH2Cl2/MeOH 9:1 yielded 8.0 mg 2-(Ethyl-{5-[1-(4-ethyl-phenyl)-1H-indol-5-yl]-pentyl}-amino)-ethanol as colorless oil, MS: 379 (MH+).
Reaction SMILES: FC(F)(F)[C:3]([N:5](C)[CH2:6][C:7]1([CH2:11][N:12]2[CH:16]=[C:15]([NH:17][C:18]3[N:23]=[C:22]4[N:24]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([N:34]6[CH2:39][CH2:38][O:37][CH2:36][CH2:35]6)[CH:29]=5)[N:25]=[CH:26][C:21]4=[CH:20][N:19]=3)[CH:14]=[N:13]2)[CH2:10][O:9][CH2:8]1)=O.C([O-])([O-])=O.[K+].[K+]>CO.O.CCOC(C)=O>[CH3:3][NH:5][CH2:6][C:7]1([CH2:11][N:12]2[CH:16]=[C:15]([NH:17][C:18]3[N:23]=[C:22]4[N:24]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[C:30]([N:34]6[CH2:39][CH2:38][O:37][CH2:36][CH2:35]6)[CH:29]=5)[N:25]=[CH:26][C:21]4=[CH:20][N:19]=3)[CH:14]=[N:13]2)[CH2:8][O:9][CH2:10]1
Reactant: CN(CC1(Cn2cc(Nc3ncc4cnn(Cc5cccc(N6CCOCC6)c5)c4n3)cn2)COC1)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CNCC1(Cn2cc(Nc3ncc4cnn(Cc5cccc(N6CCOCC6)c5)c4n3)cn2)COC1
Temperature: 55 °C
Yield: 10.9 %

Procedure:
2,2,2-trifluoro-N-methyl-N-((3-((4-((1-(3-morpholinobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1H-pyrazol-1-yl)methyl)oxetan-3-yl)methyl)acetamide (22 mg, 37.5 μmol) was dissolved in MeOH (1 mL) in a small vial. A solution of K2CO3 (26 mg, 187 μmol) in H2O (60 μL) was added to the solution, and the closed vial was heated at 55° C. for 1.5 h. The mixture was then diluted with EtOAc (7 mL) and washed with H2O (5 ml). The aqueous was extracted with a mixture of CHCl3/IPA=2:1 (3 mL×2). The organics were dried on Na2SO4, filtered and the solvent evaporated. The crude (22 mg) was purified by prep HPLC to give the title compound (2 mg). 1H NMR (d6-Acetone): δ 8.93 (s, 1H), 8.85 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.71 (s, 1H), 7.17 (t, 1H), 7.05 (s, 1H), 6.85 (dd, J=8.0, 2.2 Hz, 1H), 6.80 (d, J=7.4 Hz, 1H), 5.52 (s, 2H), 4.59 (d, J=6.1 Hz, 2H), 4.50 (s, 2H), 4.34 (d, J=6.1 Hz, 2H), 3.72 (t, 4H), 3.06 (m, 4H), 2.52 (s, 2H), 2.38 (s, 3H); LC-MS method B, (ES+) 490.2, RT=5.08 min.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:14])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.[Br:15]Br>Cl>[Br:15][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][C:5]2=[O:14])=[CH:9][CH:10]=1
Reactant: O=C1CCc2ccccc21
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2ccc(Br)cc21
Temperature: 80 °C
Yield: 19 %

Procedure:
To a 3-neck 250 mL round bottom flask equipped with a mechanical stirrer and charged with anhydrous aluminum chloride (16.6 gm, 0.125 mole) was added indanone (6.6 gm, 0.05 mole) in-two portions over 3 minutes. The reaction mixture was stirred for 10 minutes before bromine (9.7 g, 0.06 mole) was added dropwise over 10 minutes. The reaction mixture was heated to 80° C. for 5 minutes. The resulting mixture was poured into a mixture of ice (100 g) and concentrated HCl (20 mL). The resulting mixture was extracted with ether. The ether layer was separated, washed with water, dried (Na2SO4), filtered and concentrated. The crude material was purified by flash chromatography over silica gel eluting with 15% ether/hexanes to afford 6-Bromo-indan-1-one(2.0g, 19%). 1HNMR(CDCl3) δ 7.81 (d, 1H, J=1.76 Hz),7.62 (dd, 1H, J=8.36, 2.20 Hz), 7.30 (d, 1H, J=8.30 Hz), 3.03 (t, 2H, J=6.16 Hz), 2.65 (t, 2H, J=6.20 Hz). HPLC Rt=3.09 min.