Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:51]=[CH:50][CH:49]=[CH:48][C:4]=1[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[N:13](COCC[Si](C)(C)C)[CH:12]=2)=[N:7]1.FC(F)(F)C(O)=O.N>>[CH3:1][O:2][C:3]1[CH:51]=[CH:50][CH:49]=[CH:48][C:4]=1[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[NH:13][CH:12]=2)=[N:7]1
Reactant: COc1ccccc1Cn1ccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1Cn1ccc(-c2c[nH]c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)n1
Yield: 105 %

Procedure:
(S)-2-(1-((5-(1-(2-Methoxybenzyl)-1H-pyrazol-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (16 mg, 0.02 mmol) was treated with trifluoroacetic acid (500 μl, 6.49 mmol) and a solution of ammonia (7N in methanol, 500 μl, 3.50 mmol) according to the method described in Example 27 to obtain 12 mg (87% yield) of the title compound without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1F
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)Nc1ccc(F)c(C)c1

Procedure:
N-(4-Fluoro-3-methylphenyl)-2-methylacrylamide was prepared as described in Example 1a starting from 4-fluoro-3-methylaniline and methacryloyl chloride. 1H NMR (400 MHz, DMSO-d6): 1.94 (3H, s), 2.21 (3H, s), 5.50 (1H, s), 5.78 (1H, s), 7.05-7.10 (1H, m), 7.48-7.51 (1H, m), 7.57-7.59 (1H, m), 9.75 (1H, s).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[N:15]=[N+:16]([O-:24])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C(Cl)[Cl:29]>>[OH:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[N:15]=[N+:16]([O-:24])[C:17]3[CH:23]=[C:22]([Cl:29])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1
Reactant: ClCCl
Reactant: [O-][n+]1nc(Oc2ccc(OCc3ccccc3)cc2)nc2ccccc21
Solvent: O
Product: [O-][n+]1nc(Oc2ccc(O)cc2)nc2ccc(Cl)cc21
Reaction time: 0.67 h

Procedure:
A solution of 0.05 mole borontribromide in 100 cc methylene chloride is added, dropwise, to a well stirred cold (-62°) solution of 3-(4-benzyloxyphenoxy)-1,2,4-benzotriazine-1-oxide (0.05 mole) in 400 cc methylene chloride. When the addition is complete, the temperature of the reaction is allowed to rise slowly to room temperature. The reaction mixture is then poured into 1 liter of water and an additional 500 cc of methylene chloride is added. The mixture is stirred vigorously for 40 minutes and the insoluble solid is filtered.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH3:17])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[BH4-].[Na+]>CO>[CH2:16]([CH:3]([CH2:1][CH3:2])[CH:4]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=1)[OH:5])[CH3:17]
Reactant: CCC(CC)C(=O)c1ccc(NC(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)C(O)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-(2-ethylbutanoyl)phenyl)acetamide (730 mg, 3.13 mmol) in MeOH (20 mL) was cooled in an ice bath under N2 and treated with NaBH4 (148 mg, 3.91 mmol), added in one portion. The reaction vessel was removed from the ice bath and stirred overnight at RT. The reaction was concentrated and partitioned between DCM and half-saturated NaHCO3. The aqueous phase was extracted four times with DCM and the organic extracts were combined and dried over MgSO4, filtered and then concentrated. The crude product was purified by preparative TLC using 50% ethyl acetate in hexane as eluent to afford N-(4-(2-ethyl-1-hydroxybutyl)phenyl)acetamide as white solid. MS (ES+): m/z 236.24 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>>[O:8]1[C:4]2[CH:3]=[C:2]([C:18]3([OH:21])[CH2:19][CH2:20][C:15]4([O:14][CH2:13][CH2:12][O:11]4)[CH2:16][CH2:17]3)[CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7]1
Reactant: Brc1ccc2c(c1)OCC2
Reactant: O=C1CCC2(CC1)OCCO2
Product: OC1(c2ccc3c(c2)OCC3)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 6-bromo-2,3-dihydro-benzofuran (Milestone) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[CH2:6]1[O:10][C:9]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:8]=2[O:7]1>>[CH3:5][O:4][CH2:3][CH2:2][O:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][CH2:6][O:10][C:9]=2[CH:11]=1
Reactant: COCCBr
Reactant: Oc1ccc2c(c1)OCO2
Product: COCCOc1ccc2c(c1)OCO2

Procedure:
Starting from commercially available 1-bromo-2-methoxy-ethane and sesamol the title compound is obtained as colorless oil.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17]C)=[O:16])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([OH:17])=[O:16])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2cc(-c3ccccc3)on2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cc(-c3ccccc3)on2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture of methyl 3-(5-phenyl-3-isoxazolyl)benzoate (1.30 g), 1 M aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (20 ml) and methanol (10 ml) was stirred at 60° C. for 1 hr. After cooling, the reaction mixture was poured into water, and 1 M hydrochloric acid (10 ml) was added. The crystals were collected by filtration and recrystallized from tetrahydrofuran-hexane to give 3-(5-phenyl-3-isoxazolyl)benzoic acid (1.05 g, yield 85%) as colorless crystals. melting point: 250–251° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[CH2:6][N:5]([CH3:10])[CH2:4][CH2:3]1.C([Li])CCC.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](O)=[O:26])=[N:17]1>O1CCCC1.CCCCCC.CN(C)C=O>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([O:9][CH:7]2[CH2:6][N:5]([CH3:10])[CH2:4][CH2:3][N:2]([CH3:1])[CH2:8]2)=[O:26])=[N:17]1
Reactant: CN1CCN(C)CC(O)C1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CN1CCN(C)CC(OC(=O)c2n[nH]c3ccccc23)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 1,4-dimethy-6-hydroxy- hexahydro-1H-1,4-diazepine (1.9 g) in anhydrous tetrahydrofuran (10 ml), a solution of n-butyllithium in hexane (9.4 g) is added dropwise under nitrogen stream at 25° C., and the mixture is stirred for 30 minutes at the same temperature. To the reaction mixture is added dropwise, the reaction mixture prepared by the following method; to a solution of 1H-indazole-3-carboxylic acid (2.0 g) in anhydrous N,N-dimethylformamide (20 ml), N,N'-carbonyldiimidazole (2.0 g) is added at 25° C., and the mixture is heated at 80° C. for 4.5 hours and cooled to 25° C. The resulting reaction mixture is refluxed with stirring for 1 hour. Tetrahydrofuran is evaporated under reduced pressure, and the residue is diluted with water, extracted with diethyl ether. The organic layer is washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of chloroform-methanol (9:1). Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (2.4 g) as an oil. The free base is converted to 5/2 fumarate 1/4 ethanol of the title compound in a usual manner, m.p. 184-185° C. (recrystallized from ethanol).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[C:14]([NH:16][C@@H:17]([C:20](OC)=O)[CH2:18][OH:19])=O)C=CC=CC=1>CCO.CO.[Pd]>[CH2:10]1[C@@H:9]2[CH2:14][NH:16][C@H:17]([CH2:18][OH:19])[CH2:20][N:8]2[CH2:13][CH2:12][O:11]1
Reactant: COC(=O)[C@@H](CO)NC(=O)[C@H]1COCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: OC[C@@H]1CN2CCOC[C@@H]2CN1
Temperature: 50 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
Methyl N-{[(3R)-4-(phenylmethyl)-3-morpholinyl]carbonyl}-D-serinate (D48, 3.72 g, 11.55 mmol) was dissolved in EtOH (50 mL), treated with 10% Pd on C (450 mg) then placed under an atmosphere of hydrogen over the weekend. Left stirring for further 6 hours. Added 10% Pd on C (200 mg) and left under an atmosphere of hydrogen overnight. Catalyst removed by filtration through kieselguhr washed with acid, washing well with EtOH. Solvent removed under reduced pressure to afford a colourless oil. Oil dissolved in dry MeOH (15 mL) and heated at 50° C. overnight. Left heating for a further 3 hours before cooling to R.T. Solvent removed under reduced pressure. Residue triturated with DCM to afford the title compound as an off white solid in 35% yield over the 2 steps.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[C:26]([CH3:34])=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[Cl:24][C:25]1[C:26]([CH3:34])=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: Cc1c(Cl)cccc1C(=O)O
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Cl)c2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Chloro-2-methyl-benzoic acid. LC-MS (basic): tR=0.95 min; [M+H]+=480.0.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][CH:34](O)[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cccc(Br)c1)O2
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: Oc1ccc2c(c1)CCC(c1cccc(Br)c1)O2

Procedure:
2-(3-Bromophenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 700 mg of 2-(3-bromophenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 8.81 (s, 1H), 7.61 (m, 1H), 7.51 (m, 1H), 7.43 (m, 1H), 7.35 (m, 1H), 6.67-6.48 (m, 3H), 5.01 (m, 1H), 2.87 (m, 1H), 2.63 (m, 1H), 2.12 (m, 1H), 1.92 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[F:25][C:26]1[CH:27]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:31]=1[F:32]>>[F:25][C:26]1[CH:27]=[C:28]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[CH:29]=[C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:31]=1[F:32]
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ccc(COc2cc(B3OC(C)(C)C(C)(C)O3)cc(F)c2F)cc1
Product: COc1ccc(COc2cc(-c3nc(N4CCOCC4)c4sc(CN5CCN(C)CC5)cc4n3)cc(F)c2F)cc1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with yield 2-[3,4-difluoro-5-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in general procedure A. Purification on silica yielded 2-[3,4-difluoro-5-(4-methoxy-benzyloxy)-phenyl]-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-yl-thieno[3,2-d]pyrimidine. This was then reacted with trifluoroacetic acid in dichloromethane to yield the desired compound.
Reaction SMILES: [CH2:1]([C:8]1[C:31](=[O:32])[N:11]2[CH:12]=[C:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:14][C:15]([S:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[C:10]2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34]>ClCCl.CN(C)C1C=CN=CC=1>[C:33]([O:32][C:31]1[N:11]2[CH:12]=[C:13]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:14]=[C:15]([S:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10]2=[N:9][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:35])[CH3:34]
Reactant: COc1ccc(Sc2[nH]c(-c3ccccc3)cn3c(=O)c(Cc4ccccc4)nc2-3)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Sc2nc(-c3ccccc3)cn3c(OC(C)=O)c(Cc4ccccc4)nc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
To a solution of 231 (25 mg, 0.06 mmol) in 4 mL of dichloromethane, acetyl chloride (8 μL, 0.12 mmol) and 4-(dimethylamino)pyridine (DMAP) (5 mg, 0.03 mmol) were added, the resulting mixture was stirred at room temperature for 15 min. Then the solution was washed with water and the organic layer was dried over Na2SO4, filtered and the solvent removed under reduced pressure to obtain 18 mg (yield 66%) of 25a as a red oil. 1H-NMR (CDCl3): 2.10 (s, 3H), 3.88 (s, 3H), 4.20 (s, 2H), 7.00-7.02 (m, 2H), 7.22-7.33 (m, 8H), 7.61-7.64 (m, 4H), 7.68 (s, 1H). MS (ESI): m/z 482 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH:6]=[N:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[OH:14])[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.O1CCCC1.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>CCOCC>[CH3:27][N:28]([CH3:32])[C:29]([O:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:7]=[CH:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:30]
Reactant: CN(C)C(=O)Cl
Reactant: CCN(C=Nc1ccncc1O)CC
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(C=Nc1ccncc1OC(=O)N(C)C)CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.3 %

Procedure:
To a solution prepared from 4-[[(diethylamino)methylene]amino]-3-pyridinol (3.12 g), triethylamine (3.34 g) and tetrahydrofuran (50 mL) was added N,N-dimethylcarbamyl chloride (2.28 g) under nitrogen. The resulting mixture was stirred at ambient temperature for 6 hours, diluted with ether (50 mL) and filtered. The filtrate was concentrated under reduced pressure and the residue chromatographed on silica gel (elution with 10% methanol in dichloromethane) to give 3.00 g of solid. Recrystallization from ether/hexanes afforded 1.57 g of crystalline solid, m.p. 73°-74° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12]C)[NH:8][CH2:7][CH2:6]2.[BrH:14]>>[BrH:14].[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)NCC2
Agent: Br
Product: Oc1cc2c(cc1O)NCC2
Yield: 75 %

Procedure:
97.8 g of 5,6-dimethoxyindoline are dissolved in 400 ml of 47% hydrobromic acid and the solution is refluxed for four hours. The hydrobromic acid is evaporated under reduced pressure and the residue is taken up in 0.5 l of ethanol and treated with active charcoal under ethanol reflux for 30 minutes and the mixture is then filtered through celite. A volume of ethyl ether is then added progressively to the cooled filtrate. 94.8 g of 5,6-dihydroxyindoline hydrobromide are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][CH:9]=[C:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CC(=O)CSc1ccc(Cl)cc1
Solvent: O
Product: Cc1csc2ccc(Cl)cc12
Temperature: 120 °C
Yield: 38.3 %

Procedure:
1-[(4-Chlorophenyl)thio]-2-propanone (50 g, 0.25 mol) was added to polyphosphoric acid (300 g) and the mixture was stirred as the temperature was gradually raised to 120° C. as an exotherm started. The mixture was stirred at 130° C. for 1 hour, diluted with water, extracted with ethyl ether and the organic phase was dried and concentrated. The residue was stirred in methanol (200 ml), filtered and the filtrate concentrated to give 17.5 g (40%) of 5-chloro-3-methylbenzo[b]thiophene: bp 120° C. (0.6 mm).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1>C(O)CCC.O>[CH2:11]([O:12][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([NH2:17])[N:3]=1)[CH2:16][CH2:15][CH3:14]
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Solvent: O
Solvent: CCCCO
Product: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1

Procedure:
The product from step (i) (40 g) was dissolved in 19% (w/w)-sodium butoxide in butanol (250 ml). The reaction mixture was stirred under reflux for 6 h. The resultant suspension was cooled to rt, diluted with water and extracted with diethyl ether. The combined organic phase was washed with water, dried and concentrated in vacuo. The subtitle compound was crystallized from diethyl ether/isohexane (1/1, 300 ml) and obtained by filtration. Yield 19 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]1[CH:9]=[C:8]([C:10](C)(C)[O:11][SiH2]C(C)(C)C)[CH:7]=[N:6]1.P([O-])([O-])([O-])=O>CC#N>[CH3:1][O:2][C:3](=[O:19])[CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[N:6]1
Reactant: COC(=O)Cn1cc(C(C)(C)O[SiH2]C(C)(C)C)cn1
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: COC(=O)Cn1cc(CO)cn1
Reaction time: 2 h
Yield: 71 %

Procedure:
[4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyrazol-1-yl]-acetic acid methyl ester (539 mg) was dissolved in CH3CN (8 mL) followed by the addition of aqueous HF solution (47-51%, 0.33 ml). Stirring was continued for 2 hours at r.t. The reaction mixture was poured into phosphate buffer solution (pH 7.0) and extracted with chloroform. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate) to give the title compound as a colorless oil (229 mg, 67%). MS (m/e)=171.2 [MH+].
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1([CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=3)[CH:12]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH2:6]1.[OH-].[Na+]>O1CCOCC1.CO>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[O:32][CH3:33])[CH2:25][CH:12]1[C:13]2[C:18](=[CH:17][C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[CH2:19][CH2:20][CH:11]1[C:5]1([CH2:4][C:3]([OH:36])=[O:2])[CH:6]=[CH:7][CH:8]=[CH:9][CH2:10]1
Reactant: COC(=O)CC1(C2CCc3cc(OC)c(OC)cc3C2Cc2ccc(OC)c(OC)c2)C=CC=CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCC2C2(CC(=O)O)C=CC=CC2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 105426.3 %

Procedure:
To a solution of 1-[(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl]-phenyl-acetic acid methyl ester (5.85 g, 0.011 mmol) in a mixture dioxane/MeOH (4/3) (160 ml) was added dropwise 2M NaOH(aq) (81 ml). The resulting mixture was stirred at RT for 20 h under nitrogen. The mixture was then concentrated in vacuo, combined with water and AcOEt. The aqueous phase was acidified until pH 1 with 2N HCl, extracted three times with with CH2Cl2, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give the titled product (5.55 g, 97%) as yellow-green crystals.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]1[CH2:26][O:25]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:24]([OH:25])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C3CO3)cccc2c1Nc1ccccc1C
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C(O)CN3CCOCC3)cccc2c1Nc1ccccc1C
Yield: 47.1 %

Procedure:
3-Butyryl-4-(2-methylphenylamino)-8-oxiranylquinoline (1.0 g, 2.89 mmol) and morpholine (1.0 g, 11.55 mmol) in dioxan (20 ml) were heated under reflux for 9 hours. The dioxan was evaporated and the residue dissolved in ethyl acetate, washed with brine, dried and evaporated to an oil which crystallised from ether. Recrystallisation from dichloromethane/ether gave 3-butyryl-4-(2-methylphenylamino)-8-(1-hydroxy-2-morpholinoethyl)quinoline (0.59 g, 47%), m.p. 135°-137°.
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[C:10]=1[Cl:17])[CH2:6]O)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:20])=O>>[CH2:1]([CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[C:10]=1[Cl:17])[CH2:6][Cl:20])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCC(CO)Cc1ccc(Cl)c(Cl)c1Cl
Product: CCCCC(CCl)Cc1ccc(Cl)c(Cl)c1Cl
Temperature: 140 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
332 g of (XX) were added dropwise to 148 g of thionyl chloride, and the mixture was stirred for 14 hours at room temperature and for 2 hours at 140° C. Distillation gave 278 g of (XXI) of boiling point 142°-145° C./0.1 mbar.
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+]>C(O)C>[N+:12]([CH:15]=[CH:6][C:5]1[S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[CH:4]=1)([O-:14])=[O:13]
Reactant: O=Cc1cc2ccccc2s1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, step 1, benzo[b]thiophene-2-carbaldehyde (2.1 g, 0.012 mol) in ethanol (100 mL) was reacted with nitro methane (0.7 mL, 0.012 mol) and 10N NaOH (0.51 g, 0.012 mol). The resulting mixture was stirred at 0° C. for 1 hr to afford 2.1 g of the product (84% yield).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:21])[CH:9]=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]([CH2:22][CH2:23][O:24]C(=O)C)[CH2:5]1)(=O)C.[OH-].[Na+]>CCO.O>[OH:24][CH2:23][CH2:22][CH:6]1[C:7]2[C:12](=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:17])([CH3:16])[CH3:18])[C:10]([CH3:20])=[CH:9][C:8]=2[CH3:21])[NH:4][CH2:5]1
Reactant: CC(=O)OCCC1CN(C(C)=O)c2c(NC(=O)C(C)(C)C)c(C)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCO
Temperature: 60 °C
Reaction time: 10 h
Yield: 51.6 %

Procedure:
N-[1-Acetyl-3-(2-acetoxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide (4.0 g) was dissolved in EtOH (40 ml) and a solution of NaOH (2.2 g) in water (10 ml) was added, which was followed by stirring at 60° C. for 10 hr. EtOH was evaporated under reduced pressure, and CHCl3 (100 ml) was added. After washing with water, the mixture was dried over anhydrous sodium sulfate, and CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=50/1-10/1) to give 1.6 g of N-[3-(2-hydroxyethyl)-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.