Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].C(OCC)(=O)C.CO.[N:35]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:42][CH2:41][CH2:40][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:5])[CH3:2]
Reactant: NCCN1CCCC1
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CCCNCCN2CCCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Yield: 63.5 %

Procedure:
5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (8.462 g, 21.75 mmol) was dissolved in 2-pyrrolidin-1-yl-ethylamine (6.3 ml, 49.79) under stirring, the resulting solution was stirred at room temperature overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ethyl acetate (200 ml) and a little methanol until a clear solution was obtained. The mixture was washed with water (30 ml×3), saturated brine (40 ml×2) and concentrated under reduced pressure to obtain light brown oil. The oil was purified by silica gel column chromatography to obtain the title compound 3-methyl-5-[3-(2-pyrrolidin-1-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 28a (4.488 g, yield 63.5%) as a yellow oil.
Reaction SMILES: ClC(OC)=O.[O:6]([C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:17][C:18](O)=[O:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl.[CH3:32][NH:33][OH:34]>O1CCCC1.O.C(OCC)(=O)C>[O:6]([C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:17][C:18]([N:33]([CH3:32])[OH:34])=[O:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNO
Reactant: O=C(O)C=Cc1cccc(Oc2ccccc2)c1
Agent: COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(O)C(=O)C=Cc1cccc(Oc2ccccc2)c1
Reaction time: 2 h
Yield: 48 %

Procedure:
Methyl chloroformate (2.6 ml) was added dropwise to a solution of m-phenoxycinnamic acid (8 g) and triethylamine (18.5 g) in tetrahydrofuran (60 ml) at 0°. A solution of N-methylhydroxylamine hydrochloride (5.6 g) in water (5 ml) was added, and the mixture was stirred for 2 hours. Isolation with ethyl acetate afforded 3-phenoxy-N-methylcinnamohydroxamic acid (ca 4.3 g), m.pt. 124°-125° [from ethyl acetate/light petroleum (b.pt. 60°-80° C.)]. The m-Phenoxycinnamic acid used as starting material was prepared by condensation of m-phenoxybenzaldehyde with malonic acid in the presence of piperidine and pyridine.
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[CH2:15]([N:22]1[CH2:31][CH2:30][CH:29]2[C:24](=[N:25][C:26]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:27][C:28]2=O)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:15]([N:22]1[CH2:31][CH2:30][C:29]2[C:28]([Cl:12])=[N:27][C:26]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:25][C:24]=2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1N=C(CN2CCOCC2)N=C2CN(Cc3ccccc3)CCC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: ClCCCl
Product: Clc1nc(CN2CCOCC2)nc2c1CCN(Cc1ccccc1)C2
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
N,N-Dimethylaniline (1.2 g, 10 mmol) and phosphorus oxychloride (12.2 g, 80 mmol) were added to the solution of 7-benzyl-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4(4aH)-one (˜10 mmol) in 1,2-dichloroethane (30 mL, anhydrous) and were stirred in a preheated oil bath at 90° C. for 30 min. Reaction mixture was poured into ice, neutralized by solid sodium bicarbonate, extracted by ethyl acetate and dried over sodium sulfate. Solvent was removed in vacuo and brown oil residue was directly gone to next step.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][C:3]=2[O:2]1.[C:12]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[C:12]([NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[CH2:23][CH2:22]1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C(NC1CCN(Cc2ccc3c(c2)OCO3)CC1)c1ccccc1
Reaction time: 3 h

Procedure:
3,4-Methylenedioxybenzyl chloride (5.76 g.), 4-benzamido-piperidine (6.89 g.) and anhydrous potassium carbonate (7.00 g.) were stirred at room temperature for 5 hours in isopropanol (50 ml.). Additional isopropanol (100 ml.) was added and stirring continued for 3 hours. The mixture was then heated to the boiling point and filtered whilst hot. Filtration provided the title compound as the hemi-hydrate (7.94 g.), m.p. 179.5°-180.5° C. A second crop (1.23 g.) was obtained on concentration of the mother liquors. (Found: C, 69.2; H, 6.55; N, 8.2. C20H22N2O3. 1/2H2O requires C, 69.15; H, 6.7;N, 8.1%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]([CH2:20][N+:21]#[C-:22])([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[C-]#N.[Na+]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C@H:6]2[O:7][CH:22]=[N:21][C@@H:20]2[S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [C-]#N
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)[C@H]2N=CO[C@@H]2c2ccc(F)cc2)cc1

Procedure:
In a manner analogous to Preparation 1, 4-fluorobenzaldehyde (0.18 g, 1.47 mmol), tosylmethylisocyanide (0.27 g, 1.40 mmol) and NaCN (6.9 mg, 0.14 mmol) gave the desired compound as a tan solid. MS(ES+) m/z 320.6 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH:7]=[O:8])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=CCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To p-fluorophenethyl alcohol (4.5 g, 31.9 mmol) in 50 ml dichloromethane is added sodium acetate (0.5 g, 6.2 mmol) and pyridinium chlorochromate (10.4 g, 48.1 mmol) with stirring, at RT and under nitrogen. The reaction mixture is stirred for about 2 hours and then filtered through a column of Florisil using dichloromethane. The filtrate is dried, concentrated under vacuum and distilled (short path) to yield p-fluorophenylacetaldehyde (fraction at 90°, 3.5 mm Hq.).
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].[C:21](=O)([O:24]C)[O:22][CH3:23]>>[CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH:13]([C:21]([O:22][CH3:23])=[O:24])[C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)OC
Reactant: O=C1CCCc2ccc(C3CCCCC3)cc21
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1CCc2ccc(C3CCCCC3)cc2C1=O
Yield: 74 %

Procedure:
A mixture of 7-cyclohexyl-1-tetralone (9.4 g), sodium methoxide (8.9 g) and dimethyl carbonate (65 ml) was refluxed for 30 minutes in a nitrogen gas stream. After the reaction mixture was cooled, the resulting crystals were collected by filtration and suspended in ethyl acetate (250 ml), followed by addition of 6N HCl (50 ml). The organic layer was collected, while the aqueous layer was extracted with ethyl acetate. The extract was combined with the organic layer, successively washed with water and brine, and dried (MgSO4), after which the solvent was evaporated off, to yield methyl 7-cyclohexyl-1-tetralone-2-carboxylate (8.6 g, 74%) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:5](=[O:8])[NH:6][CH:7]=1.I[CH3:16]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([O:8][CH3:16])=[N:6][CH:7]=1
Reactant: CI
Reactant: COCCCOc1cc(Br)c[nH]c1=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COCCCOc1cc(Br)cnc1OC
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A mixture of 21 mmol 5-bromo-3-(3-methoxy-propoxy)-1H-pyridin-2-one, 14 mmol silver carbonate and 25 mmol iodomethane in 35 ml of benzene are stirred at 40-50° C. for 24 hours with exclusion of light. The mixture is cooled in an ice bath and the silver salts are removed by filtration. The filtrate is washed with 2% aqueous sodium hydrogencarbonate solution and with water (2×). The organic layer is dried over sodium sulphate, filtered and concentrated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and identified based on its Rf value.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[O:36]1[CH2:39][CH:38]([NH2:40])[CH2:37]1>C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:40][CH:38]2[CH2:39][O:36][CH2:37]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: NC1COC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc(C(=O)NC2COC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of 4-amino-3-methoxybenzoic acid (1 equiv) in DCM (0.1 M) was added HOBt (1.2 equiv), EDC (1.2 equiv) and DIEA (4 equiv). Oxetan-3-amine (1.2 equiv) was added and the reaction mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate. The solids were filtered off, the filtrate was concentrated and the product was purified by silica gel chromatography to afford the title compound (53% yield) as a yellow solid. MS (ESI) m/z 223.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH2:20])=[O:19])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](C(C)C)[C:6]=2[N:17]=1.[C:21]([O:25][C:26](=[O:32])[NH:27][C@@H:28]([CH3:31])[CH2:29]I)([CH3:24])([CH3:23])[CH3:22].BrC(C)C>C(O)=O>[NH2:1][C:2]1[C:3]([C:18]([NH2:20])=[O:19])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:29][C@@H:28]([NH:27][C:26](=[O:32])[O:25][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:31])[C:6]=2[N:17]=1
Reactant: C[C@@H](CI)NC(=O)OC(C)(C)C
Reactant: CC(C)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Solvent: O=CO
Solvent: CC(C)Br
Product: C[C@@H](Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=O)OC(C)(C)C

Procedure:
tert-butyl {(1S)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate (xvi-b) was prepared following the procedure detailed in the synthesis of 13 substituting tert-butyl[(1S)-2-iodo-1-methylethyl]carbamate for 2-bromopropane. HCOOH Standard Conditions. M+H=384. 1H NMR (300 MHz, d6-DMSO): δ 8.71 (s, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.57-7.49 (br s, 2H), 7.31 (dd, J=7.9, 7.3 Hz, 1H), 7.16 (dd, J=7.9, 7.3 Hz, 1H), 6.90 (br d, 1H), 4.27 (dd, J=6.1, 13.4 Hz, 1H), 4.14-3.95 (m, 2H), 1.18 (s, 9H), 1.05 (d, J=6.1 Hz, 3H)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=3)=[O:15])[C@H:11]([C:22]([F:25])([F:24])[F:23])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:27]12[CH2:33][C@H:30]([NH:31][CH2:32]1)[CH2:29][O:28]2>>[CH3:21][N:17]1[C:16]([C:14](=[O:15])[CH2:13][N:12]2[C:4]3=[N:3][C:2]([N:31]4[CH2:32][C@@H:27]5[CH2:33][C@H:30]4[CH2:29][O:28]5)=[CH:7][C:6](=[O:8])[N:5]3[CH2:9][CH2:10][C@H:11]2[C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[N:18]1
Reactant: Cn1nccc1C(=O)CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Product: Cn1nccc1C(=O)CN1c2nc(N3C[C@@H]4C[C@H]3CO4)cc(=O)n2CC[C@H]1C(F)(F)F

Procedure:
230 mg (0.61 mmol) of (8S)-2-chloro-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 107.90 mg (0.79 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in the reaction. After purification by chromatography on silica gel (eluent: 60/40 DCM/MeOH), 160 mg of (8S)-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:43]=[CH:42][C:8]2[N:9]([CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[C:17]([C:22]3[C:27]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)=[CH:26][CH:25]=[C:24]([OH:35])[CH:23]=3)[CH:16]=[CH:15]4)=[N:11][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].Br[CH2:47][CH2:48][O:49][CH3:50]>CN(C=O)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:27]2[C:22]([C:17]3[CH:16]=[CH:15][C:14]4[C:19](=[CH:20][CH:21]=[C:12]([C:10]5[N:9]([CH:36]6[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]6)[C:8]6[CH:42]=[CH:43][C:5]([C:3]([OH:2])=[O:4])=[CH:6][C:7]=6[N:11]=5)[CH:13]=4)[N:18]=3)=[CH:23][C:24]([O:35][CH2:47][CH2:48][O:49][CH3:50])=[CH:25][CH:26]=2)=[CH:29][CH:30]=1
Reactant: COCCBr
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(O)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reaction time: 8 h

Procedure:
Compound 475a (100 mg, 0.162 mmol) was dissolved in 2 mL of DMF and treated with 16.8 mg (0.7 mmol) of NaH for 30 min. 1-bromo-2-methoxy ethane (30.5 μL) was added and the mixture was agitated overnight. The next day the reaction mixture was evaporated to dryness, the oily residue dissolved in 3 mL methanol followed by the addition of 1 mL 1M NaOH. The mixture was refluxed for 2 h before it was evaporated to dryness. The product was purified by RP-HPLC for a yield of 19.3 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:15]C)=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([CH3:14])[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.Br.[OH-].[NH4+]>>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:4]3[CH2:1][CH:2]([CH3:3])[O:15][C:5]3=[CH:6][CH:7]=2)[N:12]=1
Reactant: COc1ccc2ccc(C)nc2c1C1CC1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ccc2ccc3c(c2n1)CC(C)O3
Yield: 78.3 %

Procedure:
A solution of 8-cyclopropyl-7-methoxy-2-methylquinoline (0.53 g, 2.5 mmol) in hydrobromic acid (48%; 9.9 mL, 2.5 mmol) was heated at reflux for 3 days. After cooling, the reaction mixture was neutralized to pH 8 by addition of ammonium hydroxide and extracted with dichloromethane (3×20 mL). The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by reverse phase chromatography on C18 (0-100% acetonitrile/water) afforded the title compound (0.39 g, 79%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]=2[CH:18]=1)([O-:7])=[O:6].C([O-])(O)=O.[Na+]>C(Cl)Cl>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([C:1](=[O:3])[CH3:2])[C:12]=2[CH:18]=1)([O-:7])=[O:6]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCCCc2ccc([N+](=O)[O-])cc21
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Acetyl chloride (1 g, 13 mmol) was added dropwise to a mixture of 8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.3 g, 6.8 mmol) and NaHCO3 (1 g, 12 mmol) in CH2Cl2 (50 mL). After stirring for 1 h, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography to give 1-(8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone as a yellow solid (1.3 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[K+].[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br.C(Br)C1C=CC=CC=1>CCOCC.O>[CH3:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Reactant: Cc1ccccc1CBr
Agent: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccccc1CNc1c2c(nc3ccccc13)CCCC2=O
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
9-amino-3,4-dihydroacridin-1(2H)-one (7.63 g) was suspended in 75 ml of dimethylsufoxide and 5 g of pulverized 85% potassium hydroxide was added. After 45 minutes a homogeneous solution was obtained to which was added 7.0 g of 2-methylbenzyl bromide. The reaction mixture was stirred for 30 minutes and then additional 2.0 g of the benzyl bromide was added. After 60 more minutes 300 ml of water and 30 ml of ether were added to the reaction. The precipitated product was filtered off and washed with additional ether, then flushed over a short magnesium silicate column with ethyl acetate. After evaporating the solvent, the product was again washed with cold ether to give 7.21 g of product.
Reaction SMILES: [C:1]1(S(O)(=O)=O)[C:10]2[C:5](=[CH:6][C:7](S(O)(=O)=O)=[CH:8][CH:9]=2)[CH:4]=[C:3](S(O)(=O)=O)[CH:2]=1.[N+]([O-])(O)=O>S(=O)(=O)(O)O>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)c1ccc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: c1ccc2ccccc2c1

Procedure:
For example, the industrially important 8-nitronaphthalene-1,3,6-trisulphonic acid (nitro-T-acid) is prepared by nitrating the isomer mixture of naphthalenetrisulphonic acids which is obtained in the trisulphonation of naphthalene with sulphuric acid and oleum and contains, as the main constituent, naphthalene-1,3,6-trisulphonic acid, with nitric acid in sulphuric acid, as the solvent (see F.I.A.T., Final Report 1016, pages 32-39). In the preparation process known from the literature, a procedure is followed in which the hot solution of the naphthalenetrisulphonic acids in sulphuric acid, which solution has a temperature of 150° to 155° C. and is obtained in the trisulphonation of naphthalene, is cooled to 100° C., diluted with water and cooled further to 80° C. The batch is then transferred to the nitration kettle, cooled in this kettle to 35° to 40° C. and nitrated with mixed acid (86% of nitric acid, 12% of sulphuric acid and 2% of water) at 35° to 40° C. in the course of about 10 hours.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:29]4[CH:30]=[CH:31][C:32]([N:35]5[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]5)=[N:33][CH:34]=4)=[C:14]([C:16](=[O:28])[NH:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:29]4[CH:34]=[N:33][C:32]([N:35]5[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]5)=[CH:31][CH:30]=4)=[C:14]([C:16]([NH:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[O:28])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(C(=O)Nc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2ccccc2n1)c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 20d (191 mg, 0.300 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (4 mL) was added. Once the solution was homogeneous, TFA (1 mL) was added dropwise. The mixture was stirred at rt for 4 h. The solvent was removed under reduced pressure. The residue was dissolved in DCM (10 mL) and then the solvent was removed under reduced pressure again. The residue was triturated with Et2O (20 mL), resulting in a yellow precipitate, which was isolated by filtration and washed with Et2O (2×10 mL). The residual solvent was removed under reduced pressure to afford the title compound 3. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.35 (s, 1H), 8.78 (br. s., 2H), 8.50 (d, J=2.2 Hz, 1H), 8.41 (d, J=9.0 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.21 (d, J=5.9 Hz, 1H), 7.92-8.00 (m, 2H), 7.89 (d, J=8.6 Hz, 1H), 7.70-7.79 (m, 1H), 7.48-7.58 (m, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.50 (d, J=5.9 Hz, 1H), 4.04-4.16 (m, 4H), 3.80-3.91 (m, 8H), 3.20-3.29 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H29N9O2: 536.3 (M+H). Found: 536.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19](OCC1C=CC=CC=1)=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH:19]=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccc2cc(OCc3ccccc3)ccc2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc2cc(OCc3ccccc3)ccc2n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of benzyl 6-(benzyloxy)quinoline-2-carboxylate (650 mg) in tetrahydrofuran (13.0 mL) was added a 1 M solution diisobutylaluminum hydride in toluene (2.64 mL) at −78° C., followed by stirring at −78° C. for 1 hour. To the reaction mixture was added sodium sulfate decahydrate (680 mg), followed by stirring at room temperature overnight. The insoluble material was collected by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 6-(benzyloxy)quinoline-2-carbaldehyde (170 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[C:3]=1[F:12].CCO.O.[Cl-].[NH4+]>C1COCC1.[Fe]>[Br:1][C:2]1[C:3]([F:12])=[C:4]([NH2:9])[C:5]([NH2:6])=[CH:7][CH:8]=1
Reactant: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1ccc(Br)c(F)c1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
To a solution of 4-bromo-3-fluoro-2-nitroaniline (3.0 g, 12.8 mmol) in THF (30 mL) was added EtOH (30 mL) and H2O (10 mL) followed by iron powder (3.6 g, 63.8 mmol) and ammonium chloride (1.0 g, 19.2 mmol). The resulting mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature and filtered through diatomaceous earth. The solid was washed with EtOH until no further color came through the filter. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-40% EtOAc in hexane to give the title compound (2.2 g, 84%).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([O-:8])=[O:7].[C:16]([C:18]1[CH:23]=[C:22]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[F:30])#[CH:17]>>[Cl:15][C:13]1[CH:12]=[CH:11][C:3]([O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7])=[C:2]([C:17]#[C:16][C:18]2[CH:23]=[C:22]([S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=2[F:30])[CH:14]=1
Reactant: C#Cc1cc(S(=O)(=O)CCC)ccc1F
Reactant: CC(C)(Oc1ccc(Cl)cc1Br)C(=O)[O-]
Product: CCCS(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OC(C)(C)C(=O)O)c1

Procedure:
Following the general method as outlined in Example 168, starting from 2-(2-bromo-4-chlorophenoxy)-2-methylpropanoate (Intermediate 264), and 2-ethynyl-1-fluoro-4-(propane-1-sulfonyl)-benzene (Intermediate 109) the title compound was obtained as a brown sticky solid after purification by preparative HPLC.