Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[CH:18]([C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[C:31]([CH:38]([CH3:40])[CH3:39])[C:30]=3[O:41][CH2:42][CH2:43][CH3:44])[C:22]=2[CH:21]=1)=O.O>CN(C=O)C>[CH2:4]([O:5][C:6](=[O:7])[C:8]([F:9])=[CH:18][C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[C:31]([CH:38]([CH3:39])[CH3:40])[C:30]=3[O:41][CH2:42][CH2:43][CH3:44])[C:22]=2[CH:21]=1)[CH3:3]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCCOc1c(-c2cccc3sc(C=O)cc23)cc(C(C)C)cc1C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(-c2cccc3sc(C=C(F)C(=O)OCC)cc23)cc(C(C)C)cc1C(C)C
Temperature: 40 °C

Procedure:
To a slurry of 74 mg (1.54 mmol) of NaH (50% in mineral oil) in 3 mL of dry DMF was added 285.6 mg (1.27 mmol, 2.5 equivalents) of triethyl phosphonofluoroacetate (diluted in 1 mL of dry DMF) at 0° C. After the gas evolution has ceased, 0.51 mmol of 2-formyl-4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thiophene diluted in 3 mL of dry DMF was added dropwise. The red mixture was slowly heated to 40° C. until complexion. After cooling, water was added and the solution was extracted 2 times with ethyl acetate. The organic layers were combined, washed with water and brine and dried over MgSO4. After evaporation of the solvents, the crude oil is purified over a short plug of silica gel (eluent: 95/5 hexane/ethyl acetate) to afford 2-fluoro-3-[4-(2-n-propoxy-3,5-di-iso-propylphenyl)-benzo[b]thien-2-yl]-prop-2-enoic acid ethyl ester.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]#[N:14])[C:6]([CH:19]([CH3:21])[CH3:20])=[C:5](Cl)[N:4]=1.[CH2:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]#[N:14])[C:6]([CH:19]([CH3:21])[CH3:20])=[C:5]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:4]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccccc1
Reactant: Cc1cc(C#N)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: [Na]
Product: Cc1cc(C#N)cc(Oc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Sodium (0.48 g, 21 mmol) was reacted with anhydrous benzyl alcohol (20 ml) under nitrogen at room temperature. The mixture was then cooled in an ice bath and (71) (3.22 g, 10 mmol) was added. After 1 hr., the mixture was stirred at room temperature for overnight. The mixture was evaporated in vacuo and the residue was dissolved in ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexanes (1:9)) to afford 3.18 g (68%) of a colorless syrup. 1H NMR (200 MHz, CDCl3) δ 1.28 (6H, d, J=7.2 Hz), 2.39 (3H, s), 3.40 (1H, m), 5.14 (2H, s), 5.42 (2H, s), 7.13-7.44 (13H, m).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])C1C=CC=CC=1.[CH2:40]([NH2:46])[CH:41]1[O:45][CH2:44][CH2:43][CH2:42]1.N1CCOCC1.[N-]=C=O>C1COCC1>[O:45]1[CH2:44][CH2:43][CH2:42][CH:41]1[CH2:40][NH:46][C:36]([C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([C:23]3[CH:22]=[C:21]([N:15]4[C:14](=[O:39])[C:13]5[C:17](=[CH:18][CH:19]=[C:11]([C:9]([OH:8])=[O:10])[CH:12]=5)[C:16]4=[O:20])[CH:26]=[CH:25][CH:24]=3)[O:28][C:29]=2[CH:35]=1)=[O:37]
Reactant: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Reactant: NCC1CCCO1
Agent: [N-]=C=O
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4ccc(C(=O)NCC5CCCO5)cc4o3)c1)C2=O
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of 2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol) in THF (1 ml) was added to a solution of tetrahydrofurfurylamine (14 mg, 0.14 mmol) in THF (1 ml) containing polymer bound morpholine (2.5 mmol g−1, 72 mg). After shaking overnight, polymer bound isocyanate (2.0 mmol g−1, 90 mg) was added and the reaction shaken for 4 h. The reaction was filtered and the solvent removed under reduced pressure. The residue was suspended in dioxane and palladium on carbon was added (spatula tip). The reaction vessel was purged with hydrogen and stirred at room temperature overnight. The reaction was filtered through celite and the filtrate concentrated to give the title compound (27 mg, 59%). 1H NMR (DMSO) δ 8.74(t, 1H), 8.44(dd, 1H), 8.37(m, 2H), 8.31–8.27(m, 3H), 8.12(d, 1H), 7.97(dd, 1H), 7.90(d, 1H), 7.85–7.76(m, 1H), 4.00(m, 2H), 3.79(m, 1H), 3.65(m, 2H), 1.98–1.77(4H, m). MS 510.2 m/z (M−H)−.
Reaction SMILES: Cl[C:2]1[C:3]([F:13])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+].[H][H]>C(#N)C>[F:13][C:3]1[CH:2]=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:10])[F:11]
Reactant: [H][H]
Reactant: Fc1ccc(C(F)(F)F)c(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Fc1ccc(C(F)(F)F)c(F)c1
Yield: 66.6 %

Procedure:
100 g of 3-chloro-2,4-difluorobenzotrifluoride in 500 ml of acetonitrile and 60 g of pulverulent sodium carbonate were initially introduced into a hydrogenation apparatus equipped with a diffuser stone and a stirrer. 10 g of catalyst (5% by weight of metallic palladium on activated charcoal) were then added, and hydrogen was passed in at 80° C. for 10 hours Subsequently, the batch was cooled and filtered, and the filtrate was distilled via a column packed with perforated rins made of stainless steel. 56 g of 2,4-difluorobenzotrifluoride having a boiling point of 105° to 106° C. at 1,030 mbar were obtained. The refractive index nD20 was 1.3968.
Reaction SMILES: S(Cl)([Cl:3])=O.[I:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1>CN(C=O)C.ClCCl>[I:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([Cl:3])=[O:15])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(I)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (39.53) and DMF (2 drops) were added to a solution of 4-iodophenylacetic acid (26.2 g), in dichloromethane (150 ml). The reaction mixture was stirred at ambient temperature for 18 hours and the solvent removed by evaporation to give 4-iodophenylacetyl chloride as an oil (23 g) which was purified by vacuum distillation; b.p. 118-119° C. (0.35 mmMg)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1([CH3:22])[C:16]2=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=[C:15]2[O:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][C:12]1([CH3:22])[C:16]2[C:17]([O:21][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: CC1(C)COc2cccc(O)c21
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)COc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Yield: 67.4 %

Procedure:
In a large microwave vial, 2-chloro-5-nitropyridine (386 mg, 2.436 mmol) was dissolved in 4 ml of dimethylformamide. 3,3-dimethyl-2,3-dihydro-1-benzofuran-4-ol (Intermediate 57, 400 mg) and potassium carbonate (2.02 g, 14.62 mmol) were added. The reaction mixture was heated under microwave irradiation during 30 minutes at 110 C (Biotage Initiator). The reaction mixture was filtered. The filtrated solid was washed with dichloromethane (30 ml). The volatiles were evaporated under vacuum. The residue was purified by silica gel chromatography (Companion instrument, 120 g cartridge) with cyclohexane as eluent to afford the title compound (470 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)[C:8]([O:10][CH3:11])=[O:9].S>N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(=O)c1cccn1C
Agent: S
Solvent: c1ccncc1
Product: COC(=O)Cc1cccn1C
Temperature: 63 °C
Reaction time: 27 h
Yield: 86 %

Procedure:
A solution of 50g of methyl 1-methylpyrrole-2-glyoxylate in 200 ml of pyridine is cooled to -78° C. and 64g of hydrogen sulfide is added. The mixture is sealed in a stirred autoclave and heated to 63° C. The pressure rises to about 130 p.s.i. After 27 hrs., the hydrogen sulfide is driven off in a nitrogen stream and the solution is decanted from the precipitated sulfur. Pyridine is distilled off at 20 mm Hg. The residue is distilled at 0.03 mm Hg, b.p. 68-70° C., to give 39.2g of oily methyl 1-methylpyrrole-2-acetate (86% yield).
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@@H:8]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:7]3)[CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(Cl)(Cl)Cl>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:15][C@@H:8]2[CH2:9][CH2:10][C:11]3[C:6](=[C:5]4[C:14](=[CH:13][CH:12]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[O:7]2)[CH2:41][CH:42]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCc3ccc4ncccc4c3O2)cc1
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(C[C@@H]4CCc5ccc6ncccc6c5O4)CC3)c2c1
Yield: 60.8 %

Procedure:
A solution of (6S)-toluene-4-sulfonic acid 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester (0.12 g, 0.33 mmole) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.14 g, 0.65 mmole) in anhydrous DMSO (25 mL) was stirred at 80° C. for 2 hours. The reaction mixture was then poured into chloroform (100 mL) and washed with water (3×40 mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under vacuum. Column chromatography on silica gel (5% methanol/ethyl acetate) afforded 0.083 g (62%) of the title compound. The oxalate salt was prepared in ethyl acetate and ethanol and had mp 210° C. and [α]25D=+71.43° (c=4.68, DMSO).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][C:29](Cl)=O.C(N(CC)CC)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])[C:29]([CH2:28][CH2:27][O:26][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: COCCC(=O)Cl
Reactant: O=C1CCCN1CCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Solvent: CCN(CC)CC
Product: COCCc1nc2cnc3cc(Br)ccc3c2n1CCCN1CCCC1=O

Procedure:
1-[3-(7-Bromo3-nitroquinolin-4-ylamino)propyl]pyrrolidin-2-one was treated according to the methods described in Parts B, C, and D of Examples 152-156. 3-Methoxypropionyl chloride was used in Part C, and triethylamine (1.3 equivalents) was added to the reaction mixture. The crude product obtained in Part D was purified by flash chromatography on silica gel (eluting sequentially with 100:0 and 92.5:7.5 chloroform:methanol) followed by recrystallization from acetonitrile. The crystals were washed with acetonitrile and diethyl ether and dried in a vacuum oven at 60° C. to provide 1-{3-[7-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one as a light grey solid.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>ClCCl>[CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:23]([O:24][CH2:25][CH:26]1[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:33]3[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:39])[CH2:2]2
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)OCC1c3ccccc3-c3ccccc31)C2
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 0.5 mmol) in dichloromethane (3 mL) and triethylamine (100 mg, 138 μL, 1.0 mmol) was treated with 9H-fluoren-9-ylmethyl carbonochloridate (128.0 mg, 0.5 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was washed with 1 N HCl, water, 50% saturated bicarbonate and brine. The organic layer was dried over Na2SO4, filtered and concentrated to obtain a solution of 3-(9H-fluoren-9-yl)methyl 8-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate in DCM (2 mL), which was used directly for the next step. LC/MS m/z 435.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)[C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]#[N:10])([CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH:16]([CH3:21])[O:17][CH:18]([CH3:20])[CH2:19]2)[CH2:23][N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)=[CH:4][CH:3]=1
Reactant: ClCn1cncn1
Reactant: CC1CN(CCCC(C#N)c2ccc(Cl)cc2)CC(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(CCCC(C#N)(Cn2cncn2)c2ccc(Cl)cc2)CC(C)O1

Procedure:
This compound (1.2 g.) was prepared using the procedure described in Example 2b except using 1.0 g. (3.3 mmoles) of 2-(4-chlorophenyl)-5-(2,6-dimethyl-4-morpholinyl)valeronitrile, 0.38 g. (3.3 mmoles) of 1-(chloromethyl)-1,2,4-triazole, and 0.16 g. (3.6 mmoles) of sodium hydride in 35 ml. of DMF and was isolated as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([C:21]([OH:23])=[O:22])[O:12]1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(O)(C)C>[CH:24]([NH:27][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([C:21]([OH:23])=[O:22])[O:12]1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(Cl)ncnc21
Solvent: CC(C)O
Product: CC(C)Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@H]2OC(C)(C)O[C@H]21
Temperature: 25 °C

Procedure:
A mixture of (3aS,4S,6R,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (5.82 g) and isopropyl amine (7.27 ml) in isopropanol (20 ml) was heated under reflux for 40 h, cooled to room temperature and concentrated in vacuo. The resulting residue was partitioned between ethyl acetate (75 ml) and citric acid (0.5M, 75 ml). The layers were separated, and the organic phase washed with citric acid solution (2×50 ml). The combined organic extracts were washed with water (50 ml) and brine (80 ml), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a light brown foam (4.49 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:12][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: O=Cc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
N-methyl piperazine (2.50 mL, 22.5 mmol) was added dropwise to a solution of 3-chloro-4-nitrobenzaldehyde (2.09 g, 11.3 mmol) and acetic acid (0.29 mL, 5.14 mmol) in toluene (11.7 mL) at room temperature. The reaction mixture was stirred for 1.5 h at room temperature before the addition of further toluene (4.4 mL) and sodium triacetoxyborohydride (3.58 g, 16.9 mmol). The reaction mixture was stirred at room temperature overnight and then quenched by the addition of MeOH (3 mL) and saturated aqueous NaHCO3 (23 mL). The reaction mixture was stirred for 30 min. The phases were separated and the aqueous layer was extracted with toluene (2×30 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash column chromatography (EtOAc:MeOH:NEt3 9:1:0.1) to give the title compound (2.17 g, 71%) as an orange oil.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18])([O-:10])=[O:9].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C@H:29]([NH2:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1>ClCCl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C@H:29]([NH:31][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N+:8]([O-:10])=[O:9])(=[O:19])=[O:18])[CH3:30])[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc([C@@H](C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Yield: 98.9 %

Procedure:
A 2.0 ml portion of triethylamine and 1.9 g of orthonitrobenzenesulfonyl chloride were added to a mixed solution of 1.0 g of (1R)-1-(3-methoxyphenyl)ethylamine and 10 ml of dichloromethane under ice-cooling and stirred for 5Hours. Thereafter, work-up and purification were carried out in the standard method to obtain 2.2 g of N-[(1R)-1-(3-methoxyphenyl)ethyl]-2-nitrobenzene sulfonamide as yellow crystals. EN: 335.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:21](=O)[CH3:22].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:21][CH3:22])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Cl)cc(NCC2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(CC1CCOCC1)c1cc(Cl)cc(C(=O)OC)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzoate (0.40 g, 1.35 mmol) and acetaldehyde (0.120 g, 2.71 mmol) in dichloroethane (5 mL), acetic acid (0.48 g, 8.1 mmol) was added and the reaction stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (0.663 g, 4.05 mmol) was added at 0° C. and the reaction stirred for 3 h at room temperature. On completion, the solvent was removed under reduced pressure and the crude material purified by column chromatography to the title compound (0.38 g, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.C1C(=O)N([Br:25])C(=O)C1>>[Br:25][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 95.3 %

Procedure:
1,3-Dinitrobenzene (25 g, 149 mmol) was dissolved in sulfuric acid (44.5 mL, 835 mmol) and NBS (31.8 g, 178 mmol) was added. The mixture was stirred at 60° C. for 2 days. The reaction was cooled to ambient temperature and the mixture was poured into ice water to form a precipitate. The product was collected by filtration, washed with water and hexanes to yield 35.1 g (142 mmol, 96%) of 1-bromo-3,5-dinitrobenzene as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O.C(O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]1[C:8]([NH2:13])=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccccc1CNc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccccc1CNc1ccccc1N
Yield: 92.3 %

Procedure:
A solution of 32 g (0.13 mole) of (2-methoxy-benzyl)-(2-nitro-phenyl)-amine (1) and 3.2 g Pd/C in 200 mL of 1:1 ethyl acetate:ethanol is treated at 40 psi of hydrogen for 1 hour. The reaction mixture is then filtered through celite and washed with 200 mL of ethanol. The solvent is then removed in vacuo to afford 28.2 g (0.12 mole, 92%) of N-(2-Methoxy-benzyl)-benzene-1,2-diamine (2).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:19]([C:13]1([C:15]([O:17][CH3:18])=[O:16])[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:20]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C1c2ccccc2Oc2ccccc21
Agent: [K+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCC1(C(=O)OC)c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
10.0 g (0.042 mol) of methyl 9-xanthenecarboxylate (obtainable according to step 1.1.a) are dissolved in 100 mL of tetrahydrofuran and combined batchwise with 5.16 g (0.044 mol) of potassium tert-butoxide while cooling. Then at about 18° C. to 22° C., 6.296 mL (0.083 mol) of bromoethane are added dropwise; after it has all been added, the mixture is stirred for about 1.5 hours at ambient temperature. The precipitate formed is suction filtered and the solvent is removed by distillation. The residue remaining is taken up in diethyl ether and extracted with water. The organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The crude product obtained is used in the next step without any further purification. Yield: 7.92 g of yellow oil (70% of theoretical yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[C:6]([CH:16]=O)[N:5]=[C:4]2[C:18]([C:21]3[S:25][C:24]([CH3:26])=[N:23][CH:22]=3)=[N:19][O:20][C:3]=12.[NH:27]1[C:34](=[O:35])[CH2:33][C:31](=[O:32])[NH:30][C:28]1=[O:29]>C(O)(C)C>[Cl:1][C:2]1[C:3]2[O:20][N:19]=[C:18]([C:21]3[S:25][C:24]([CH3:26])=[N:23][CH:22]=3)[C:4]=2[N:5]=[C:6]2[C:7]=1[N:8]1[CH2:9][C@@H:10]([CH3:15])[O:11][C@@H:12]([CH3:14])[C@@H:13]1[C:33]1([C:31](=[O:32])[NH:30][C:28](=[O:29])[NH:27][C:34]1=[O:35])[CH2:16]2
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: Cc1ncc(-c2noc3c(Cl)c(N4C[C@@H](C)O[C@@H](C)C4)c(C=O)nc23)s1
Solvent: CC(C)O
Product: Cc1ncc(-c2noc3c(Cl)c4c(nc23)CC2(C(=O)NC(=O)NC2=O)[C@H]2[C@H](C)O[C@H](C)CN42)s1
Temperature: 80 °C
Yield: 13.6 %

Procedure:
To isopropanol (20 ml) was added to 7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)-3-(2-methylthiazol-5-yl)isoxazolo[4,5-b]pyridine-5-carbaldehyde (Intermediate 414, 0.26 g, 0.66 mmol) and barbituric acid (0.085 g, 0.66 mmol), and the mixture was heated to 80° C. for about 2 days. The mixture was concentrated, and crystallization of the crude mixture from methanol gave 45 mg of the title compound.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=O)C.ClC1C=CC(CC2C=CC=C3C=2C2C(COC)=C(C=[N:50][OH:51])N=CC=2N3)=CC=1>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17]1[C:18]([CH2:19][O:20][CH3:21])=[C:6]([CH:4]=[N:50][OH:51])[N:7]=[CH:8][C:9]=1[NH:10]2
Reactant: COCc1c(C=NO)ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c12
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c2c1COC
Product: COCc1c(C=NO)ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c12

Procedure:
The preparation takes place from 5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester over alcohol and aldehyde, such as described for 5-(4-chlorobenzyl)-4- methoxymethyl-β-carboline-3- carbaldehyde-oxime, melting point 209°-212° C.