Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:28]3[CH:29]=[CH:30][C:25]([CH:23]=[O:24])=[CH:26][CH:27]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(C=O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (1 g, 2.71 mmol), (4-formylphenyl)boronic acid (0.487 g, 3.25 mmol, available from Aldrich), Pd(Ph3P)4, (0.156 g, 0.135 mmol) and potassium carbonate (0.487 g, 3.52 mmol) were combined in dry Ethanol (7 ml) and dry toluene (7.00 ml) and the reaction mixture was de-gassed for 10 mins. The reaction mixture was heated at 85° C. overnight. The reaction mixture was allowed to cool to r.t. and concentrated. The crude reaction mixture was partitioned between water (15 ml) and ethyl acetate (5 ml) and stirred at r.t. for 30 mins. A light grey solid precipitated out and was filtered off, washed with water (5 ml) and dried in a vacuum oven to give 854 mg of grey solid. LCMS (Method B): Rt=1.00, MH+=395
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)([O-:12])=[O:11].[Na]>CS(C)=O>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: [Na]
Solvent: CS(C)=O
Product: CCCCCCCCOc1ccc([N+](=O)[O-])cc1
Yield: 30 %

Procedure:
1-bromooctane (1 g, 5.18 mmole) and 4-nitrophenol, sodium salt (0.92 g, 5.71 mmole) were refluxed in DMSO (30 ml) at 120° C. for 5 hours. The DMSO was distilled off to near dryness. The resulting brown residue was loaded onto a silica column and eluted with 10:1 mixture of petroleum ether and diethylether. The yield was 30%. 1H NMR (CDCl3, peaks at=8.18 (m, 2H), 6.93 (m, 2H), 4.04 (t, 2H), 1.81 (p, 2H), 1.33 (m, 10H), 0.89 (t, 3H). Elemental analysis calculated for C14H21O3N: C, 66.91; H, 8.42; N, 5.57. Found: C, 66.97; H, 8.34; N5.52.
Reaction SMILES: CCCP(=O)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1.[CH2:30]([N:32]([CH2:40][CH3:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1)[CH3:31].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:40]([N:32]([CH2:30][CH3:31])[C:33]1[CH:34]=[C:35]([NH:39][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:8]([CH3:7])=[C:9]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)[CH:21]=[CH:20][N:19]=3)[CH:10]=2)[CH:36]=[CH:37][CH:38]=1)[CH3:41]
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CCN(CC)c1cccc(N)c1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1cccc(NC(=O)c2ccc(C)c(Nc3nccc(-c4cccnc4)n3)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1.05 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), N,N-diethyl-1,3-benzenediamine (115 mg, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is purified by chromatography on silica gel, eluent 2% methanol in dichloromethane and crystallised from acetone to give the title compound as a crystalline solid. 1H-NMR (400 MHz, DMSO-d6, δ): 1.07 (t, 6H); 2.31 (s, 3H); 3.29 (m, 4H); 6.38 (m, 1H); 7.06 (m, 2H); 7.11 (m, 1H); 7.36 (d, 1H); 7.43-7.50 (m, 2H); 7.67 (m, 1H); 8.21 (m, 1H); 8.43 (m, 1H); 8.51 (d, 1H); 8.66 (dd, 1H); 9.12 (s, 1H); 9.24 (m, 1H); 9.90 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[CH:5]([NH2:9])[CH2:6][CH2:7][CH3:8])[CH3:2].[C:13](Cl)(=[O:16])[CH:14]=[CH2:15]>C(Cl)Cl>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[CH:5]([NH:9][C:13](=[O:16])[CH:14]=[CH2:15])[CH2:6][CH2:7][CH3:8])[CH3:12]
Reactant: C=CC(=O)Cl
Reactant: CCCC(N)C(OCC)OCC
Solvent: ClCCl
Product: C=CC(=O)NC(CCC)C(OCC)OCC

Procedure:
This compound was made from 25 g (0.14 mol) of aminopentanal diethyl acetal, 12.9 g of acryloyl chloride, 35 g of 14N NaOH and 65 mL of CH2Cl2 using the same procedures as for ABDA (no pH adjustment). The product (32.5 g) had a gc retention time of 7.80 min.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[Cl:7][CH2:8][C:9](OC)=[O:10]>CO>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:9](=[O:10])[CH2:8][Cl:7]
Reactant: COC(=O)CCl
Reactant: NCC(O)CO
Solvent: CO
Product: O=C(CCl)NCC(O)CO
Reaction time: 5 h
Yield: 95 %

Procedure:
A solution of 25 grams (g.) (0.27 mole) of 3-amino-1,2-propanediol in 50 milliliter (ml.) methyl alcohol is added slowly to a solution of methyl chloroacetate, 33.0 g. (0.30 mole) in 50 ml. methyl alcohol at 5°-10° C. The solution is stirred for five hours at 5°-10° C. and is then allowed to stand in the cold for four days. The solution is then evaporated in vacuum to leave 43 g. of the desired product, a viscous oil, nD30 1.5148. (95% yield).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:30][C:29]([F:32])([F:31])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[NH:33]1[CH:37]=[CH:36][CH:35]=[N:34]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:33]4[CH:37]=[CH:36][CH:35]=[N:34]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:28][C:29]([F:32])([F:31])[CH2:30]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: c1cn[nH]c1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(-n4cccn4)cc3Cl)C[C@H]2C(=O)N2CC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 134 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-azetidine-1-carbonyl)-cyclopentanecarboxylic acid-(1-cyano-cyclopropyl)-amide (example 119 step 4) and pyrazole. White solid (36%). MS (EI): 538.1 (M+H)+.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[C:7]#[CH:8].[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(O)(=O)C>O1CCCC1>[CH2:11]([O:10][C:6](=[O:9])[C:7]#[C:8][C:14]1([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]1)[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C#CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 105.6 %

Procedure:
n-Butyllithium (175 mL, 0.28 mol) was added dropwise over 45 minutes to a stirred, cooled (−70° C.) solution of ethyl propiolate (32 mL, 0.32 mol) in tetrahydrofuran (250 mL). The mixture was stirred at −70° C. for 10 minutes, then a solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (18.6 g, 0.093 mol) in tetrahydrofuran (250 mL) was added dropwise over 1 hour maintaining the internal temperature below −70° C. The mixture was stirred at −70° C. for 1 hour, acetic acid (21 mL) in tetrahydrofuran (50 mL) was added. The mixture was warmed to room temperature and the solvent was evaporated under reduced pressure. Saturated aqueous sodium hydrogen carbonate (300 mL) and ethyl acetate (650 mL) were added and the layers were separated. The aqueous fraction was extracted with ethyl acetate (2×650 mL) and the combined organic fractions were washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a short silica gel column, eluting with 1:1 isohexane:ethyl acetate, to give the title compound (29.2 g, contains trace impurity). m/z (ES+) 298 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)[O:9][C:8](=[O:20])[CH:7]=1>C(Cl)(Cl)Cl>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH3:19])=[CH:13][CH:14]=2)[O:9][C:8](=[O:20])[C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCCOc1ccc2c(O)cc(=O)oc2c1
Solvent: ClC(Cl)Cl
Product: CCCOc1ccc2c(O)c([N+](=O)[O-])c(=O)oc2c1

Procedure:
Fuming nitric acid (15 ml) was added to a stirred suspension of 4-hydroxy-7-n-propoxycoumarin (m.p. 216°-8°; 3.0g) in chloroform (300 ml) at room temperature over one hour. After a further hour, the solvent was removed in vacuo and 6N hydrochloric acid (60 ml) added to the residue. Filtration and recrystallisation from ethanol gave the product, m.p. 151°-2°, (C12H11NO6 requires C, 54.34; H, 4.18; N, 5.28. Found: C, 54.38; H, 4.28; N, 5.24).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[C:9](OC)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:16])[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccnc1
Reactant: Cc1cccc(Cl)n1
Product: O=C(Cc1cccc(Cl)n1)c1cccnc1

Procedure:
In a similar manner as described in Example 1 from 6-chloro-2-picoline (9.3 g, 73 mmol) and methyl nicotinate (10.0 g, 73 mmol), 2-(6-chloro-2-pyridinyl)-1-(3-pyridinyl)ethanone was obtained as a syrup. This syrup (10 g, 70 mmol) was treated with hydroxylamine hydrochloride (24.3 g, 350 mmol) followed by the addition of a sodium hydroxide solution (14 g, 350 mmol in 30 mL of water) as described in example 1 to give 2-(6-chloro-2-pyridinyl)-1-(3-pyridinyl)ethanone oxime (14.4 g, 80%) as a white solid. 1H NMR (CDCl3): δ 8.84 (d, 1H), 8.40 (dd, 1H), 8.00 (m, 1H), 7.50 (t, 1H), 7.2–7.4 (m, 3H), 4.26 (s, 2H); MS m/z 248 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9].[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:5]([O:4][C:3]1[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:2]=1[Cl:1])[C:6](=[O:12])[C:7]([CH3:11])([CH3:10])[CH2:8][F:9]
Reactant: BrBr
Reactant: CC(C)(CF)C(=O)COc1ccc(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 100 %

Procedure:
244.6 g (0.88 mol) of crude 1-(2,4-dichloro-phenoxy)-3,3-dimethyl-4-fluoro-2-butanone were dissolved in 700 ml of chloroform, and 46 ml of bromine were added dropwise at 30° C. at a rate such that decolorization continuously occurred. When the addition had ended, the mixture was subsequently stirred for 30 minutes and then concentrated by distilling off the chloroform in vacuo. 315 g (100% of theory) of 1-bromo-1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were obtained as a viscous oil which could be further reacted in crude form.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][O:14][C:15]3[CH:30]=[CH:29][C:18]([CH2:19][CH:20]([C:25]([O:27]C)=[O:26])[C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:24][O:23][C:21]([CH:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[CH:30][CH:29]=1)[C:25]([OH:27])=[O:26])=[O:22]
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To a solution of dimethyl 4-[2-(6-quinolinoxy)ethoxy]benzylmalonate (0.44 g, 1.07 mmol) in a mixture of methanol (4.3 ml) and tetrahydrofuran (2.1 ml) at 0° C. is added a 2 mol/L aqueous solution of sodium hydroxide (0.59 ml, 1.18 mmol). The mixture is stirred for 2 h at room temperature, and then the solvent is removed under a vacuum. The residue was dissolved in saturated aqueous sodium bicarbonate (10 ml) and washed with ethyl acetate (10 ml). The aqueous solution is acidified to pH 2–3 with dilute hydrochloric acid and extracted with ethyl acetate (3×15 ml). The combined extracts are washed with water (20 ml) and brine (20 ml), dried over sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate to give the title compound (0.23 g, 54%). HRMS calcd for C22H25NO6: 399.4402. Found: 399.4405. MA calcd for C22H25NO6: C, 66.15%; H, 6.31%; N, 3.51%. Found: C, 66.32%; H, 6.34%; N, 3.48%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[C:27]#[N:28])=[C:17]3[CH:16]=[N:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(Cl)ncnc32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(n2ncc3c(Oc4ccccc4C#N)ncnc32)C1
Temperature: 160 °C
Yield: 43.6 %

Procedure:
A mixture of 3-(4-Chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 32; 40 mg, 0.12 mmol), 2-hydroxybenzonitrile (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 15.5 mg, 0.13 mmol) and potassium carbonate (15 mg, 0.25 mmol) in dimethylformamide (0.6 mL) was heated in a microwave oven at 160° C. for 10 min. The reaction mixed was cooled and filtered. Volatiles were evaporated and the residue purified twice by chromatography on silica gel, eluting first with 25% ethyl acetate/hexanes and then with 20% ethyl acetate/hexanes to give 3-[4-(2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (22 mg, 47%) as a viscous oil
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:64][N:65]1[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][CH2:73]O)[CH2:67][CH2:66]1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:73][CH2:72][CH2:71][N:68]5[CH2:69][CH2:70][N:65]([CH3:64])[CH2:66][CH2:67]5)[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:14])=[O:15])=[CH:11][CH:12]=2)=[CH:31][CH:32]=1
Reactant: CN1CCN(CCCO)CC1
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
250 mg (0.55 mmol) of methyl 2-[4-(4-fluorophenoxy)benzenesulfonyl]-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxlate are dissolved in 5 ml of THF. At room temperature, 216 mg (0.825 mmol) of triphenylphosphine, 142 μl (0.825 mmol) of DEAD and 120 mg (0.825 mmol) of 3-(4-methylpiperazin-1-yl)propan-1-ol are added, and the solution is stirred at room temperature for 18 hours. The solvent is then removed, and the residue is chromatographed on silica gel, allowing the desired product to be isolated as a colorless solid. Yield 76%.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23])([O-:19])=[O:18].[OH-].[Na+].Cl>C(OCC)(=O)C.C(N(CC)CC)C>[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:23])([O-:19])=[O:18]
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 3.90 g (17.50 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 40 ml of dry ethyl acetate, add 3.26 g (17.56 mmol) of 2-nitrobenzoyl chloride dissolved in 5 ml of dry ethyl acetate and 1.76 g of triethylamine. Allow the reaction mixture to stir for 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the solid has completely disappeared. Immediately acidify with concentrated HCl and extract the product with ethyl acetate. Eliminate the solvent at low pressure and recombine the crude product with dry ether, obtaining a white solid. Purify the reaction product by recrystallization (EtOH/H2O). This yields 3.34 g (51%) of 4-[2-(2-nitrobenzoylamino)benzoylamino]butanoic acid as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[CH3:27])(O)O>>[CH3:27][C:19]1[CH:20]=[C:21]([C:22]([OH:24])=[O:23])[CH:25]=[CH:26][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14]
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: Cc1cc(C(=O)O)ccc1B(O)O
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3C)c(C)c2)o1

Procedure:
The title compound was prepared from 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268 A1) and 4-borono-3-methylbenzoic acid (D33) using a similar procedure to Description 11 as a white solid (31%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:5]2[N:4]=1.O1CCCC1.CO.[Br:25]N1C(=O)CCC1=O>>[Br:25][C:9]1[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:5]2[C:6]=1[CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncc2ccc(-c3ccccc3)n2n1
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ncc2c(Br)cc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Into a 30 mL vial, 2-Methylsulfanyl-7-phenyl-pyrrolo[2,1-f][1,2,4]triazine (0.295 g, 0.00122 mol), Tetrahydrofuran (10 mL, 0.1 mol) and Methanol (5 mL, 0.1 mol) were added. N-Bromosuccinimide (0.239 g, 0.00134 mol) was added over 10 minutes. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum. The solid was partitioned with water, filtered and washed with water to give a yellow solid. The solid was dried under vacuum over night to give 5-Bromo-2-methylsulfanyl-7-phenyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (0.34 g, 87%). NMR 1H (DSMO-d6)-8.93 (s, 1H), 8.19 (d, 2H, J=7.61 Hz), 7.61 (s, 1H), 7.53 (t, 2H, J=8.60 Hz), 7.42 (t, 1H, J=7.37), 2.58 (s, 3H)
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[C:7]([CH3:30])=[N:8][C:9]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26](OC)=[O:27])(=[O:19])=[O:18])=[O:15])=[N:10][C:11]=1[CH3:12].[CH3:31][SH:32]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:7]([CH3:30])=[N:8][C:9]([NH:13][C:14]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([S:32][CH3:31])=[O:27])(=[O:19])=[O:18])=[O:15])=[N:10][C:11]=1[CH3:12]
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c(Cl)c(C)n1
Reactant: CS
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CSC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c(Cl)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trimethylaluminum (6.0 ml, 2 M) is charged via syringe to 15 ml dry toluene under nitrogen atmosphere and 3.8 g N-[(5-chloro-4,6-dimethylpyrimidin-2-yl)-aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide is added portionwise. After stirring at room temperature for one hour, methyl mercaptan (gas) is passed through the reaction mixture until the initial temperature rise subsided, whereupon the addition is discontinued. The reaction mixture is allowed to stir at room temperature for 1 hour, and quenched with 25 ml of 10% HCl. The resultant white suspension is filtered to give the desired product.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O.C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([F:7])=[CH:9][CH:10]=2)=[O:13])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1cccs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccc(F)cc2)s1
Reaction time: 4 h

Procedure:
To a stirred mixture of 29.5 parts of 2-methylthiophene, 39.65 parts of p-fluorobenzoyl chloride and 280 parts of methylene chloride are added portionwise 40 parts of aluminium chloride while keeping the temperature at 20° C (water-bath). Upon completion, stirring is continued for 4 hours at room temperature. The reaction mixture is poured onto crushed ice and 50 parts of hydrochloric acid, while stirring vigorously. The layers are separated and the aqueous phase is washed with chloroform. The organic layers are dried and evaporated. The residue is taken up in benzene and the latter is evaporated again. The residue solidifies on triturating in petroleumether. The solid product is filtered off and crystallized from ethanol at -20° C, yielding p-fluorophenyl 5-methyl-2-thienyl ketone; mp. 68° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[OH:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:14]([O:13][C:11](=[O:12])[CH2:10][C:5]1[CH:6]=[CH:7][C:8]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=2)=[C:3]([C:1]#[N:2])[CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2C#N)cc1
Temperature: 90 °C
Yield: 69.2 %

Procedure:
To a stirred solution of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (1.00 mg, 4.25 mmol) and methyl 4-hydroxybenzoate (776 mg, 5.10 mmol) in DMSO (20 ml) was added K2CO3 (704 mg, 5.10 mmol). The reaction was heated to 90° C. overnight via an oil bath. The reaction was diluted with ethyl acetate and 10% aqueous sodium carbonate. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with 10% aqueous sodium carbonate and brine, dried over MgSO4, concentrated and purified by silica gel chromatography to give methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (1.08 g).