Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH3:16]>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: O=Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C=O)c1
Temperature: 85 °C
Reaction time: 0.58 h
Yield: 89.5 %

Procedure:
3-Hydroxybenzaldehyde (61 g) was added over 40 minutes to a suspension of sodium hydride (13.0 g) in dimethylformamide (700 cm3), the temperature of the reaction mixture being kept below 10° C. by means of a CO2 /oxitol bath. After stirring for 35 minutes, 1-bromobutane (73 g) was added dropwise over one hour and the mixture was then stirred at room temperature for 2.5 hours followed by heating at 85° C. for a further 2.5 hours. The resulting mixture was poured into ice water (1000 cm3) and was allowed to stand overnight before extracting with 40°-60° petrol/ether (3:1) (5×200 cm3). The combined organic layers were washed with 1M sodium hydroxide solution containing sodium chloride, dried over sodium sulphate, treated with activated charcoal, filtered and then evaporated down to give a golden brown mobile oil (79.7 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:14]([O:22][CH3:23])(=[O:21])[C:15]#[C:16][C:17]([O:19][CH3:20])=[O:18]>C1(C)C=CC=CC=1>[C:9]([O:8][C:7]([NH:6][C:2]1[CH:3]=[CH:4][C:5]([OH:1])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:15]=1[C:14]([O:22][CH3:23])=[O:21])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)Nc1ccco1
Reactant: COC(=O)C#CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1c(O)ccc(NC(=O)OC(C)(C)C)c1C(=O)OC
Yield: 37 %

Procedure:
A solution of tert-butyl furan-2-ylcarbamate C3-2 (55.0 g, 300.2 mmol) and dimethyl but-2-ynedioate (73.5 mL, 600.4 mmol) in toluene (100 mL) was heated at 45° C. for 4 hrs. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, PE to EA:PE (1:20, v:v)) to give compound C3-2 as a light yellow solid (36.1 g, yield: 37%). 1H NMR (DMSO-d6, 400 MHz) δ: 1.41 (s, 9H), 3.69 (s, 3H), 3.73 (s, 3H), 7.02 (d, J=8.8 Hz, 1H), 7.35 (d, J=9.2 Hz, 1H), 8.93 (s, 1H), 10.07 (s, 1H); MS (ESI+): m/z 238 (M-87).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31](Br)=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:37][O:38][CH2:39][Sn](CCCC)(CCCC)CCCC>O1CCOCC1.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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:37][O:38][CH3:39])=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)COC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COCc1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3OC)c3ccc4c(c3)OCO4)cn(C)c2c1
Reaction time: 8 h
Yield: 11.6 %

Procedure:
To a solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (from Example 85, 300 mg, 0.53 mmol) in 1,4-dioxane (1.5 ml) under a nitrogen atmosphere was added methoxymethyltributylstannane (220 mg, 0.66 mmol), followed by tetrakis(triphenylphosphine)palladium(0) (35 mg). The mixture was heated to reflux for 16 hours, and then cooled. An additional portion of tetrakis(triphenylphosphine)palladium(0) (30 mg) was added, and reflux was continued for a further 8 hours. The solvent was removed in vacuo, and the residue was flash chromatographed using a gradient elution of a mixture of 1% methanol and 99% dichloromethane, through to 5% methanol and 95% dichloromethane, to give the title compound (33 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=O)[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:10][CH2:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[S:40])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12]2)[CH2:10][CH2:9]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NC(=O)NC4=O)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCC4(CC3)NC(=O)NC4=O)c(F)c2)C(=O)O1
Yield: 22.6 %

Procedure:
A stirred suspension of 32 (0.210 g, 0.500 mmol) in dioxane (5.0 mL), under nitrogen was treated with Lawesson's Reagent (0.202 g, 0.500 mmol), refluxed for 4 h and concentrated in vacuo. The residue was chromatographed on silica gel with mixtures of MeOH—NH4OH—CHCl3, containing 1-10% MeOH and 0.1-0.5% NH4OH and the resulting product was crystallized from MeOH—CHCl3—EtOAc to give 0.0491 g of 3: mp 218.5° C.; HR FAB MS theory for C19H22FN5O4S (M+): 435.1376; found 435.1370. Anal. calcd for C19H22FN5O4S.0.5 H2O: C, 51.34; H, 5.21; N, 15.76. Found: C, 51.69; H, 5.00; N, 15.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11]COC)=[CH:9][N:10]=1)[CH:6]=[O:7].Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[OH:11][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[N:10][CH:9]=1
Reactant: COCOc1cnc(OC)cc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C=O)c(O)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 0.17 mol, 1 eq.) in THF (150 mL) was added HCl (3 N, 250 mL, 4.4 eq.). The reaction was stirred at 50° C. for 1 h, cooled to rt, and diluted with water (500 mL). The mixture was neutralized to pH 7-8 with solid K2CO3. The pale yellow solid was collected, washed with water, and dried to give 5-hydroxy-2-methoxyisonicotinaldehyde (17.9 g, 74.6%) as a pale yellow solid. 1H NMR (400 MHz; DMSO) δ=10.31 (s, 1H), 8.03 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H). LRMS (M+H+) m/z 154.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-])=O)=[C:13]([CH:16]=1)[NH:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:20]>[C].[Pt].C1(C)C=CC=CC=1>[ClH:20].[CH2:1]([O:8][C:9]1[CH:16]=[C:13]([NH:14][CH3:15])[C:12]([NH2:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pt]
Agent: Cl
Solvent: Cc1ccccc1
Product: CNc1cc(OCc2ccccc2)ccc1N
Reaction time: 0.5 h
Yield: 91 %

Procedure:
5% platinum carbon (2.15 g, water content: 53.1%) was added to a toluene (300 mL) suspension of 5-benzyloxy-N-methyl-2-nitroaniline (20 g, 77.4 mmol), and catalytic hydrogenation reaction was performed at 4 atm. The reaction solution was filtered to remove a catalyst. The catalyst was washed with 2-propanol (40 mL), and the washing liquid was added to the precedent filtrate. Under ice cooling, concentrated hydrochloric acid (6.6 mL, 77.4 mmol) was added to the mixture, and the mixture was stirred under the same temperature for 30 minutes. The resulting precipitated crystals were collected by filtration, then washed with 2-propanol (60 mL), and dried at 50° C., thereby obtaining 18.6 g of a light-pink, crystal target compound (yield: 91%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:9])[CH:5]=[C:6]([N:11]([CH2:12][CH2:13][OH:14])[CH3:10])[N:7]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CNCCO
Solvent: CCO
Product: Cc1cc(N(C)CCO)nc(Cl)n1
Yield: 34.5 %

Procedure:
Part A: A solution of 2,4-dichloro-6-methylpyrimidine (1.0 g) and 2-(methylamino)ethanol (0.4 g) in ethanol (50 mL) was refluxed for 24 hours. The solvent was evaporated to give a crude residue, which was chromatographed on silica gel using 5% methanol in chloroform to yield 2-chloro-4-methyl-6-(N-methyl-2-hydroxyethylamino)pyrimidine (370 mg). Mass spec. (NH3 --CI/DDIP): 202 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:12][C:13]#[C:14][CH3:15])[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]=1.Cl[CH2:17][C:18]1[N:27]=[C:26]([CH3:28])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[N:3]([CH2:12][C:13]#[C:14][CH3:15])[C:4]2[C:9](=[O:10])[N:8]([CH2:17][C:18]3[N:27]=[C:26]([CH3:28])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[N:7]=[CH:6][C:5]=2[N:11]=1
Reactant: CC#CCn1c(Br)nc2cn[nH]c(=O)c21
Reactant: Cc1nc(CCl)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC#CCn1c(Br)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 365 mg 2-bromo-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one, 265 mg 2-chloromethyl-4-methyl-quinazoline and 210 mg potassium carbonate in 6 ml acetonitrile is stirred for 17 h at ambient temperature. Then the reaction mixture is filtered through 5 g aluminium oxide with ethyl acetate and the filtrate is evaporated down. The residue is triturated in diisopropylether, separated from the ether and dried.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Cl[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][N+:12]=1[O-:20]>O>[N+:17]([C:15]1[CH:14]=[CH:13][N+:12]([O-:20])=[C:11]([O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:16]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])c(Oc2cccnc2)c1
Yield: 83 %

Procedure:
Sodium hydride (0.27 g of an 80% dispersion in oil, 9 mmol) was added to a solution of 3-hydroxypyridine (0.854 g, 9 mmol) in ThF (3 ml) at 0° C. The mixture was then stirred for 1 h at room temperature before 2-chloro-4-nitropyridine-N-oxide* (2 g, 9 mmol) was added. The resulting solution was heated at reflux for 16 h, cooled, poured into water (100 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica using ethyl acetate as eluant to afford the title compound (1.74 g, 83%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)cc(I)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1c(Cl)cc(I)cc1Cl
Yield: 99 %

Procedure:
A solution of 2,6-dichloro-4-iodobenzoic acid (5.50 g, 17.4 mmol) in thionyl chloride (52 mL) was heated under reflux for 2 hours then diluted with toluene and concentrated under reduced pressure. The resultant residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the desired compound as a yellow oil (5.75 g, 99% yield). 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Li]CCCC.[I:21]I.O>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[C:4]([I:21])[CH:3]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
To the solution of tert-butyl (6-chloropyridin-3-yl)carbamate (160 g, 0.7 mol) in 1 L of anhydrous THF was added n-BuLi (600 mL, L5 ml) at −78° C. under N2 atmosphere. After the addition was finished, the solution was stirred at −78° C. for 30 min, and the solution of I2 (177.68 g, 0.7 mol) in 800 mL of anhydrous THF was added. Then the solution was stirred at −78° C. for 4 hrs, TLC indicated the reaction was over. Water was added for quench, and EtOAc was added to extract twice. The combined organic phases were washed with brine, dried over Na2SO4, filtered and purified by flash chromatography to afford 80 g of tert-butyl (6-chloro-4-iodopyridin-3-yl)carbamate as a yellow solid (32.3%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:1][C:2]1([CH3:15])[C:3]2[CH:4]=[C:5]([C:16]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[O:26])[CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC1(C)c2ccccc2-c2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)c2ccccc2-c2ccc(C(=O)c3ccccc3C(=O)O)cc21
Temperature: 25 °C
Yield: 80 %

Procedure:
9,9-dimethyl-9H-fluorene (40 g, 1 eq, 0.206 mol) and Phthalic anhydride (33.6 g, 1.1 eq, 0.227 mol) were placed in a reaction vessel, and added with Dichloromethane (1.5 l). At 0° C., aluminum chloride (40.8 g, 1.5 eq, 0.309 mol) was gradually added thereto, and the temperature was raised up to room temperature. Then, the resultant mixture was stirred for 12 hours. After the reaction was completed, the resultant product was gradually added with distilled water at 0° C. The resultant product was extracted with an excess of dichloromethane, and washed several times with distilled water. After solvent removal, the produced solid was placed in a Hexane 2 l-containing vessel, washed, filtered, and dried, 2-(9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (56.4 g, yield 82%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[CH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:42]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH:28]([CH2:29][CH2:30][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:42]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CCCc4ccccc4)cc3)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4OC4CCc4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-{4′-[3-methyl-4-(4-phenyl-but-1-enyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.343 g, 0.72 mmol) in CH2Cl2 (3.5 mL) was added meta-chloroperoxybenzoic acid (0.181 g, 0.79 mmol), and the reaction was stirred at room temperature overnight. Analytical LCMS indicated the starting material was still present, so additional meta-chloroperoxybenzoic acid was added, and the reaction was stirred overnight at room temperature. After aqueous workup, the organic layer was dried over MgSO4, filtered, and concentrated, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[CH:14]1([NH:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:20]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O-:21])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: ONC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOc1cc(C=[N+]([O-])C2CCCCC2)ccc1OC
Yield: 57 %

Procedure:
A solution of 3-ethoxy-4-methoxybenzaldehyde (1 eq.) in benzene was refluxed with N-cyclohexylhydroxylamine (1.3 eq.) in the presence of p-toluenesulfonic acid (0.1 eq.) for 72 h. The title compound was isolated in 57% yield as a solid, m.p. 113.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[N:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:24][CH:25]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2ccnn2Cc2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Reaction time: 5 h

Procedure:
A mixture of 5 mmol of 5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine in 25 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product as a tan solid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[C:1]([NH:5][S:14]([CH3:13])(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a 0° C. solution of 10 g (136.7 mmol) of t-butylamine and 15.2 g (150.4 mmol) of triethylamine in 350 mL of dichloromethane was added 15.7 g (136.7 mmol) of methanesulfonyl chloride in 20 mL of dichloromethane over 15 minutes. Continue stirring at 0° C. for 30 minutes then warm to room temperature over one hour. The mixture was washed once with 250 mL of 10% aqueous sodium bisulfate. The organic portion was separated and the aqueous portion was extracted two times with 100 mL each of dichloromethane. The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The residue was recrystallized from petroleum ether and dried in vacuo to afford 12.2g (59%) N-t-butyl methanesulfonamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([O:14][C:15]1[C:20](=[O:21])[CH:19]=[CH:18]O[C:16]=1[CH3:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:14][C:15]1[C:20](=[O:21])[CH:19]=[CH:18][N:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:16]=1[CH3:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCC(=O)O
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCC(=O)O

Procedure:
β-Alanine (5 g) in water (50 ml) is added to 3-benzyloxy-2-methyl-4-pyrone (10 g) in 95% ethanol (100 ml) and sodium hydroxide (4 g) in water (50 ml) is then slowly added to the reaction mixture until a pH of 13 is obtained. The solution is refluxed for 15 minutes during which time the colour changes from yellow to amber. After cooling, the solution is acidified to pH 2.5 with concentrated HCl (about 2 ml) and is then rotary evaporated at 50° C. The resulting oil is subjected to a methylene chloride/water extraction. The solid which remains is triturated with acetone and recrystallised from water to give 3-benzyloxy-1-(2'-carboxyethyl)-2-methylpyrid-4-one, m.p. 81°-83° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Sn](C)(C)C)[CH:5]=[C:4]([CH3:12])[N:3]=1.Br[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20][N:21]2[CH:24]2[CH2:26][CH2:25]2)=[CH:16][C:15]=1[F:33].CN(C)P(N(C)C)(N(C)C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:24]1([N:21]2[C:22]3[C:17](=[CH:16][C:15]([F:33])=[C:14]([C:6]4[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([CH3:12])[CH:5]=4)[CH:23]=3)[C:18](=[O:32])[C:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:20]2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(Br)c(F)cc2c1=O
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O

Procedure:
2,6-Dimethyl-4-(trimethylstannyl)pyridine (part g (10.1 g) and 1.52 g dichlorobis(triphenylphosphine)-palladium was added to a stirred solution of 12.13 g ethyl 7-bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (part f) and 10 ml hexamethylphosphoramide (HMPA) in 240 ml dioxane under nitrogen. The reaction mixture was heated under reflux for 24 hours, then cooled and partitioned between water and methylene dichloride. The organic extract was washed with sodium chloride solution, dried (magnesium sulfate) and concentrated to give 12.0 g ethyl 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, m.p. 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4](Cl)[N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([NH:18][CH3:19])=[O:17].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([NH:18][CH3:19])=[O:17])[C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:7]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Yield: 8 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-trifluoromethylpyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (no microwave—20° C., 2 days) to afford 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-N-methyl-benzamide as a white solid in 8% yield. Mp: (209° C.); MS: 331.05 (M+H); 1H NMR (chloroform-d): δ 11.63 (br s, 1H), δ 8.59 (d, J=8 Hz, 1H), δ 8.47 (s, 1H), δ 7.59 (t, J=8 Hz, 1H), δ 7.52 (d, J=8 Hz, 1H), δ 7.19 (t, J=8 Hz, 1H), δ 6.20 (br s, 1H), δ 3.04 (d, J=5 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[CH:5]=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1.S(Cl)([Cl:26])=O>>[I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[CH:5]=[C:4]([I:11])[C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([Cl:26])=[O:19])=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=1
Reactant: CCc1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Reactant: O=S(Cl)Cl
Product: CCc1c(I)cc(I)c(-c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)c1I

Procedure:
2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carboxylic acid (13) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3′-ethyl-3-nitrobiphenyl-4-carbonyl chloride (14).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:14][Mg]Br>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:7]([OH:8])[CH3:14])[CH:9]=1
Reactant: C[Mg]Br
Reactant: COc1cc(Cl)cc(C=O)c1OC
Solvent: CCOCC
Product: COc1cc(Cl)cc(C(C)O)c1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a stirred solution of 5-chloro-2,3-dimethoxy-benzaldehyde (7.0 g, 34.90 mmol) in dry diethyl ether (500 mL) at 0° C. was added methylmagnesium bromide of 3.0 M in diethyl ether (29 mL, 87.22 mmol). The reaction mixture was brought to room temperature and stirred for 30 min; refluxed for 3 h; then cooled to 0° C. and quenched by adding saturated aqueous NH4Cl. The two liquid layers were separated. The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried, and concentrated to the crude compound which was purified by silica gel column (10-25% ethyl acetate in hexanes) to afford 1-(5-chloro-2,3-dimethoxy-phenyl)-ethanol (5.67 g, 75%): 1H NMR (400 MHz, CDCl3): δ 7.00 (d, 1H), 6.81 (d, 1H), 5.11 (m, 1H), 3.86 (s, 6H), 2.30 (d, 1H), 1.48 (d, 3H).