Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:31])=[C:21]([N:26]4[CH2:30][CH:29]=[CH:28][CH2:27]4)[C:22]=3[O:24][CH3:25])[C:17](=[O:32])[C:16]([C:33]([OH:35])=[O:34])=[CH:15]2)[CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C@@H:28]2[CH2:27][N:26]([C:21]3[C:22]([O:24][CH3:25])=[C:23]4[C:18]([C:17](=[O:32])[C:16]([C:33]([OH:35])=[O:34])=[CH:15][N:14]4[CH:11]4[CH2:12][CH2:13]4)=[CH:19][C:20]=3[F:31])[CH2:30][C@@H:29]2[O:1][N:2]=1
Reactant: ON=C(Cl)c1ccccn1
Reactant: COc1c(N2CC=CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1c(N2C[C@@H]3ON=C(c4ccccn4)[C@@H]3C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
Chloro oxime 2e (70 mg; 0.44 mmol), olefin 119 (100 mg; 0.29 mmol) and sodium bicarbonate (50 mg) in ethyl acetate (10 mL) were heated at reflux temperature overnight. The solid was filtered and the filtrate evaporated. The residue was triturated with methanol to yield acid 122.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[CH3:27][NH:28][CH3:29]>CO>[CH3:27][N:28]([C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH:7]([CH3:8])[CH2:2]1)[CH3:29]
Reactant: CNC
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(N(C)C)CC3C)c(F)c2)C(=O)O1
Yield: 70 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with 40% aqueous solution dimethylamine (1.72 mmol) in methanol (10 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 70% yield.
Reaction SMILES: [C:1]([NH:10][NH2:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:12][C:13]([Cl:19])([Cl:18])[C:14](=[NH:17])OC>>[Cl:12][C:13]([Cl:19])([Cl:18])[C:14]([NH:11][NH:10][C:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])=[NH:17]
Reactant: NNC(=O)c1ccccc1O
Reactant: COC(=N)C(Cl)(Cl)Cl
Product: N=C(NNC(=O)c1ccccc1O)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 3.8 g (0.025 mole) salicoylhydrazine and 10 ml (14.3 g, 0.08 mole) methyl 2,2,2-trichloroacetimidate was stirred 16 hours at room temperature. The solid that formed was washed with petroleum ether and dried to give 7.5 g (100% Yield; mp 168°-169° C.). The structure was confirmed via infrared and elemental analysis.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:11][CH:10]=1
Reactant: OC1CCNCC1
Reactant: Cc1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CCC(O)CC2)cc1
Reaction time: 18 h
Yield: 482.9 %

Procedure:
1.15 g (0.00114 mol) of 4-hydroxypiperidine were dissolved in 15 ml of dimethylformamide and cooled to 0°. 1.92 g (0.001037 mol) of 4-methylbenzyl bromide and 1.59 ml (0.0114 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 18 hrs., the solvent was distilled off and the residue was taken up in ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dichloromethane/methanol (9:1) as the eluent. 1.028 g (48%) of 1-(4-methyl-benzyl)-piperidin-4-ol were obtained as beige crystals; m.p. 72°-74°.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH:5]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][CH2:7][CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([O:11]CC)=[O:10])C.[OH-].[K+]>O.CO>[C:34]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][CH:5]([CH2:6][CH2:7][CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]([OH:11])=[O:10])[C:4]([OH:40])=[O:3])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)C(CCC(Cc1ccccc1-c1ccccc1)C(=O)OCC)Cc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(CCC(Cc1ccccc1-c1ccccc1)C(=O)O)Cc1ccccc1-c1ccccc1
Yield: 85 %

Procedure:
To the 2,5-bis(2-phenyl-benzyl) adipic acid diethylester, obtained as described above, were added 180 mL of a solution of 6 M KOH in H2O/MeOH and the reaction mixture was refluxed for 16 hours. MeOH was removed on a rotary evaporator and the aqueous layer was washed with Et2O (2×200 mL). The alkaline aqueous layer was acidified, at 0° C., with HCl 37% to pH 1. A white/yellow powder was formed, filtered off and washed with water and a little hexane. Said powder was thoroughly dried, to afford 77.0 g of 2,5-bis(2-phenyl-benzyl) adipic acid (85% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]([O:24][CH3:29])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C(O)c3ccccc3)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(c1ccccc1)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 6-(hydroxy-phenyl-methyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.15 g, 0.42 mmol) in THF (5 mL) was added sodium hydride (60%, 0.02 g, 0.50 mmol) and the mixture was stirred for 1 h. Methyl iodide (52 μL, 0.84 mmol) was added and the reaction mixture was stirred for 18 h at ambient temperature. Water (10 mL) was added and the product was extracted with EtOAc (2×10 mL). The combined organic phase was dried (MgSO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-70% EtOAc in 40-60 petroleum ether) gave the title compound (0.11 g, 70%) as an oil. MS: [M+H]+=369.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16].[BH4-].[Na+].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCCOc1cc(C=O)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1cc(CO)ccc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the title A compound, 4-methoxy-3-(3-methoxy-propoxy)-benzaldehyde (2.02 g, 8.9 mmol) in 60 mL of THF is added portion wise sodium borohydride (0.74 g, 18.73 mmol) at 0° C. The reaction mixture is stirred for 6 hours at room temperature. After addition of H2O, the aqueous layer is extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as a colorless oil: TLC, Rf (hexane/AcOEt 1/1)=0.34.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.O.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:13][C:3]1[C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7][N:6]2[C:8]([NH2:11])=[N:9][N:10]=[C:5]2[C:4]=1[CH3:12]
Reactant: C1CCNC1
Reactant: Cc1c(Cl)nn2c(N)nnc2c1C
Solvent: O
Product: Cc1c(N2CCCC2)nn2c(N)nnc2c1C
Temperature: 65 °C

Procedure:
6-Chloro-7,8-dimethyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.006a, 500 mg) were initially charged in pyrrolidine (5 ml) at RT while stirring. Then the mixture was heated to 65° C. for 4 h. Thereafter, the pyrrolidine was drawn off, and the residue was taken up with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 438 mg of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 68.2 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (2.62 g, 14 mmol), cesium carbonate (5 g, 15 mmol) and ethyl bromoacetate (1.56 ml, 14 mmol) was stirred at room temperature for 1 h. The mixture was partitioned between water (200 ml) and diethyl ether (2×100 ml). The combined organic phases were dried over magnesium sulphate and concentrated to give a yellow oil which crystallised to give 4-ethoxycarbonylmethyl-piperazine-1-carboxylic acid tert-butyl ester as a pale yellow solid (2.6 g)
Reaction SMILES: CCCC[Sn]([C:14]1[N:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(CCCC)CCCC.Cl[C:21]1[N:26]=[C:25]2[S:27][C:28]([CH3:30])=[CH:29][C:24]2=[CH:23][C:22]=1[C@@H:31]([N:33]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:43])[CH3:32]>O1CCOCC1.C(OCC)(=O)C>[CH3:30][C:28]1[S:27][C:25]2=[N:26][C:21]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:19]=3)=[C:22]([C@@H:31]([N:33]3[C:34](=[O:43])[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:41]3=[O:42])[CH3:32])[CH:23]=[C:24]2[CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1cc2cc([C@H](C)N3C(=O)c4ccccc4C3=O)c(Cl)nc2s1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc2cc([C@H](C)N3C(=O)c4ccccc4C3=O)c(-c3ccccn3)nc2s1
Temperature: 100 °C

Procedure:
In a reaction vessel was combined 2-(1,1,1-tributylstannyl)pyridine (0.124 ml, 0.370 mmol), tetrakis triphenylphosphine(0) (35.6 mg, 0.031 mmol), (S)-2-(1-(6-chloro-2-methylthieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione (110 mg, 0.308 mmol) in dioxane (3 mL). The reaction was heated to 100° C. for 2 d, cooled to rt, and diluted with ethyl acetate. The organic phase was washed with NaHCO3 and brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography afforded (S)-2-(1-(2-methyl-6-(pyridin-2-yl)thieno[2,3-b]pyridin-5-yl)ethyl)isoindoline-1,3-dione. 1H NMR (400 MHz, CDCl3) δ 8.64 (ddd, J=4.7, 1.8, 0.8 Hz, 1H), 7.72 (td J=7.8, 2.0 Hz, 1H), 7.67 (m, 3H), 7.62 (m, 2H), 7.29 (ddd, J=7.4, 4.9, 1.6 Hz, 1H), 6.98 (q, J=1.4 Hz, 1H), 6.30 (q, J=7.0 Hz, 1H), 2.60 (d, J=1.2 Hz, 3H), 1.97 (d, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:26])([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:26][CH3:27])([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(-c3ncccn3)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(-c3ncccn3)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Hydroxy-4-(4-pyrimidin-2-yl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester 81 (138 mg, 0.39 mmol) was dissolved in DMF (2 mL) and cooled to 0° C. MeI (0.1 mL) was added followed by the addition of NaH (26 mg, 60% suspension in mineral oil). After 30 min at 0° C., the reaction was quenched with sat. NH4Cl and extracted with ethyl acetate. The combined organic layers was washed with brine, dried and concentrated in vacuo. The residue was purified with prep TLC plates (developing with 50% ethyl acetate/hexanes) to yield a colorless film (80 mg) as the title compound.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9]([CH2:12]O)=[N:10][N:11]=2)=[CH:3][CH:2]=1.S(Cl)([Cl:29])=O.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:9]([CH2:12][Cl:29])=[N:10][N:11]=2)=[CH:3][CH:2]=1
Reactant: OCc1nnc(-c2ccc(-c3ccccc3)cc2)n1-c1ccccc1F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1ccccc1-n1c(CCl)nnc1-c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
[5-Biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl]methanol (1.81 g) was suspended in toluene (25 ml), followed by addition of thionyl chloride (1.5 ml) and chloroform (25 ml), and stirred at 60° C. for 5 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the reaction solution, which was washed with saturated aqueous sodium hydrogen carbonate solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting white solid was washed with a mixture solution of n-hexane and ethyl acetate, to afford the entitled compound as white solid (1.54 g, 81%). The physico-chemical values are as follows.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[C:12]([NH2:20])=[CH:11][C:10]=1[C:21]([F:24])([F:23])[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](C1NC=CN=1)(C1NC=CN=1)=[O:26]>ClC1C=CC=CC=1Cl>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]2[C:12]([NH:20][C:25](=[O:26])[C:16]3[N:15]2[CH:19]=[CH:18][N:17]=3)=[CH:11][C:10]=1[C:21]([F:24])([F:22])[F:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(C(F)(F)F)c(NCc2ccccc2)cc1-n1ccnc1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: Clc1ccccc1Cl
Product: O=c1[nH]c2cc(C(F)(F)F)c(NCc3ccccc3)cc2n2ccnc12
Yield: 41.7 %

Procedure:
A solution of N-benzyl-5-(1H-imidazol-1-yl)-2-(trifluoromethyl)benzene-1,4-diamine (160 mg; 0.48 mmol; 1 eq) and carbonyl diimidazole (156 mg; 0.96 mmol; 2 eq) in 1,2-dichlorobenzene (20 ml) is stirred under argon at reflux for 3 h. Concentration, filtration over a small silicagel pad with ethyl acetate as eluent and purification by prep CCM on silicagel (ethyl acetate) affords the title product (72 mg; 0.2 mmol; 42%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([S:19][CH3:20])[CH:12]=1.[Na].C[OH:28]>O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([S:19]([CH3:20])=[O:28])[CH:12]=1
Reactant: CO
Reactant: COc1ccccc1OCCNC(C)Cc1ccc(OC)c(SC)c1
Agent: [Na]
Solvent: O
Product: COc1ccccc1OCCNC(C)Cc1ccc(OC)c(S(C)=O)c1

Procedure:
In 100 ml of a mixture of methanol and water (5:1) was dissolved 1.8 g of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole and after adding dropwise thereto 10.5 ml of an aqueous solution of 0.5M sodium metaperoiodate at 0° C., the mixture was stirred overnight at 4° C. The crystals formed were removed by filtratation and the filtrate was concentrated under reduced pressure and the residue formed was purified by a silica gel column chromatography (eluate: a mixture of chloroform and methanol (97:3 by volume ratio) to provide 722 mg of oily 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisole. The product was dissolved in 10 ml of methanol and after adding thereto a solution of 252 mg of oxalic acid di-hydrate dissolved in 6 ml of methanol, the mixture was allowed to stand overnight at room temperature. The resulting crystaline material was recovered by filtration and recrystallized from ethanol to provide 700 mg of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisole oxalate having a melting point of 172°-174° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([S:27]([N:3]2[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[CH3:1])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(Cl)c2)c1C
Yield: 49.3 %

Procedure:
Using ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (1.53 g), sodium hydride (60% in oil, 303 mg) and 3-chlorobenzenesulfonyl chloride (848 mg), a procedure as in Reference Example 41 was performed to give the title compound as a brown oil (yield 800 mg, 30%).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: COc1ccccc1B(O)O
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: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1-c1nc2c(C)cccc2cc1C=O
Yield: 90.1 %

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline 3-carbaldehyde (0.206 g, 1 mmol), 2-methoxyphenyl boronic acid (0.167 g, 1.1 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.058 g, 0.05 mmol, 0.05 eq), and sodium carbonate (0.530 g, 5 mmol, 5 eq) in acetonitrile (7.5 mL) and water (2.5 mL). After purification, 2-(2-methoxyphenyl)-8-methylquinoline-3-carbaldehyde (0.250 g, 90%) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.86 (1H, s), 8.88 (1H, s), 8.13 (1H, d, J=8.1 Hz), 7.85 (1H, d, J=7.1 Hz), 7.56-7.74 (3H, m), 7.22-7.30 (2H, m), 3.78 (3H, s), 2.80 (3H, s) Mass Spectrum (ESI) m/e=278.0 (M+1)
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C(O)COCCO>[CH3:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[N:19]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH3:15])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1ccccc1N
Reactant: Cc1cccc2c1=NC(=O)C1CCOC=21
Solvent: OCCOCCO
Product: Cc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Temperature: 250 °C
Yield: 81.6 %

Procedure:
4-Oxo-6-methyl-2,3-dihydrofuro[3,2-c]quinoline (201 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and 2-methylaniline (267 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted with 20 ml of saline and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried with anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 237 mg of a desired compound as solid in 82 % of yield.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1c(Br)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 1 h

Procedure:
A mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (3.64 g) and N-bromosuccinimide (1.78 g) in carbon tetrachloride (30 ml) was stirred and heated under reflux for 1 hour. Further N-bromosuccinimide (0.89 g) was added, and reflux was continued for a further 1 hour. The mixture was cooled, filtered, and the filtrate was evaporated in vacuo to give an orange solid. Recrystallization from petroleum ether gave 5-amino-4-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole in the form of white crystals (2.6 g) m.p. 119°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:6]
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 2-fluoro-5-methoxy-4-nitro-benzoic acid (Intermediate 29; 861 mg, 4.00 mmol) in DMA (20 mL) was added 4-amino-1-methylpiperidine (Fluorochem; 503 mg, 4.40 mmol) followed by DIPEA (1.4 mL, 8.00 mmol) and HATU (1.68 g, 4.40 mmol) and the resulting yellow solution stirred at room temperature for 1 hr. The solvent was removed under reduced pressure and the residue taken up in methanol (approx 10 mL) and loaded onto a 20 g SCX-2 cartridge washing with methanol (50 mL) and eluting with 7 N methanolic ammonia (50 mL) to give a yellow solid, 1.47 g. This was purified by flash silica chromatography (Companion, 40 g, 0-5% ammonia in methanol/DCM) to give the desired product as a pale yellow solid (1.25 g, 4.00 mmol, 100%.)