Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:40][CH:41]=2)[CH2:31][CH2:30]1>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1) and 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography). Title compound: ESI-MS: 535.1 [M+H]+; tR=3.45 min (System 1); TLC: Rf=0.19 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C[O:12][P:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[O:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([P:13]2(=[O:12])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[O:14]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COP1Oc2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)cc1)P1(=O)Oc2ccccc2-c2ccccc21
Temperature: 130 °C

Procedure:
35 g (0.2 mol) of 4-chlorobenzoyl chloride were warmed to 90° to 100° C. under a nitrogen atmosphere. 46 g of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise while stirring. The internal temperature was then increased gradually to 130° C. When the reaction was complete, the mixture was digested with 50 ml of toluene. 60 g (85% of theory) of the abovementioned substance of melting point 125° to 131° C. were obtained.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:26])=O.Cl>CN(C)C=O.ClCCl>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([Cl:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred mixture of triphenylacetic acid (21.7 g; 0.075 mol) and dry dimethylformamide (2 drops) in dry dichloromethane (100 cm3) was treated with oxalyl chloride (14 g; 0.11 mol) which was added in 4 approximately equal portions over ˜25 minutes. The mixture was stirred at 35° until evolution of hydrogen chloride had ceased (˜4 hrs). The resulting colourless solution was evaporated in vacuo at 40° to constant weight to give the title compound as a colourless crystalline solid.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([C:11]([O:13]CC)=[O:12])=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([CH3:17])[C:3]=1[CH3:18].[OH-].[Na+].Cl>CO.C1COCC1>[OH:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=[O:12])=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([CH3:17])[C:3]=1[CH3:18]
Reactant: CCOC(=O)c1oc2c(O)c(C)c(C)cc2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(C)c(C(=O)O)oc2c(O)c1C
Temperature: 0 °C

Procedure:
Ethyl 7-hydroxy-3,5,6-trimethylbenzofuran-2-carboxylate (90 g, 0.37 mole) (from Preparation 2, Step 3) was dissolved in 1:1 MeOH/THF (600 mL) and cooled to 0° C. Dropwise addition of 2N NaOH (750 mL) followed by warming to room temperature for a 2 hr period effected saponification of the ester. The reaction was acidified with conc. HCl (150 mL) and the product extracted into EtOAc, dried (Na2SO4) and the solvent evaporated to give the carboxylic acid used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:6](N[C@@H]1CCN(C)C1)=[O:7].[CH2:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)[CH3:22]>>[CH2:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:6](=[O:7])[C:5]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:25][CH2:24]1)[CH3:22]
Reactant: CCN1CCC(N)CC1
Reactant: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1[N+](=O)[O-]
Product: CCN1CCC(NC(=O)c2ccc([N+](=O)[O-])c(OC)c2)CC1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 188, on a 9.28 mmol scale utilising 1-ethylpiperidin-4-amine (Fluorochem; 1.19 g, 9.28 mmol), as a brown solid (3.3 g, 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:25][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NC1CCCCC1
Product: O=C(NC1CCCCC1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-cyclohexyl-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.33 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.42 mmol of cyclohexylamine. LC/MS [10.52 min; 440 (M+1)]
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1.[Cl:26]N1C(=O)CCC1=O>CN(C=O)C.[Cl-].[Na+].O>[Cl:26][C:5]1[N:4]=[CH:3][C:2]([N:7]2[CH2:12][CH2:11][CH:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[N:1][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnccn3)CC2)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnc(Cl)cn3)CC2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The tert-butyl 1′-pyrazin-2-yl-4,4′-bipiperidine-1-carboxylate (64 mg, 0.19 mmol, prepared as described for Example 8) and N-chlorosuccinimide (27 mg, 0.20 mmol) were dissolved in DMF (0.9 ml) and the solution stirred overnight at 50° C. The slurry was diluted with 15% brine:water (40 ml) and extracted with ethyl acetate (3×25 ml). The combined organic fraction was washed with brine, dried over magnesium sulfate, filtered, and the volatiles removed in vac. The crude material was purified by chromatography on silica gel with 10% acetone:hexanes to yield the title compound.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI>CC(C)=O>[CH2:1]([C:5]1[N:6]([CH3:14])[CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1nc(C(=O)OC)c[nH]1
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCCc1nc(C(=O)OC)cn1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into flask containing a solution of methyl 2-butyl-1H-imidazole-4-carboxylate (1.2 g, 6.6 mmol) in acetone (40 ml), Cs2CO3 (6.5 g, 19.8 mmol) and methyl iodide (0.5 ml, 6.6 mmol) were added. The reaction mixture was stirred at RT for 4 h and the solvent was evaporated. The residue was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified with flash chromatography. Yield 500 mg. 1H-NMR (400 MHz; CDCl3): δ 0.937 (t, 3H), 1.35-1.44 (m, 2H), 1.68-1.75 (m, 2H), 2.69 (t, 2H), 3.62 (s, 3H), 3.86 (s, 3H), 7.50 (s, 1H).
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].O[CH:6]1[C:15]2[C:10](=[C:11]([F:22])[CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:14]=2[Cl:16])[S:9][CH2:8][CH2:7]1>S(=O)(=O)(O)O>[F:1][CH2:2][CH2:3][O:4][CH:6]1[C:15]2[C:10](=[C:11]([F:22])[CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:14]=2[Cl:16])[S:9][CH2:8][CH2:7]1
Reactant: OCCF
Reactant: CCOC(=O)c1cc(F)c2c(c1Cl)C(O)CCS2
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(F)c2c(c1Cl)C(OCCF)CCS2
Yield: 79 %

Procedure:
5 ml of 2-fluoroethanol and 3 drops of concentrated sulfuric acid were added to 2.4 g (8.2 mmol) of 4-hydroxy-5-chloro-6-ethoxycarbonyl-8-flurothiochroman (corresponding to compound of the formula (IX)), and the mixture was refluxed under heat for 5 hours. After allowed to cool, the reaction mixture was poured into an ice bath, and extracted with ethyl acetate twice. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 2.2 g (yield 79%) of 4-(2-fluoroethoxy)-5-chloro-6-ethoxycarbonyl-8-fluorothiochroman (corresponding to compound of the formula (X)).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(Cc3ccccc3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C23H22FN5O2, 419.2
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH3:16][N:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=[O:24].Cl[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33]>CCCCCC.C1COCC1>[CH3:33][O:32][C:27]1[CH:26]=[C:31]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][N:17]([CH3:16])[C:18]2=[O:24])[CH:30]=[CH:29][CH:28]=1
Reactant: CN1CCCCCC1=O
Reactant: COc1ccccc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C2CCCCN(C)C2=O)c1
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium (0.05 mole) in hexane (34.4 ml), was treated with 2,2,6,6-tetramethylpiperidine (9.3 ml) followed by dry THF (100 ml) under an inert atmosphere at 0° C. The mixture was treated with N-methylcaprolactam (6.9 ml, 55 mM) and stirred for 30 minutes. A solution of butyl lithium (0.05 mole) in hexane (34.4 ml) was added, the reaction mixture stirred 15 minutes then treated with o-chloroanisole (3.1 ml). After 30 minutes a solution of butyl lithium (0.05 moles) in hexane (31.25 ml) was added, the mixture stirred for 15 minutes and treated with o-chloroanisole (3.1 ml). After a further 30 minutes, the reaction was quenched with water (100 ml) and the solvents removed under reduced pressure. The residue was partitioned between 5 N HCl (100 ml) and toluene (250 ml). The organic phase was washed with brine, dried and the solvents removed under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[N:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35](Cl)(=[O:37])=[O:36])[CH:34]=1.O>C1COCC1>[Cl:28][C:29]1[C:30]([F:40])=[CH:31][C:32]([F:39])=[C:33]([S:35]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:8][CH:9]=[N:10][N:11]=2)(=[O:37])=[O:36])[CH:34]=1
Reactant: COc1ccc(CNc2nncs2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (WO 2010/079443; 5.00 g, 19.9 mmol) in THF (60 mL), lithium bis(trimethylsilyl)amide (1.0 M solution in THF; 24.0 mL, 24.0 mmol) was added at −78° C. The reaction solution was stirred at room temperature for 10 minutes, and a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride (5.41 g, 21.9 mmol) in THF (15 mL) was then added thereto at −78° C. The reaction solution was stirred at room temperature for 2 hours, and water (100 mL) was then added to the reaction solution, followed by extraction with ethyl acetate (100 mL). The thus obtained organic layer was washed with saturated saline (100 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=9:1) to yield the title compound (5.31 g, 58%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=2[CH:11]=[O:12])=[CH:4][CH:3]=1.[CH:18]([Mg]Br)=[CH2:19].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:10]=2[CH:11]([OH:12])[CH:18]=[CH2:19])=[CH:6][CH:7]=1
Reactant: O=Cc1c(F)cccc1Sc1ccc(F)cc1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1c(F)cccc1Sc1ccc(F)cc1
Temperature: -78 °C

Procedure:
2-(4-fluorophenylthio)-6-fluorobenzaldehyde (2.06 g, 8.23 mmol) is dissolved in 21 ml of dry THF and cooled to -78° C. Vinylmagnesium bromide solution (12.4 ml of a 1.0M solution in THF) is then added dropwise and the reaction mixture is allowed to warm to room temperature. The reaction mixture is then poured into saturated NH4Cl and extracted twice with diethyl ether. The extracts are washed with water and then brine and dried over K2CO3 to afford the subtitle compound.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:37](=[O:36])[CH2:38][OH:39])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)CO)C4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f26) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([O:8][CH3:9])[CH:7]=1.ClC(Cl)(Cl)C(=N)O[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: COc1cc(Cl)ccc1C
Reactant: N=C(OCN1C(=O)c2ccccc2C1=O)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cl)c(CN2C(=O)c3ccccc3C2=O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
To a solution of 5-chloro-2-methylanisole (200 mg, 1.28 mmol, purchased from APOLLO) and (1,3-dioxoisoindolin-2-yl)methyl 2,2,2-trichloroacetimidate (411 mg, 1.28 mmol, Synthesis, 2003, 7, 1065-1070) in DCM (30 mL) was added trimethylsilyl trifluoromethansulfonate (14.2 mg, 0.064 mmol) at room temperature under nitrogen. After stirring for 3 hours at room temperature, the reaction mixture was quenched with solid potassium carbonate and evaporated. The residue was chromatographed on a column of silica gel, eluting with EtOAc-Hexane=1:5 to 1:3, to give the title compound (174 mg, 43%) as white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.11 (3H, s), 3.79 (3H, s), 4.91 (2H, s), 6.81 (1H, s), 7.05 (1H, s), 7.60-7.80 (2H, m), 7.80-8.00 (2H, m). MS (ESI) m/z not observed M+ peak.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][NH3+:18].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O>>[Cl:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][NH:18][CH2:24][C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[CH:10][C:9]([C:13]#[N:14])=[CH:8]2
Reactant: N#Cc1ccc2c(Cl)c(OCC[NH3+])ccc2c1
Reactant: O=Cc1ccco1
Agent: [Cl-]
Product: N#Cc1ccc2c(Cl)c(OCCNCc3ccco3)ccc2c1
Yield: 78 %

Procedure:
Prepared from 2-[(1-chloro-6-cyanonaphthalen-2-yl)oxy]ethanaminium chloride and furan-2-carbaldehyde in 78% yield as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]=[C:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=1)C.[OH-].[K+].CO.Cl>O>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:6]([C:7]2[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=2)=[CH:5][C:4]([OH:27])=[O:3])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: CCOC(=O)C=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)cc(C(=CC(=O)O)c2ccc(OC)c(OC)c2)c1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
3-(3,4-Dimethoxyphenyl)-3-(3,5-dimethoxyphenyl)acrylic acid ethyl ester (0.76 g, 2.05 mmol), potassium hydroxide (5 N, 8.10 ml, 20.52 mmol), methanol (6 ml), and H2O (1.5 ml) were mixed and stirred at rt for a couple of hours. The methanol was evaporated in vacuo leaving a clear solution, which was extracted with ether (2×60 ml) to get rid of the impurities. The aqueous phase was acidified with conc. HCl to pH around 23 to form a white precipitation, which was extracted with CH2Cl2 (2×100 ml), dried over MgSO4, filtered and concentrated to give 3-(3,4-dimethoxy-phenyl)-3-(3,5-dimethoxy-phenyl)-acrylic acid as a foamy solid (0.69 g, 98%); mp, 90-920C: 1HNMR (CDCl3) δ 6.90-6.75 (m, 4H, double bond protons and 2COOH), 6.50-6.24 (m, 12H, Ar), 3.92-3.75 (multiple singlets, 24H, 8OCH3), isomer ratio based on 1HNMR close to 43%:57%; Anal. Calcd. For C19H20O6: C, 66.27; H, 5.85. Found: C, 66.02; H, 5.81.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](Cl)=[N:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:25][C@H:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1>O1CCOCC1>[CH2:7]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([N:30]2[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:25])[CH2:31]2)=[N:16][N:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@H]1CNCCN1
Reactant: Clc1nnc(Cc2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1CN(c2nnc(Cc3ccccc3)c3ccccc23)CCN1
Temperature: 100 °C
Yield: 64.1 %

Procedure:
Solid Na2CO3 (400 mg, 3.8 mmol, 3.8 eq) is added to a solution of 1-benzyl-4-chlorophthalazine (250 mg, 0.98 mmol, 1 eq) and (5)-2-methyl-piperazine (400 mg, 4.0 mmol, 4.0 eq) in dioxane (5 mL). The resulting suspension is heated at 100° C. for 48 h. The reaction mixture is concentrated, EtOAc (50 mL) and water (15 mL) are added. The organic fraction washed with water and then brine, then is dried over sodium sulfate. The solvent is evaporated under reduced pressure to afford the title compound as a white solid (200 mg, 64% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][N:10]1[C:14]([CH2:15][OH:16])=[CH:13][C:12]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11]1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][N:10]1[C:14]([CH:15]=[O:16])=[CH:13][C:12]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCn1nc(COc2ccccc2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCn1nc(COc2ccccc2)cc1C=O
Temperature: 100 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
Manganese dioxide (6.94 g, 79.9 mmol) was added portionwise to a stirred solution of [2-(5-hydroxymethyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (2.5 g, 5.33 mmol) in 1,4-dioxane (45 mL). The mixture was stirred at 100° C. for 16 hours and then filtered through a pad of diatomaceous earth. The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 50/50). The desired fractions were collected and the solvents were evaporated in vacuo to yield [2-(5-formyl-3-phenoxymethyl-pyrazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (0.81 g, 44% yield) as a yellow solid.
Reaction SMILES: [Zn:1].[O-2].[Zn+2].[N+:4]([O-:7])([OH:6])=[O:5]>O>[N+:4]([O-:7])([O-:6])=[O:5].[Zn+2:1].[N+:4]([O-:7])([O-:6])=[O:5]
Reactant: [Zn]
Reactant: O=[N+]([O-])O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: O=[N+]([O-])[O-]
Reaction time: 0.62 h

Procedure:
For use in preparing the aforementioned 15-0-0-5Zn solution, zinc nitrate solution containing about 16.5% zinc may be obtained commercially or prepared by reaction of metallic zinc or zinc oxide with nitric acid and introducing sufficient water to the reaction mixture to provide a zinc nitrate product solution containing about 16.5% zinc (47.8% zinc nitrate). This is accomplished by adding commercially available granular zinc oxide (containing about 80% zinc ) to a mixture of water and commercial strength (about 55%) nitric acid solution in a vessel provided with agitation and means for temperature control, e.g., coil(s) for steam heating and water cooling, together with a temperature sensing device. Typically, a 10 part batch of said zinc nitrate solution is prepared by adding to the reaction vessel about 5.8 parts of 55% nitric acid and 2.1 parts of water. After thorough mixing, granular zinc oxide is added over a period of about 15 to 30 minutes, accompanied by vigorous agitation. Once vigorous reaction has begun and during the period that it is self-sustaining, cooling is employed to maintain a reaction mix temperature of around 140° to 180° F. The rate of addition of zinc oxide granules is governed by the ability to maintain such temperature. The total reaction, generally requiring around 30-45 minutes, is usually deemed complete when substantially no particles of unreacted zinc oxide remain in the reaction mixture and the pH of said mixture has risen from about 0 to about 2 to 3.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].CCN=C=NCCCN(C)C.Cl.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:24]1[CH2:25][CH2:26][N:21]([C:1](=[O:8])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: C#CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C#CCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of hex-5-ynoic acid (500 mg, 4.46 mmol), DMAP (27 mg, 0.23 mmol) and EDC hydrochloride (940 mg, 4.90 mmol) in DCM (10 mL) was added morpholine (391 μL, 4.46 mmol). The reaction was stirred at RT overnight and then diluted with DCM (50 mL). The resulting solution was washed with water (3×10 mL), brine (10 mL) and aq hydrochloric acid (2 M, 2×20 mL) and was then dried, filtered and evaporated in vacuo to afford the title compound (11) (808 mg, 100%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ: 3.65-3.71 (4H, m), 3.63 (2H, d), 3.45-3.54 (2H, m), 2.46 (2H, t), 2.26-2.33 (2H, m), 1.98 (1H, t), 1.88 (2H, quin).