Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[N:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[F:16])[CH2:6][CH:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: Nc1ccccc1F
Reactant: CC(=O)N1c2ccccc2C(=O)CC1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccccc2C(=Nc2ccccc2F)CC1C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
[Step 1] 50 mg of 1-acetyl-4-oxo-2-methyl-1,2,3,4-tetrahydroquinoline and 83 mg of 2-fluoroaniline were dissolved in 2 mL of toluene, and 125 μL of titanium tetrachloride (1.0 M dichloromethane solution) was added to the solution under ice cooling. The resulting mixture was stirred for one hour under ice cooling, and then was stirred for 3 hours at 80° C. After completion of the reaction, the reaction liquid was filtered through Celite and was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (diethyl ether:hexane=2:1), and thus 60 mg (81%) of 1-acetyl-2-methyl-4-[(2-fluorophenyl)imino]-1,2,3,4-tetrahy droquinoline was obtained as a yellow oily substance.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[N:23][CH:22]=1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:27][C:24]2[CH:25]=[CH:26][N:21]=[CH:22][N:23]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccncn1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Product: O=C(Nc1ccncn1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (100 mg, 0.35 mmol) and 4-pyrimidinamine (CAN 591-54-8, 39.5 mg, 0.41 mmol) as starting materials; off white solid (63 mg, 49.7%). MS (ESI): 367.2 (M+H)+.
Reaction SMILES: OC[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14](CO)=[CH:13][CH:12]=2)=[CH2:10])=[CH:5][CH:4]=1.[OH:21][CH2:22]C1C=CC(COC(C2C=CC=C(CO)C=2)=C)=CC=1>>[CH2:7]([O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=1)=[CH2:10])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:20][CH:19]=1
Reactant: C=C(OCc1ccc(CO)cc1)c1cccc(CO)c1
Reactant: C=C(OCc1ccc(CO)cc1)c1ccc(CO)cc1
Product: C=C(OCc1ccccc1)c1ccc(OC)cc1

Procedure:
α-[4-(Hydroxymethyl)benzyloxy][4-(hydroxymethyl)styrene] and α-[4-(Hydroxymethyl)benzyloxy][3-(hydroxymethyl)styrene]
Reaction SMILES: C([O:3][CH:4]=[CH:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])C.[CH3:12][C:13]([CH2:15][C:16]([CH3:18])=O)=[O:14].[H-].[Na+]>C1COCC1>[OH:3][C:4]1[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[CH:18]=[CH:16][C:15]=1[C:13](=[O:14])[CH3:12]
Reactant: CC(=O)CC(C)=O
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(F)(F)F)cc1O
Yield: 28.5 %

Procedure:
4-Ethoxy-1,1,1-trifluoro-3-buten-2-one (5 g, 29.7 mmol) followed by 2,4-pentadione (3.05 ml, 29.7 mmol) were added to a cooled 0° C. suspension of NaH (2.38 g, 59.4 mmol) in THF (120 mL). The reaction mixture was refluxed for 4 hrs and then partitioned between 1N HCl and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a red oil. Purification by flash column chromatography (0% to 10% EtOAc in hexanes) gave the title compound as a yellow oil (1.73 g, 29%). 1H NMR (400 MHz, CDCl3): δ 2.69 (s, 3H), 7.15 (d, J=9.9 Hz, 1 H), 7.25 (s, 1 H), 7.86 (d, J=8.3 Hz, 1 H), 12.29 (s, 1 H).
Reaction SMILES: [OH:1][CH:2]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[CH2:3][N:4]([CH3:15])[C:5](=[O:14])/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:15][N:4]([CH2:3][C:2]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=1)=[O:1])[C:5](=[O:14])/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc(C(O)CN(C)C(=O)/C=C/c2cccnc2)ccc1O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COc1cc(C(=O)CN(C)C(=O)/C=C/c2cccnc2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a solution of (E)-N-[2-hydroxy-2-(3-methoxy-4-hydroxyphenyl)ethyl]-N-methyl-3-(3-pyridyl)-2-propenoic acid amide (656 mg, 2 mmol) in dioxane (12 ml), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (468 mg, 2 mmol) was added under argon and stirred at room temperature for 2 hours. After the precipitated crystal was filtered out, the solvent was distilled out under reduced pressure and the residue was purified by column chromatography (chloroform:methanol=50:1) and dried under reduced pressure to yield the titled compound (362 mg, 56%).
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.Cl.[F:28][C:29]([F:40])([F:39])[O:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37]N)=[CH:33][CH:32]=1>>[CH3:24][CH:23]([CH3:25])[C:22]([NH:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]3[C:35]4[C:34](=[CH:33][CH:32]=[C:31]([O:30][C:29]([F:40])([F:39])[F:28])[CH:36]=4)[NH:37][CH:2]=3)[CH2:14][CH2:13]2)[CH:16]=1)=[O:26]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC3OCCO3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCc3c[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[3-(1,3-dioxolan-2-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-[4-(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS m/e: 474.2 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:25]=[CH:24][C:13]([CH:14]=NC2C=CC(Cl)=CC=2C)=[CH:12][CH:11]=1>CCOCC>[Cl:9][C:10]1[CH:25]=[CH:24][C:13]([CH:14]=[N+:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O-:8])=[CH:12][CH:11]=1
Reactant: ONc1ccccc1
Reactant: Cc1cc(Cl)ccc1N=Cc1ccc(Cl)cc1
Solvent: CCOCC
Product: [O-][N+](=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
N-phenylhydroxylamine (0.052 mole) was dissolved in ether (20 cc). This solution was treated with N-(p-chlorobenzylidene)-2-methyl-4-chloroaniline (13.8 g.) dissolved in ether (50 cc). After 15 min., white crystals had begun to form. Filtration and washing with ether gave α-p-chlorophenyl-N-phenylnitrone.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]([Cl:20])([Cl:19])[CH:12]([NH2:18])[NH:13][C:14](=[O:17])[CH2:15][Cl:16].C(N(CC)CC)C>CC(C)=O>[Cl:10][C:11]([Cl:19])([Cl:20])[CH:12]([NH:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:13][C:14](=[O:17])[CH2:15][Cl:16]
Reactant: NC(NC(=O)CCl)C(Cl)(Cl)Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCl)NC(NC(=O)c1ccccc1)C(Cl)(Cl)Cl
Reaction time: 2 h

Procedure:
Benzoyl chloride (4.7g) in acetone (5ml) was added dropwise to a solution of 1,1,1-trichloro-2-amino-2-(chloroacetamido)ethane (8g) in acetone (50ml) containing triethylamine (3.4g). The temperature rose to 50°. The mixture was stirred for 2 hours. The salt was filtered off and the filtrate poured into water. The solid formed was collected, washed with water and dried (10g). Recrystallisation from nitromethane gave pure 1,1,1-trichloro-2-benzamido-2-(chloroacetamido)ethane (8.7g. m.p. 211°-213°).
Reaction SMILES: O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=2)=[N:17][CH:18]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:39]=2)O1.ClCCl>COCCOC.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.O>[N:42]1([CH2:41][CH2:40][N:38]2[CH:39]=[C:35]([C:13]3[CH:14]=[N:15][C:16]([C:19]4[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=4)=[N:17][CH:18]=3)[CH:36]=[N:37]2)[CH2:43][CH2:44][O:45][CH2:46][CH2:47]1
Reactant: OCc1cccc(-c2ncc(Br)cn2)c1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: OCc1cccc(-c2ncc(-c3cnn(CCN4CCOCC4)c3)cn2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
7.2 425 g (20.0 mmol) of tripotassium phosphate trihydrate and 842 mg (1.2 mmol) of bis(triphenylphosphine)palladium chloride are added to a solution, kept under nitrogen, of 2.65 g (10.0 mol) of [3-(5-bromopyrimidin-2-yl)-phenyl]methanol and 3.38 g (11.0 mmol) of 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl}morpholine in 50 ml of 1,2-dimethoxyethane, and the mixture is stirred at 80° C. for 18 hours. Dichloromethane and water are added to the reaction mixture, which is then filtered through kieselguhr, and the residue is washed with dichloromethane. The organic phase is separated off, dried over sodium sulfate and evaporated. The residue is recrystallised from 2-propanol, giving (3-{5-[1-(2-morpholin-4-ylethyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}phenyl)methanol as yellowish crystals; ESI 366.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[N:6]([S:7]([O-:10])(=[O:9])=[O:8])[C:5](=[O:11])[CH:4]1[NH:12][C:13](=[O:61])[C:14]([C:36]1[N:37]=[C:38]([NH:41]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:39][CH:40]=1)=[N:15][O:16]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH+]1C=CC=CC=1>C(O)=O>[Cl:1][CH2:2][C@H:3]1[N:6]([S:7]([OH:10])(=[O:8])=[O:9])[C:5](=[O:11])[C@H:4]1[NH:12][C:13](=[O:61])[C:14]([C:36]1[N:37]=[C:38]([NH2:41])[S:39][CH:40]=1)=[N:15][OH:16]
Reactant: O=C(NC1C(=O)N(S(=O)(=O)[O-])C1CCl)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: c1cc[nH+]cc1
Solvent: O=CO
Product: Nc1nc(C(=NO)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2CCl)cs1
Temperature: 60 °C

Procedure:
A suspension of 1.02 g of the product of Step B in 9.1 ml of formic acid containing 33% water was heated at 60° C. for 15 minutes and was reacted as in Step C of Example 3 to obtain 119 mg of racemate of syn isomer of cis 4-chloromethyl-3-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-2-oxo-azetidine-1-sulfonic acid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[C:15](=[O:16])[CH2:14][O:13][C:12]2=[O:17])=[CH:5][CH:4]=1.[CH3:20][NH2:21]>CO.O1CCCC1>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:17])[O:13][CH2:14][C:15]([NH:21][CH3:20])=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1COC(=O)N1CCc1ccc(C(F)(F)F)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)NCCc1ccc(C(F)(F)F)cc1
Reaction time: 12 h

Procedure:
A solution of 0.75 g (2.74 mmol) of 3-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3-oxazolidine-2,4-dione obtained in step 2.1., in 10 ml of methanol is admixed with 8 ml (16.47 mmol) of a solution (2M) of methylamine in tetrahydrofuran. Stirring is continued at ambient temperature for 12 hours.
Reaction SMILES: [Mg].[C:2](=[O:4])=[O:3].Cl.Br[C:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH2:19][Cl:20])=[CH:12][CH:11]=1)([CH3:9])[CH3:8].ClC(C1C=CC(C(=O)CCCCl)=CC=1)(C)C>C(#N)C.[Br-].C([N+](CC)(CC)CC)C.[Ag]>[Cl:20][CH2:19][CH2:18][CH2:17][C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]([CH3:9])([CH3:8])[C:2]([OH:4])=[O:3])=[CH:15][CH:14]=1)=[O:21]
Reactant: O=C=O
Reactant: CC(C)(Br)c1ccc(C(=O)CCCCl)cc1
Agent: [Ag]
Agent: CC(C)(Cl)c1ccc(C(=O)CCCCl)cc1
Agent: CC[N+](CC)(CC)CC
Solvent: CC#N
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
Fit a jacketed glass cell of about 50 mL capacity with an expanded silver mesh cathode (14 cm2 geometric area), a roughly concentric magnesium sacrificial anode, a tube to deliver carbon dioxide gas and a magnetic stir bar. Add a solution of hydrogen chloride remediated 1-[4-(1-bromo-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one and 1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.79 g, 89 mole %, 3:1 ratio of tertiary benzylic bromide to tertiary benzylic chloride by NMR, approximately 8.6 mmol total active tertiary benzylic halide) in acetonitrile (45 mL) and tetraethylammonium bromide (0.19 g). Close the cell and cool to −10° C. with a continuous carbon dioxide sparge for 169 minutes at an average current density of 13 mA cm−2. Warm to contents of the cell to ambient temperature, drain the contents, acidify with chilled aqueous 6M hydrochloric acid, extract and evaporate the solvent in vacuo to give the title compound (1.53 g, 66%).
Reaction SMILES: OC1C=CC(/C=C/C[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=CC=1OC.[CH3:32][O:33][C:34]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[CH:40][C:35]=1[CH:36]=[CH:37][CH2:38]Br>>[O:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[CH2:15][CH2:16][N:11]([CH2:38][CH:37]=[CH:36][C:35]3[CH:40]=[CH:41][C:42]([O:46][CH3:47])=[C:43]([O:44][CH3:45])[C:34]=3[O:33][CH3:32])[CH2:12][CH2:13]2)=[CH:18][CH:19]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1cc(/C=C/CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)ccc1O
Reactant: COc1ccc(C=CCBr)c(OC)c1OC
Product: COc1ccc(C=CCN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)c(OC)c1OC

Procedure:
The same procedure was followed as in Example 11 using the compound (9) synthesized in Example 2 and (2,3,4-trimethoxy)cinnamyl bromide to produce the above.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>C(Cl)(Cl)Cl>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][CH:2]2[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCNCC1
Reactant: COc1cccc2c1CCC2Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1CCC2N1CCCCC1
Reaction time: 8 h

Procedure:
A solution of 1-chloro-4-methoxyindan (from Step 3) in chloroform (130 ml) is added over a period of ten minutes to a stirred mixture of piperidine (284 ml) in chloroform (400 ml) under nitrogen. The reaction mixture is heated to reflux for six hours and allowed to stand at RT overnight. The mixture is treated with 10% aqueous HCl and the organic layer separated. The aqueous layer is extracted with methylene chloride and the combined organic extracts washed with 10% aqueous HCl. The organic layer is evaporated in vacuo and the residue partitioned between 5% aqueous HCl and ether. The combined aqueous fraction is washed with ether, made alkaline, and the alkaline layer extracted with ether. The ether extract is washed, dried and concentrated in vacuo yielding the piperidine indan as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:32]=[N:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([OH:41])[CH:35]=2>CN(C=O)C>[F:30][C:31]1[CH:32]=[N:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[C:36]([O:41][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)[CH:35]=2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1ccc2cc(F)cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cc(F)cnc4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (144 mg, 0.43 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (91 mg, 0.66 mmol) and 3-fluoro-7-hydroxyquinoline (77 mg, 0.47 mmol), (prepared as described for the starting material in Example 157), in DMF (3 ml) was stirred at 100° C. for 2 hours and then allowed to cool to ambient temperature. The reaction mixture was evaporated to dryness and the residue chromatographed on silica eluting with methanol/dichloromethane/aqueous ammonia (0.880) (5/100/1). The relevant fractions were combined and evaporated to dryness to give 4-(3-fluoro-quinolin-7-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (87 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[H-].[Na+].[Cl:16][CH2:17][CH2:18][CH2:19]I>CN(C=O)C>[Cl:16][CH2:17][CH2:18][CH2:19][N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:13]
Reactant: O=C1CCc2cc(F)c(F)cc2N1
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(F)c(F)cc2N1CCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A reaction flask was charged with 6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (97KK47) (0.181 g, 0.99 mmol) in dry DMF (5 mL) under an argon atmosphere. Washed NaH (0.026 g, 1.08 mmol) was added and the mixture was stirred at rt for 0.5 h. Then 3-chloro-1-iodopropane (0.205 g, 1.00 mmol) dissolved in DMF (1 mL) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into Et2O. The combined organic layers were washed with aqueous 4% MgSO4, dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; DCM) to give the title compound (112KK03) (0.122 g, 47%). 1H NMR (CD3OD) δ 6.99-6.86 (m, 2H), 4.03-3.99 (m, 2H), 3.60 (t, J=6.1, CH2), 2.84-2.81 (m, 2H), 2.63-2.59 (m, 2H), 2.13-2.06 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:10](OCC)(=[O:12])C>>[Cl:9][C:3]1[C:2]([N:1]=[C:10]=[O:12])=[C:7]([CH3:8])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1ccnc(Cl)c1N
Reactant: CCOC(C)=O
Product: Cc1ccnc(Cl)c1N=C=O

Procedure:
3-Amino-2-chloro-4-methylpyridine (4.3 g) was added to a solution of trichloromethyl chloformate (6.0 g) in ethyl acetate (100 ml) at 0° to 5° C. with stirring and the mixture was refluxed under heating for 6 hours. After removal of the solvent under reduced pressure, 2-chloro-4-methyl-3-pyridylisocyanate (4.9 g) was obtained. A mixture of 2-chloro-4-methyl-3-pyridylisocyanate (4.9 g) and trimethylsilyl azide (11 g) was refluxed under heating for 30 hours. After removal of excess trimethylsilyl azide under reduced pressure, methanol was added to the resulting residue. Thereafter, the methanol was distilled off under reduced pressure. The resulting residue was purified by flash column chromatography (eluent chloroform:ethanol=15:1) to obtain the desired 1-(2-chloro-4-methyl-3-pyridyl)-5(4H)-tetrazolinone (3.0 g). n.p. 160°-162° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:16].[CH3:17][S:18](Cl)(=[O:20])=[O:19].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])=[C:3]([F:16])[CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)c(F)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: Cn1c(C#N)ccc1-c1ccc(NS(C)(=O)=O)c(F)c1
Reaction time: 4 h
Yield: 79.5 %

Procedure:
5-(4-amino-3-fluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.15 g, 0.70 mmol) was dissolved in pyridine (1.5 mL), methane sulfonyl chloride (0.05 mL, 0.63 mmol) was added, the mixture was stirred for 4 hours, and then water was added. The mixture diluted with ethyl acetate and the mixture was washed with water, saturated CuSO4, 2N HCl, brine, dried over MgSO4, and concentrated. Flash chromatography (5%-50% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2-fluorophenyl]methane sulfonamide (0.147 g).
Reaction SMILES: [CH2:1]([N:13]1[C:17]([CH:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)C(OCC)=O)=[N:16][N:15]=[N:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>C(O)C>[CH2:18]([C:17]1[N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:14]=[N:15][N:16]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCCCCCCCCCCCn1nnnc1C(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCn1nnnc1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
(±)-1-Dodecyl-α-phenyl-1H-tetrazole-5-acetic acid, ethyl ester, i.e., the compound of Example 13(c) (14 g; 0.034 mmoles) was dissolved in absolute ethanol (175 mL) and treated with sodium hydroxide pellets (2.7 g; 0.069 mmoles). The solution was stirred for 30 minutes forming a gelatinous precipitate. The solid was removed by filtration, dissolved in water, and then acidified to a pH of 1.0 using concentrated HCl. The precipitate was collected by filtration and washed with water. Yield: 8.5 g (76%), mp 50°-51° C.
Reaction SMILES: C([O:4][C:5]1[CH:37]=[CH:36][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[N:12]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]2=[O:35])=[CH:7][CH:6]=1)(=O)C.Cl>CO.C1(C)C=CC=CC=1>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:15])[N:12]([C:16]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]2=[O:35])=[CH:36][CH:37]=1
Reactant: CC(=O)Oc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A solution of 2.99 g of a 28% w/v methanolic solution of sodiumamethoxide in 10 ml of methanol was added dropwise, whilst ice-cooling, to a solution of 7.86 g of 5-(4-acetoxybenzyl)-3-triphenylmethyl-thiazolidine-2,4-dione [prepared as described in step (c) above] in 70 ml of toluene, and the resulting mixture was stirred at room temperature for 1 hour, after which it was allowed to stand overnight at the same temperature. The pH of the reaction mixture was then adjusted to a value of 4 by the addition of 1N aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the crystals which appeared in the residue were collected, washed with hexane and dried, to give 6.0 g of the title compound.