Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH:34]1([NH:37][CH2:38][C@@H:39]2[CH2:43][CH2:42][CH2:41][NH:40]2)[CH2:36][CH2:35]1>>[CH:34]1([NH:37][CH2:38][C@@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:36][CH2:35]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: C1CN[C@H](CNC2CC2)C1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Yield: 73.4 %

Procedure:
5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (167 mg, 0.33 mmol) was condensed with cyclopropyl-(S)-1-pyrrolidine-2-ylmethyl-amine (69 mg, 0.49 mmol) to give 152 mg (72%) of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.S(Cl)([Cl:16])(=O)=O>C(OCC)(=O)C.C(Cl)Cl>[NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[C:3]=1[Cl:16]
Reactant: Cc1nc2cc(F)c(N)cc2o1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc2cc(F)c(N)c(Cl)c2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Amino-5-fluoro-2-methylbenzoxazole (12 g, 72.22 mMole) was dissolved in ethyl acetate (100 mL) containing dry pryidine (5.8 mL, 72.22 mMole). At room temperature and with good stirring, sulfuryl chloride (7.0 mL, 86.66 mMole) was added drop by drop over a 20-minute period. After stirring at room temperature for about 30 minutes, the reaction was diluted with ethyl acetate, washed with 2N-HCl, dried (MgSO4), filtered and concentrated to give a solid. This solid was dissolved in methylene chloride and passed through a short column of silica gel eluting with methylene chloride to give the product. Yield 5.0 g.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>CN(C)C=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.3 %

Procedure:
To a solution containing 4-bromoaniline (7.42 g, 0.0431 mol) and 2-bromoacetophenone (8.58 g, 0.0431 mol) in N,N-dimethylformamide (200 mL) N,N-diisopropylethylamine was added dropwise and the reaction mixture was stirred at ambient temperature for five hours. The solvent was removed under reduced pressure and the residue partitioned between dichloromethane (150 mL) and water (100 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was suspended in diethyl ether and the precipitate was collected by filtration and dried to yield 2-(4-bromoanilino)-1-phenyl-1-ethanone (10.03 g, 0.0346 mol) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30]Cl.[OH-].[Na+].C=O>[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.C(Cl)Cl>[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][N:10]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(c1ccccc1)c1ccccc1Nc1ncccc1[N+](=O)[O-]
Reactant: CN(C)CCCCl
Agent: C=O
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: Cl
Solvent: ClCCl
Product: CN(C)CCCN(c1ccccc1C(=O)c1ccccc1)c1ncccc1[N+](=O)[O-]

Procedure:
A mixture 2 g (0.006 mole) of [2-[(3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone, 3 g (0.019 mole) of 3-dimethylaminopropyl chloride hydrochloride, 10 ml of 50% aqueous sodium hydroxide, 5 drops tricaprylylmethyl ammonium chloride (phase transfer catalyst) and 15 ml methylene chloride was stirred and maintained at reflux for 18 hrs. Chemical ionization mass spectral analysis indicated only a trace of the starting methanone was present with good conversion to the title compound. The reaction mixture was partially neutralized with 10% hydrochloric acid. The diluted but still basic mixture was extracted with methylene chloride and the methylene chloride layer evaporated to give 1.1 g brown residue predominantly the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Oc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Yield: 75.7 %

Procedure:
1 g of 2-Fluoro-5-Nitro benzotrifluoride (4.78 m.moles) was dissolved in 3 ml of DMF. To this solution was added 640 mg (5 m.moles) of 2-chloro-phenol and 2.76 grams of potassium carbonate. The reaction mixture was heated for 4 hours at 100° C. The reaction was cooled to room temperature and 200 ml of water added. It was then extracted 4 times with methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate and the solvent evaporated to yield a pale yellow oil. It was purified using silica-gel column chromatography (1:3 ethyl acetate hexane) to yield 1.15 g (87.5% yield) of pure 1-Chloro-2-[4-Nitro-2-(Trifluoromethyl)phenoxy]benzene as product.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Na].[CH:11]([C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:27])=[CH2:26])([CH3:13])[CH3:12].I[CH3:30]>C1COCC1>[CH3:30][C@@H:21]([CH2:22][CH2:23][CH2:24][C:25]([CH3:27])=[CH2:26])[C:20]([N:15]1[C@@H:14]([CH:11]([CH3:13])[CH3:12])[CH2:18][O:17][C:16]1=[O:19])=[O:28]
Reactant: C=C(C)CCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Reactant: CI
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: C=C(C)CCC[C@H](C)C(=O)N1C(=O)OC[C@@H]1C(C)C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
As reported by Schinzer et al.104 Sodium hexamethyldisilazane (13 ml of 1.0 M in THF, 13 mmol, 1.1 equiv) was added dropwise to a solution of imide 73 (3.0 g, 11.9 mmol, 1 equiv) in THF (15 ml) at −78° C. The reaction mixture was stirred for 30 min and a solution of iodomethane (3.74 ml, 60 mmol, 5 equiv) in THF (2 ml) was added dropwise. After stirring for 10 h at −78° C., the reaction was quenched with saturated aqueous ammonium chloride (10 ml), and extracted with ether (4×50 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude product 74 (12:1 ratio of diastereomers by 1H NMR). Purification by flash column chromatography (10% EtOAc/hexanes) afforded compound 74 (2.69 g, 85%) as a colorless oil: [α]22D=+ 87.2 (c=0.5, CHCl3); TLC Rf=0.47 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 4.674 (s, 1H), 4.642 (s, 1H), 4.45-4.42 (m, 1H), 4.265-4.23 (t, 2J=9 Hz, 1H), 4.2-4.17 (dd, 2J=9.6 Hz, 3J=3 Hz, 1H), 3.75-3.69 (m, 1H), 2.36-2.29 (m, 1H), 2.01-1.97 (t, 2J=7.2 Hz, 2H), 1.68 (s, 3H), 1.57-1.30 (m, 4H), 1.195-1.183 (d, 3J=7.2 Hz, 3H), 0.9-0.888 (d, 3J=7.2 Hz, 3H), 0.861-0.85 (d, 3J=6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.338, 153.886, 145.779, 110.214, 63.414, 58.628, 37.903, 37.866, 32.833, 28.632, 25.381, 22.538, 18.165, 18.132, 14.901.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH:21]3[CH:28]4[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:30][CH:22]3[CH2:23]5)[CH2:27]4)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=O)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1>[CH:22]12[CH2:30][CH:26]3[CH2:25][CH:24]([CH2:29][CH:28]([CH2:27]3)[CH:21]1[NH:20][C:19](=[O:31])[C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:9]3[CH2:8][CH2:7][CH:6]([CH2:4][OH:3])[CH2:11][CH2:10]3)=[CH:14][CH:15]=1)[CH2:23]2
Reactant: CCOC(=O)C1CCC(Oc2ccc(C(=O)NC3C4CC5CC(C4)CC3C5)cc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(OC2CCC(CO)CC2)cc1
Temperature: -35 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
In a flame dried flask was 4-[4-(adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexane carboxylic acid ethyl ester (2 g, 4.7 mmol) dissolved in dry THF (300 mL) and cooled to −35° C. To this solution was added 1M DIBAL in toluene (14 mL, 14.1 mmol) and the mixture was stirred at −35° C. for 3 hrs. and left in a freezer at −18° C. for 16 hrs. Due to incomplete reaction an additional portion of 1M DIBAL (5 mL) was added and the mixture was stirred at −18° C. for 1 hr. The reaction was quinched by slowly addition of sat. aq. NH4Cl followed by evaporation to ¼ of the volume and extracted with DCM (3×50 mL). The combined organic phases were evaporated in vacuo and the residue purified using column chromatography (Isco, 120 gram column) and a solvent gradient of heptane/AcOEt from 0 to 100%. Desired fractions were collected and the solvent evaporated in vacuo affording 1 g (60%) of N-adamantan-2-yl-4-(4-hydroxymethyl-cyclohexyloxy)-benzamide as an oil.
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:8]=[CH:7][C:6]([C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][CH2:11][C:12]#[N:13])=[CH:5][CH:4]=1.Cl[C:21]1[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=1.[Cl-].[NH4+]>CN(C)C=O.C(OCC)C.C(O)C>[Cl:27][C:26]1[C:21]([CH:11]([N:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=2)[C:12]#[N:13])=[N:22][CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:25]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCO
Solvent: CN(C)C=O
Product: N#CC(N=C(c1ccccc1)c1ccccc1)c1ncc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 60% sodium hydride (4.0 g) in dry dimethylformamide at 0-2° C. under nitrogen was dropwise added a solution of N-(diphenylmethylene)aminoacetonitrile (11.1 g) in dry dimethylformamide (60 ml) and the mixture was stirred for 1 hour at 0° C., 2,3-Dichloro-5-trifluoromethyl pyridine (7 ml) in dry dimethylformamide (20 ml) was added dropwise over 10 minutes. The mixture was stirred at 0° C. for 30 minutes and then warmed to 22° C. over 3 hours. The mixture was re-cooled to less than 10° C., and ethanol (3 ml) was added dropwise and stirring continued for 15 minutes. The mixture was poured as a thin stream into a stirred mixture of diethyl ether (500 ml) and 20% saturated aqueous ammonium chloride solution. The phases were separated and the organic phase was washed with 20% saturated aqueous ammonium chloride solution (2×150 ml). The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated onto flash silica (50 g). Chromatography over silica eluting with 5-20% diethyl ether in 40/60° Bp petrol gave the title compound, m.p. 108-110° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[B:10](OC)([O:13]C)[O:11]C>C1COCC1>[C:5]1([CH3:8])[CH:6]=[CH:7][C:2]([B:10]([OH:13])[OH:11])=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: Cc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)cc1
Temperature: -78 °C

Procedure:
Under nitrogen, a solution of 94.1 g (0.55 mol) of 4-bromotoluene in 400 mL of anhydrous THF was treated with 14.5 g (0.60 mol) of magnesium turnings. The reaction was stirred at reflux for 2 h, cooled to -78° C., treated with a solution of 156 mL (1.38 mol) of trimethyl borate in 475 mL of THF, stirred for 1 h, and allowed to warm to ambient temperature. The reaction mixture was concentrated in vacuo and partitioned between aqueous base and methylene chloride. The pH of the aqueous phase was adjusted to one with hydrochloric acid and extracted with methylene chloride. The organic phase was dried (MgSO4) and concentrated in vacuo to give 4-tolylboronic acid: NMR (CDCl3)δ2.45 (s, 3H), 7.31 (d, J=8 Hz, 2H), 8.13 (d, J=8 Hz, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:12]([NH2:13])=[N:11][C:10](Cl)=[CH:9][N:8]=1)=[O:6].[NH4+].[Cl-].[CH3:17][OH:18]>>[CH3:3][O:4][C:5]([CH:7]1[C:12]([NH2:13])=[N:11][CH:10]=[CH:9][N:8]1[O:18][CH3:17])=[O:6]
Reactant: CO
Reactant: COC(=O)c1ncc(Cl)nc1N
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: COC(=O)C1C(N)=NC=CN1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. 75 mg (1.866 mmol) 60% sodium hydride in oil was added in portions to 5 ml MeOH and the mixture was stirred at room temperature for 30 min. After re-cooling to 0° C. 350 mg (1.866 mmol) 3-amino-5-chloro-pyrazine-2-carboxylic acid methyl ester (GB 1248146) was added and the mixture was allowed to warm to room temperature and stirred over night. Saturated aqueous NH4Cl was added and the mixture was extracted with DCM and EtOAc, the combined organic layers were washed with saturated aqueous sodium chloride, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to EtOAc) to provide the title compound as colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:12][C:13]([OH:15])=O)[NH:11][CH:10]=[CH:9][S:8]2)[CH:2]=1.[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>>[CH:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[NH:16][C:13](=[O:15])[CH2:12][C:7]1([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:11][CH:10]=[CH:9][S:8]1)=[O:20]
Reactant: Nc1ccccc1C=O
Reactant: O=C(O)CC1(c2cccnc2)NC=CS1
Product: O=Cc1ccccc1NC(=O)CC1(c2cccnc2)NC=CS1

Procedure:
This compound was prepared according to the method described in Example 1c by employing 2-(3-pyridyl)-thiazole acetic acid (Step b) and o-aminobenzaldehyde (Aldrich). Mp: 70-73° C. MS m/z: 324 (M+1). Calc'd for C17H13N3O2S: 323.07.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][CH2:9][CH:5]1[C:6]([OH:8])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:35][C:36](=[O:43])[C:37](=[CH:41][CH:42]=2)[C:38]([OH:40])=[O:39])=[CH:30][CH:29]=1>ClCCl.CN(C)C(=O)C>[C:1]([N:4]1[CH2:11][CH2:10][CH2:9][CH:5]1[C:6]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[NH:35][C:36](=[O:43])[C:37](=[CH:41][CH:42]=2)[C:38]([OH:40])=[O:39])=[CH:32][CH:33]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCC1C(=O)O
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a solution of 11.8 g (75 m mol) of N-Acetyl-DL-proline and 10.5 ml (75 m mol) of triethylamine in 150 ml dichloromethane at -15° C., is added 9.75 ml (75 m mol) of isobutyl chloroformate. The reaction mixture is stirred at about -10° C. for 30 min. To this reaction mixture is added a cold solution of 11.5 g (50 m mol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid and 7.7 ml (55 m mol) triethylamine in 200 ml of N,N-dimethylacetamide, which is stirred while cooling in an ice bath for 3 hrs, then overnight at room temperature. The reaction mixture is evaporated to dryness, the residue is triturated with water, and the solid collected by filtration. The solid is washed with water and acetonitrile and dried to yield 13.2 g of 6-[4-(N-Acetyl-DL-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid, m.p. 279°-281° dec.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([F:13])[C:6]=1[F:14])=[N+]=[N-]>CCO.[Pd]>[F:14][C:6]1[C:7]([F:13])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[CH2:4][NH2:1]
Reactant: COc1cc(F)c(F)c(CN=[N+]=[N-])c1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(F)c(F)c(CN)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-azidomethyl-2,3-difluoro-5-methoxy-benzene (710 mg, 3.57 mmol) in EtOH (20 mL) was added Pd/C 10% (70 mg) and the reaction mixture was stirred at RT overnight under an H2 atmosphere. The reaction mixture was filtered through Celite, followed by washing with EtOH and CH2Cl2. The combined filtrates were evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (CH2Cl2/acetone 9:1, then CH2Cl2/MeOH 9:1) to afford the title compound as a yellowish oil. TLC Rf (CH2Cl2/MeOH 9:1)=0.32; MS (LC/MS): 174.0 [M+H]+; tR (HPLC conditions c): 2.30 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH:10]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:18])=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1,3-bis(4-chlorophenyl)-prop-2-en-1-one and diethyl malonate, diethyl 2-[1,3-bis(4-chlorophenyl)-3-oxopropyl]-malonate was obtained as colourless solid.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8](Cl)=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:27])(=[O:26])[N:17]=2)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C)C=O>[N:29]([C:8]1[C:9]2[C:14](=[N:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:28])[C:7]=1[C:16]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[S:18](=[O:26])(=[O:27])[N:17]=1)=[N+:30]=[N-:31]
Reactant: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(Cl)c2cccnc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(N=[N+]=[N-])c2cccnc21
Temperature: 25 °C
Yield: 24.6 %

Procedure:
A solution of the product of Example 165 (0.1 g, 0.24 mmol) and sodium azide (0.037 g, 0.571 mmol) in dimethylformamide (2.5 ml) was stirred at 80° C. for 1.5 hours, allowed to cool to room temperature and concentrated under reduced pressure. The crude residue was purified by a C8 HPLC column eluting with 20% to 80% acetonitrile in water with 1% trifluoroacetic acid to give the title compound (0.025 g, 26% after column purification). MS (ESI−) m/z 422 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7.35 Hz, 3H), 1.38 (m, 2H), 1.67 (m, 2H), 4.42 (t, J=7.54 Hz, 2H), 7.41 (d, J=7.72 Hz, 1H), 7.46 (dd, J=7.91, 4.60 Hz, 1H), 7.56 (m, 1H), 7.76 (m, 1H), 7.91 (dd, J=8.09, 1.10 Hz, 1H), 8.41 (dd, J=8.09, 1.84 Hz, 1H), 8.84 (dd, J=4.41, 1.84 Hz, 1H), 12.74 (s, 1H).
Reaction SMILES: C(O[NH:9][CH2:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[C:20]([O:23][C:24](=O)[CH3:25])(=[O:22])C>C(O)=O.ClCCl>[CH2:24]([O:23][C:20]([NH:9][CH2:10][CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])=[O:22])[C:25]1[CH:17]=[CH:16][CH:15]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(CNOCc1ccccc1)C(=O)O
Solvent: O=CO
Solvent: ClCCl
Product: CCCCCC(CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 199.2 %

Procedure:
To a cold solution of 2-(benzyloxyaminomethyl)heptanoic acid (1.57 g, 5.92 mmol) in HCO2H (29 mL) and dichloromethane (29 mL) was added acetic anhydride (5.9 mL, 62.75 mmol) at 0° C. The mixture was stirred at 0° C. for 3 hours. The volatiles were removed by evaporation under vacuum. Dichloromethane (50 mL) was added to the residue, and the solution was washed with brine, and dried over MgSO4. Filtration and evaporation under vacuum provided the title compound (1.73 g, 100%). 1H NMR (400 MHz, CHCl3) δ 8.07 (br s, 1H), 7.29 (m, 5H), 4.91–4.71 (m, 2H), 3.76 (m, 2H), 2.67 (m, 1H), 1.54 (m, 1H), 1.41(m, 1H), 1.20 (m, 6H), 0.80 (t, J=7.0 Hz, 3H). MH+ 294.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:10]([CH:12]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:4]1)[CH3:2].Cl.Cl[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37]>>[CH3:37][N:36]([CH3:38])[CH2:35][CH2:34][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[CH2:15][CH2:14][CH2:13][CH:12]2[C:10]([N:9]([CH2:8][C:6]1[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)[C:23]1[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=1)=[O:11]
Reactant: CCn1cc(CN(C(=O)C2CCCc3c(O)cccc32)c2ccc(C(C)C)cc2)cn1
Reactant: CN(C)CCCl
Agent: Cl
Product: CCn1cc(CN(C(=O)C2CCCc3c(OCCN(C)C)cccc32)c2ccc(C(C)C)cc2)cn1
Yield: 30.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) and 2-chloro-N,N-dimethylethylamine hydrochloride (0.22 g) as starting materials, 5-[2-(dimethylamino)ethyloxy]-N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.15 g) was obtained.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[F:21])[C:10]2[C:5](=[CH:6][C:7]([O:24][CH3:25])=[C:8]([O:22][CH3:23])[CH:9]=2)[N:4]=1.Cl.Cl.[CH3:28][N:29]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[C:30](=[O:37])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[CH3:36].N12CCCN=C1CCCCC2.O1CCOCC1>O.C(OCC)(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:24][CH3:25])=[C:8]([O:22][CH3:23])[CH:9]=3)[N:4]=[C:3]([N:41]3[CH2:40][CH2:39][CH:38]([N:29]([CH3:28])[C:30](=[O:37])[C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4[CH3:36])[CH2:43][CH2:42]3)[N:12]=2)=[C:15]([F:21])[CH:16]=1
Reactant: CN(C(=O)[C@@H]1CCCN1C)C1CCNCC1
Reactant: COc1cc2nc(Cl)nc(Nc3ccc(Cl)cc3F)c2cc1OC
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COc1cc2nc(N3CCC(N(C)C(=O)[C@@H]4CCCN4C)CC3)nc(Nc3ccc(Cl)cc3F)c2cc1OC

Procedure:
2-Chloro-N-(4-chloro-2-fluorophenyl)-6,7-dimethoxyquinazoline-4-amine hydrochloride (405 mg), N,1-dimethyl-N-piperidin-4-yl-L-prolinamide dihydrochloride (447 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (608 mg) were added to 1,4-dioxane (20 mL), followed by heating under reflux for 24 hours. After concentration of the reaction solution, ethyl acetate and water were added to the residue, the organic layer was separated, and the water layer was further extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over magnesium sulfate and then filtered. The solvent was evaporated under a reduced pressure. By purifying the residue by silica gel flash column chromatography (chloroform-MeOH), N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N,1-dimethyl-L-prolinamide was obtained. This was dissolved in ethyl acetate (10 mL), and 4 M HCl/ethyl acetate solution (0.5 mL) was added thereto. By evaporating the solvent under a reduced pressure and recrystallizing the resulting residue from EtOH-diethyl ether, N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N,1-dimethyl-L-prolinamide dihydrochloride (155 mg) was obtained as pale yellow powder.