Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([CH3:14])=[C:12](I)[C:11]([F:16])=[C:10]([O:17][CH3:18])[C:9]=1[NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])#[N:7].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>[Cl-].[Na+].O>[C:6]([C:8]1[C:9]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:10]([O:17][CH3:18])[C:11]([F:16])=[C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]=1[CH3:14])#[N:7]
Reactant: COc1c(F)c(I)c(C)c(C#N)c1NC(=O)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(F)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Under nitrogen atmosphere, tetrakistriphenylphosphine palladium(0) (288 mg, 0.25 mmol) was added to an N,N-dimethylformamide (15 ml) suspension of N-(2-cyano-5-fluoro-4-iodo-6-methoxy-3-methylphenyl)-2,2,2-trifluoroacetamide (I-35) (500 mg, 1.24 mmol), phenylboronic acid (228 mg, 1.87 mmol), potassium phosphate n-hydrate (890 mg, 3.1 mmol), followed by stirring with heating under reflux for 15 hours and a half. After cooling to room temperature, water and saturated brine were added to the reaction liquid, followed by extraction three times with ethyl acetate, the organic layer was washed with saturated ammonium chloride water, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (5:1) was concentrated under reduced pressure to obtain the entitled compound (427 mg, 98%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7](Cl)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>N1C=CC=CC=1.CN(C=O)C>[C:7]([NH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: NCC(O)CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)NCC(O)CO
Reaction time: 1 h

Procedure:
To a mechanically stirred solution of 3-amino-1,2-propanediol (32 g, 0.35 mol) in 100 mL of pyridine and 250 mL of DMF was added a solution of stearoyl chloride (100.0 g, 0.33 mol) in 150 mL of DMF. After stirring for 1 h, precipitation occurred and an additional 100 mL of DMF was added. After 2 h, the gelatinous mass was filtered, washed with water, and air dried. The solid was recrystallized successively from EtOH, isopropanol, and chloroform to give 74 g (63%) as a white powder (mp 111.5-113.5° C.). 1H-NMR: 0.86 (t, 3H, CH3), 1.25 (broad m, 28H, (CH2)14), 1.55 (m, 2H, NHCOCH2CH2), 2.20 (t, 2H NHCOCH2), 3.4 (m, 2H, CH2NH), 3.55 (d, 2H, CH2OH). 3.75 (m, 1H, CH), 5.8 (m, 1H, NH).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.[CH:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>Cl>[CH:21]1([CH2:27][CH2:28][CH2:29][N:30]2[CH2:2][CH:3]3[CH:5]([C:4]3([CH3:20])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[C:6]2=[O:8])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Reactant: NCCCC1CCCCC1
Agent: Cl
Product: CC1(c2cccc([N+](=O)[O-])c2)C2CN(CCCC3CCCCC3)C(=O)C21
Yield: 72.6 %

Procedure:
A solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 5, 1 g, 3.36 mmol) in 3-cyclohexylpropylamine ([Preparation—Eur. J. Med. Chem. (1992), 27, 321–330], 2.9 g, 20.5 mmol) was heated to 160° C. for 16 h. The mixture was cooled, 2N hydrochloric acid solution (20 ml) was added and the mixture was extracted with dichloromethane (3×20 ml). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (200 g) column chromatography eluting with dichloromethane then diethyl ether. Appropriate fractions were combined and concentrated in vacuo to give the title compound as an amber oil (870 mg, 73%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]1=2.C(N(CC)CC)C.[N:22]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.OP(O)(O)=O>ClCCCl.CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:25]1[CH2:26][CH2:27][N:22]([S:28]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]2=3)(=[O:30])=[O:29])[CH2:23][CH2:24]1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: COC(=O)c1cnc2c(c1)NCCO2
Agent: CN(C)c1ccncc1
Agent: O=P(O)(O)O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc2c(c1)N(S(=O)(=O)N1CCOCC1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
Methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (97 mg, 0.50 mmol) was suspended in 4 mL of DCE and sequentially treated with DMAP (61 mg, 0.50 mmol) and triethylamine (0.077 mL, 0.55 mmol). Morpholine-4-sulfonyl chloride (102 mg, 0.55 mmol) was added and the mixture was stirred at ambient temperature for 2 hours and then heated to 50° C. for 2 days. The mixture was cooled to ambient temperature and diluted with 10 mL of DCM and the whole solution poured into 15 mL of 1M aqueous H3PO4. The layers were separated and the aqueous layer was extracted with 10 mL of DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by normal phase flash chromatography (gradient elution 50% to 100% EtOAc/Hexanes) to provide 88 mg (51%) of the title compound as a thick tan oil. 1H NMR (CDCl3) δ 8.59 (d, 1H), 8.34 (d, 1H), 4.48 (m, 2H), 3.86 (s, 3H), 3.77 (m, 2H), 3.69 (m, 4H), 3.26 (m, 4H). LCMS (+ESI) m/z=344.1 [M+H]+.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([S:13][C:14]2[CH:15]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11]>Cl.C1COCC1.O>[CH:3]([C:4]1[CH:5]=[C:6]([S:13][C:14]2[CH:15]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:2]
Reactant: COC(OC)c1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Sc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[3-(3-dimethoxymethyl-4-nitro-phenylsulfanyl)-phenyl]-benzenesulfonamide (0.027 mol) in 12N HCl (25 mL), THF (75 mL) and water (50 mL) was stirred overnight at room temperature, and then the mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous Na2CO3 solution. The solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2). The product fractions were collected and the solvent evaporated to yield the title compound as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C@@H:11]([CH3:14])[CH2:12][CH3:13])[CH2:7]C(O)=O)=[O:4].Cl.Cl.[CH2:17]([NH:24][NH2:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N([OH:55])N=NC=2C=1>C1COCC1>[CH2:17]([NH:24][NH:25][C:7]([C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C@@H:11]([CH3:14])[CH2:12][CH3:13])=[O:55])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: On1nnc2ccccc21
Reactant: NNCc1ccccc1
Reactant: CC[C@H](C)[C@H](CC(=O)O)NC(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NNCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
A solution of Example 3A (3.32 g, 17.5 mmol) in THF (70 mL) was treated with benzylhydrazine di-HCl salt (3.42 g, 1 equivalent), diisopropylethyl amine (9.2 mL, 3 equivalents), EDAC (6.05 g, 1.8 equivalents), and HOBT (3.56 g, 1.5 equivalents), and stirred at 25° C. for 16 hrs. The solvents were evaporated, and the crude residue was partitioned between chloroform and 10% sodium bicarbonate. The organic layer was separated, washed with 10% sodium bicarbonate, brine, dried over sodium sulfate, filtered and the solvents were evaporated. The crude residue was purified using 1% methanol/chloroform to give 2.41 g (47%) of the title compound.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([NH:10][S:11](Cl)(=[O:13])=[O:12])[CH3:9].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([O:7][S:11](=[O:13])(=[O:12])[NH:10][CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CCNS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCNS(=O)(=O)Oc1ccccc1
Yield: 70.8 %

Procedure:
A solution of 18.8 g (0.2 mole) of phenol and 38.4 g (0.27 mole) of ethylaminosulfonyl chloride (prepared using procedure of Example 2, pt. a) in 150 ml of toluene was stirred and heated at reflux for 16 hr. The solution was cooled and then treated with 250 ml of a 20% sodium bicarbonate solution. The layers were separated and the organic layer was washed successively with 250 ml of a 20% sodium bicarbonate solution, two 300-ml portions of water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure and the oily residue was purified by chromatography (4.5×105 cm glass column; 550 g of silica gel; ethyl acetate-hexanes, 1:16). Fractions containing the product were combined and the solvents evaporated under reduced pressure to give 28.5 g (71%) of the title compound as a colorless liquid. Elemental analysis suggested that the product contained water.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1.NC1C=CC=C(C)C=1C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13]([CH2:12][C:11]([CH3:10])=[O:15])=[O:14])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1ccc(N)c(C)c1
Reactant: C=C1CC(=O)O1
Agent: Cc1cccc(N)c1C
Product: CC(=O)CC(=O)Nc1ccc(C)cc1C

Procedure:
After the pressure drop (column 1: approx. 45 mbar, column 2: approx. 25 mbar) und the temperature profile (73-77° C.) had stabilized, m-xylidine (16.9 kg/h) was fed to the 2nd plate and diketene (total 12.0 kg/h) to plate Nos. 14, 15 and 16 of the first column. The diketene feed was started only after the xylidine-containing reflux had reached plate No. 14.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([O:7]CC)=O)=[O:2].[CH:10]1([C:13](=[N:15]O)[NH2:14])[CH2:12][CH2:11]1>CCO>[CH:10]1([C:13]2[N:15]=[C:5]([CH2:4][NH:3][CH:1]=[O:2])[O:7][N:14]=2)[CH2:12][CH2:11]1
Reactant: CCOC(=O)CNC=O
Reactant: NC(=NO)C1CC1
Solvent: CCO
Product: O=CNCc1nc(C2CC2)no1
Temperature: 25 °C

Procedure:
A solution of ethyl formylaminomethyl-carboxylate (150 mmol) and cyclopropyl carboxamide oxime (100 mmol) in 100% EtOH (100 ml) was charged with Na (200 mg) and crushed molecular sieves (4 Å) (10 g). The mixture thus obtained was stirred and heated to reflux for 8 hours. The mixture was cooled to room temperature, filtered through filter aid and the filtrate was evaporated in vacuo. The oily residue was partitionated into a CHCl3 phase which was dried with Na2SO4 and evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][NH:13][C:12](=[O:16])[CH:11]=2)=[N:6][CH:7]=1.[C:17]([O:21][C:22]([N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][C:28]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][C:28]([CH2:34][CH2:35][N:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]4[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=4)=[CH:11][C:12]3=[O:16])=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)cc1
Reactant: O=c1cc(OCc2ccc(Br)cn2)cc[nH]1
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ccc(OCc4ccc(Br)cn4)cc3=O)cc2C1

Procedure:
7-{2-[4-(5-Bromo-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester is prepared following example 24.1 from 562 mg (2.00 mmol) 4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 22.2) and 863 mg (2.00 mmol) 7-[2-(toluene-4-sulfonyloxy)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 7).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:7][N:6]=1.ClC[CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([O-:23])=[O:22].O1CCC[CH2:27]1>CCOCC>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:27][O:23][C:21](=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19])[C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[CH:7][N:6]=1
Reactant: C1CCOC1
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: COc1ccc(NC(=O)C2CC2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(N(COC(=O)C(C)(C)C)C(=O)C2CC2)cn1
Reaction time: 0.33 h

Procedure:
Sodium hydride (0.5 g, 0.019 mol) was suspended in dry tetrahydrofuran followed by addition of N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide and a gas was evolved. The reactoin was stirred for 20 minutes and then chloromethylpivalate (2.9 g, 0.019 mol) was added. The reaction was stirred for two hours until pH was near neutral, and then diluted with ether and washed with water. The ether phase was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 3.4 g of a yellow oil. This was extracted with hexane leaving some residue and passed through a 1" pad of florisil. This gave an evaporation of the solvent in vacuo, 1.8 g of tht title compound as a yellow oil. The structure was confirmed by MS, IR and NMR analysis.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[Br:29][CH:30]=[CH:31][CH2:32]Br>>[Br:29][CH:30]=[CH:31][CH2:32][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:5]([CH2:4][C:3]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=2[F:1])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=2[CH3:15])=[CH:18][CH:19]=1
Reactant: BrC=CCBr
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Product: Cc1c(N(Cc2ccc(OCC=CBr)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]

Procedure:
The product from Example 33A and 1,3-dibromo-1-propene were processed as described in Example 33B to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[NH4+].[H][H]>CN(C=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@H]1CCOC1
Agent: [Ni]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1O[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
100 g of 4-[(3-chloro4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline are hydrogenated in 400 ml DMF in the presence of 33.1 g Raney nickel and 18.7 g ammonium chloride at 40° C., until the calculated amount of hydrogen has been taken up. The catalyst is filtered off and the filtrate is added dropwise to 1.2 l water. The suspension is stirred for 2.5 h at 0° C., suction filtered and washed with 500 ml of water. The residue is dried overnight at 55° C. under reduced pressure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[CH2:9]1.[Cl:15][C:16]1[C:22](Cl)=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1>CN(C=O)C.CCOC(C)=O>[NH2:20][C:19]1[C:18]([N+:24]([O-:26])=[O:25])=[CH:17][C:16]([Cl:15])=[C:22]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]#[N:14])[CH2:9]2)[CH:21]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: N#CC1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CC1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (2.93 g, 21.3 mmol) was added to a mixture of pyrrolidine-3-carbonitrile hydrochloride (1.41 g, 10.6 mmol) and 4,5-dichloro-2-nitroaniline (2.00 g, 9.7 mmol) in DMF (8 mL). The reaction mixture was stirred at 120° C. overnight, diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, concentrated and the crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([N+:13]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>[Ni].CO>[Cl:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])c1cc(F)c(Cl)c2cccnc12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1cc(F)c(Cl)c2cccnc12
Yield: 49.3 %

Procedure:
In a similar fashion using route 6 general procedure 14, 5-chloro-6-fluoro-8-nitroquinoline (Intermediate 41) (300 mg, 1.34 mmol), Raney nickel (60 mg, 20% wt), hydrazine hydrate (270 mg, 5.40 mmol) and MeOH (5 ml) gave the title compound (130 mg, 49%) which was used in the next step without purification.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1.[CH2:13]([OH:15])C>O1CCCC1>[CH3:13][O:15][C:9]([CH:8]1[CH:7]([C:6]([OH:11])=[O:12])[CH:4]2[CH:5]=[CH:1][CH:2]1[CH2:3]2)=[O:10]
Reactant: CCO
Reactant: C1=CCC=C1
Reactant: O=C1C=CC(=O)O1
Solvent: C1CCOC1
Product: COC(=O)C1C2C=CC(C2)C1C(=O)O
Yield: 79.6 %

Procedure:
In a reactor, cyclopentadiene (66 g) was charged, and tetrahydrofuran solvent (500 g) and maleic anhydride (98 g) were added thereto, and the mixture was stirred homogeneously. To the reaction mixture, pure ethanol (500 g) was added and the reaction was carried out with stirring at 50° C. for 8 hours. when the reaction was completed, the solvent was removed by using a rotary evaporator, and the residue was distilled under reduced pressure to obtain 156 g (yield: 87%) of mono-methyl cis-5-norbornene-endo-2, 3-dicarboxylate represented by chemical formula XI.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:19]([CH3:23])[C:20](O)=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:19]([CH3:23])[C:20]([Cl:27])=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Cl)c1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(3-benzyloxy-5-trifluoromethyl-phenyl)-propionic acid (1.4 g, 4.0 mmol) in CH2Cl2 was added oxalyl chloride (0.76 mL, 8.0 mmol), followed by 3 drops of DMF. After stirring for 15 minutes at room temperature, the mixture was concentrated to give the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][Si:11]([CH3:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:21]C(OC(Cl)C)=O>ClCCl.C(OCC)(=O)C>[ClH:21].[CH3:20][Si:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: C[Si]1(c2ccccc2)CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[Si]1(c2ccccc2)CCNCC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.6 g of 1-benzyl-4-methyl-4-phenyl-[1,4]azasilinane is put in 32 ml of anhydrous dichloromethane under nitrogen. At 0° C., 2.5 ml of 1-chloroethyl chloroformate is added dropwise to the reaction mixture. The reaction mixture is gradually brought back to room temperature and then stirred for 2 h under reflux. After complete conversion, the reaction mixture is concentrated under vacuum and dried, then the residue is dissolved in 50 ml of methanol at room temperature. The mixture is stirred under reflux for 2 h. After evaporation of the solvent under vacuum, the yellow solid obtained is then suspended in ethyl acetate. The suspension is refluxed for some minutes and then gradually cooled to room temperature. The crystals thus formed are filtered, washed with ethyl acetate and dried under vacuum. 2.13 g of 4-methyl-4-phenyl-[1,4]azasilinane hydrochloride is obtained in the form of white crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:6]=2[N:7]=1.Cl.[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:32][CH2:31][CH:30]([O:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:36])[CH2:29][CH2:28]2)=[CH:22][C:21]=1[C:43]([F:46])([F:45])[F:44])([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][CH:27]2[CH2:28][CH2:29][CH:30]([O:33][CH2:34][C:35]([N:37]3[CH2:42][CH2:41][N:40]([CH2:2][C:3]4[O:4][C:5]5[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:6]=5[N:7]=4)[CH2:39][CH2:38]3)=[O:36])[CH2:31][CH2:32]2)=[CH:22][C:21]=1[C:43]([F:46])([F:45])[F:44])([O-:19])=[O:18]
Reactant: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCNCC1
Reactant: FC(F)(F)c1ccc2oc(CCl)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(Cc2nc3cc(C(F)(F)F)ccc3o2)CC1
Temperature: 100 °C

Procedure:
A mixture of 2-chloromethyl-5-trifluoromethyl-benzoxazole (50 mg, 0.214 mmol), 2-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanone hydrochloride (100 mg, 0.214 mmol), potassium carbonate (60 mg, 0.428 mmol), and DMF (1 mL) was heated at 100° C. for two hours before the reaction mixture was cooled, diluted with EtOAc (60 mL), washed with water (2×40 mL), washed with brine (1×40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to an orange residue that was purified by silica gel chromatography, eluting with a gradient of 0 to 100% EtOAc in heptanes, to provide 2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-benzooxazol-2-ylmethyl)-piperazin-1-yl]-ethanone as a stiff, orange solid (69 mg, 51%). (CI, m/z): [M+H]+ 360; 1H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 8.05 (d, J=9.23 Hz, 1H), 7.97 (d, J=8.54 Hz, 1H), 7.77 (dd, J=8.57, 1.44 Hz, 1H), 7.43 (d, J=7.71 Hz, 1H), 7.06 (s, 1H), 6.84 (dd, J=9.30, 2.51 Hz, 1H), 3.99 (s, 2H) 4.12 (s, 2H), 3.45 (br s, 5H), 2.52-2.64 (m, 4H), 1.95-2.04 (m, 2H), 1.92 (d, J=10.59 Hz, 2H), 1.28-1.40 (m, 2H), 1.19-1.27 (m, 2H); 19F NMR (376 MHz, DMSO-d6): δ ppm −59.45 (s, 3F)-59.17 (s, 3F).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:19])[O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C.O>C(OCC)(=O)C>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([O:1][NH:2][C:3](=[O:19])[O:4][CH2:5][CH:6]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C(NO)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NOC(=O)c1ccc(Cl)cc1)OCC1c2ccccc2-c2ccccc21

Procedure:
To a solution of (9H-fluoren-9-yl)methyl hydroxycarbamate (5.20 g, 20.4 mmol) in ethyl acetate (300 mL) at −10° C. is added 4-chlorobenzoyl chloride (3.56 g, 20.3 mmol). Triethylamine (3 mL, 21.3 mmol) is added dropwise keeping the internal temperature below −5° C. After 10 min water (100 mL) is added and the separated aqueous layer is