Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][CH3:20]>>[CH:14]1([CH2:13][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([N:19]([CH3:20])[CH3:18])=[O:11])[CH2:16][CH2:15]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(=O)O
Agent: Cl
Product: CN(C)C(=O)[C@H](CC1CC1)NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (CAN 89483-06-7) and dimethylamine hydrochloride as starting materials. MS (EI): m/e=256.3 [M]+.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([O:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>ClCCCl>[ClH:1].[CH3:29][O:28][CH2:27][CH2:26][O:25][CH:23]1[CH2:24][NH:21][CH2:22]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: COCCOC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCCl
Solvent: CO
Product: COCCOC1CNC1
Product: Cl
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 92.9 %

Procedure:
1-Chloroethyl chloroformate (102 μL, 0.9 mmol) was added to a solution of 1-benzhydryl-3-(2-methoxyethoxy)-azetidine (215 mg, 0.7 mmol) in 1,2-dichloroethane (3 mL) at room temperature. The reaction mixture was then heated up to 70° C. and stirred for 2.5 hours. After cooling down to room temperature, methanol (3 mL) was added and the reaction mixture was stirred overnight at 70° C. The mixture was then concentrated to dryness and the residue was triturated in pentane (2×15 mL) to give a yellow oil (109 mg, 90%) which was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[NH:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:17][C:18]([F:26])([F:25])[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21]>C(Cl)(Cl)Cl>[CH3:23][O:22][C:20](=[O:21])[C:19]([OH:24])([C:18]([F:26])([F:25])[F:17])[C:13]1[C:14](=[O:15])[N:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[NH:11][C:12]=1[CH3:16]
Reactant: Cc1cc(=O)n(-c2ccc(C(C)C)cc2)[nH]1
Reactant: COC(=O)C(=O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)C(O)(c1c(C)[nH]n(-c2ccc(C(C)C)cc2)c1=O)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a chloroform solution (5 ml) of 1-(4-isopropylphenyl)-3-methyl-5-pyrazolone (108 mg, 0.5 mmol), methyl trifluoropyruvate (78 mg, 0.5 mmol) was added at room temperature and the mixture was stirred at 80° C. for 2 hours. After removing the solvent under reduced pressure, the title compound was obtained as a pale yellow solid (186 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C@@H:13]3[CH2:17][O:16][C:15](=[O:18])[NH:14]3)=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21]N(C)C=O.CI>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C@@H:13]3[CH2:17][O:16][C:15](=[O:18])[N:14]3[CH3:21])=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C1N[C@H](c2ncc(-c3cccc(Br)n3)s2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)OC[C@H]1c1ncc(-c2cccc(Br)n2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40 %

Procedure:
(S)-4-[5-(6-bromopyridin-2-yl)thiazol-2-yl]oxazolidin-2-one (488 mg, 1.50 mmol) obtained in Step 4 and sodium hydride (60% oily, 72 mg, 1.80 mmol) were suspended in tetrahydrofuran (5 ml) and dimethylformamide (5 ml) in an Ar stream and methyl iodide (0.1 ml, 1.65 mmol) was added while ice-cooled and stirred at room temperature for 12 hours. After the reaction solution was concentrated, water was added and it was extracted with ethyl acetate. After the organic layer was washed with a saturated brine and dried over magnesium sulfate, it was concentrated and the residue was purified by flash chromatography on silica gel (chloroform:methanol=20:1) and the title compound (205 mg, 40%) was obtained.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH3:22])=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[CH3:23][N:24](C)C=O>[Pd].C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:7]1[C:6]2[CH:20]=[C:2]([C:23]#[N:24])[C:3]([O:21][CH3:22])=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][N:8]=1
Reactant: CN(C)C=O
Reactant: COc1cc2c(cc1Br)C(c1ccccc1Cl)=NCC(=O)N2
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=O)N2
Temperature: 110 °C

Procedure:
5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ib) was prepared from 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Id) by reaction with zinc cyanide in the presence of a palladium catalyst (tetrakistriphenyl phosphine palladium) according to conditions similar to those described by Tschaen et al., Synthetic Communications, 24:887-90 (1994). A mixture of 0.9491 g (0.0025 mole) of 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Id), 0.176 g (0.0015 mole) of zinc cyanide, 4 mL of dimethylformamide and 0.289 g (0.00025 mole) of tetrakistriphenyl phosphine palladium was heated at 110° C. under an argon atmosphere for 24 hours. The mixture was then cooled, taken up in ethyl acetate and washed with 0.2 M sodium carbonate solution. The aqueous phase was reextracted with ethyl acetate, and the ethyl acetate layers washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate-hexane (4:1) to give 0.620 g of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ib). MH+/Z=326.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.FC(F)(F)S(O[Si:21]([CH3:24])([CH3:23])[CH3:22])(=O)=O>C(Cl)Cl>[CH3:22][Si:21]([CH3:24])([CH3:23])[O:14][C:12]([C:9]1[CH:8]=[CH:7][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:11][CH:10]=1)=[CH2:13]
Reactant: CC(=O)c1ccc(-n2cncn2)cc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C)c1ccc(-n2cncn2)cc1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a stirred solution of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)ethanone (4.5 g, 24.0 mmol) in DCM at 0° C., were added TEA (3.7 g, 36.1 mmol) and trimethylsilyl trifluoromethanesulfonate (8 g, 36 mmol) and the resultant reaction mixture was stirred for 1 h. The reaction mixture was quenched with a mixture of sat aq sodium bicarbonate solution and ether. The ether layer and was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (5.5 g) which was taken directly to next step.
Reaction SMILES: [N:1]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:14])[C:8]([OH:12])([CH3:11])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3].CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[N:1]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:14])[C:8]([O:12][S:35]([CH3:34])(=[O:37])=[O:36])([CH3:11])[CH2:9][S:10][C@H:5]12)=[N+:2]=[N-:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(COC(=O)C2N3C(=O)[C@H](N=[N+]=[N-])[C@H]3SCC2(C)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)C2N3C(=O)[C@H](N=[N+]=[N-])[C@H]3SCC2(C)OS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.1 h
Yield: 94.8 %

Procedure:
A solution of p-methoxybenzyl 7α-azido-3-hydroxy-3-methyl-cepham-4-carboxylate (310 mg., 0.82 mMol) and Et3N (1.72 μl, 1.23 mMol) in anhydrous CH2Cl2 (4 ml.) is cooled in an ice bath under N2. A solution of MeSO2Cl (83 μl, 1.07 mMol) in anhydrous CH2Cl2 (1 ml.) is added dropwise with stirring over 6 min. The resulting solution is stirred 15 more min. in the cold, then diluted with ice cold CH2Cl2 (5 ml.) and washed with ice cold H2O (5 ml.), 5% HCl (5 ml.), and 5% NaHCO3 (5 ml.). The CH2Cl2 solution is dried over MgSO4, filtered, and evaporated in vacuo to provide p-methoxybenzyl 7α-azido-3-methanesulfonyloxy-3-methyl-cepham-4-carboxylate (355 mg.) as a pale yellow gum: ir (CHCl3) 4.78, 5.63, 5.78, 6.64, 7.43, 7.99, 8.48, and 11.08μ; nmr (CDCl3) δ2.03 (s, 3, CH3), 2.68 (s, 3, SO2CH3), 3.00 (d, l, J=14Hz, SCH), 3.80 (s, 3, OCH3), 3.82 (d, l, J=14Hz, SCH), 4.47 (d, l, J=1.3Hz, H7), 4.65 (s, l, H4), 4.97 (d, l, J=1.3 Hz, H6), 5.00 and 5.28 (ABq, 2, J=10.5 Hz, CH2Ar), and 6.87 and 7.33 (two d's, 4, J=9Hz, ArH).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:24])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:7]=1>C1COCC1>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:5]([OH:24])=[O:4])=[CH:11][CH:10]=1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(C(=O)O)cc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 94.7 %

Procedure:
An aqueous (10 mL) solution of sodium hydroxide (0.53 g, 13.18 mmol) was added into the solution of 25 (1.35 g, 4.39 mmol) in THF (60 mL) and the resulting solution was stirred at room temperature for 48 h and at 60° C. for 14 h. Then the solvent was removed under reduced pressure. Water (20 mL) was added and pH was adjusted to 7 with HCl. The white solid precipitate was filtered off, washed with water and dried under vacuum. 1.22 g (95%) of white solid 26 was obtained. 1H NMR (300 MHz, DMSO-d6) δ 1.39 (br s, 11H), 1.52 (m, 2H), 1.64 (m, 2H), 2.92 (m, 2H), 6.84 (m, 1H), 7.28 (d, 2H), 7.85 (d, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl[C:31]([O:33][CH3:34])=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:16]([C:31]([O:33][CH3:34])=[O:32])[CH3:17])=[CH:12][C:11]([F:18])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1c(CNC)c2cc(F)ccc2n1Cc1cccc2ccccc12
Product: CCOC(=O)c1c(CN(C)C(=O)OC)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-methylaminomethyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 86.1.) was reacted with methyl chloroformate as described in Example 77.1. to give 5-fluoro-3-[(methoxycarbonyl-methyl-amino)-methyl]-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless foam. MS: 419.5 ([M−H]−).
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCOCC>[CH2:1]([N:8]1[CH:14]2[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCC1NCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: c1ccc(CN2C3CCCCC32)cc1
Yield: 75 %

Procedure:
Cyclization of 2-Benzylamino-cyclohexanol. Diethyl azodicarboxylate (Aldrich, 95%, 3.6 ml, 22.6 mmol) was slowly added to an ether solution (50 ml) of 2-benzylaminio-cyclohexanol (3.1 g, 15 mmol) and PPh3 (5.94 g, 22.6 mmol) under N2, with stirring, in an ice-bath. After addition, the ice bath was removed, and the mixture stirred at room temperature for 36 h. The resulting crystalline precipitate was filtered and the solvent removed from the filtrate by rotary evaporation to yield the crude product, which was purified by column chromatography (petroleum ether: diethyl ether=50:50) (2.1 g, 75% yield).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].Cl.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][SH:36]>>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][S:36][C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:30])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:17])([CH3:16])[C:10]=2[CH:18]=1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CN(C)CCS
Agent: Cl
Product: CN(C)CCSc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 2-dimethylaminoethanethiol hydrochloric acid salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([F:23])[C:9]=2F)=[CH:4][CH:3]=1.[F:25]C1C=C(B(O)O)C=CC=1OCCCCCCCC.BrC1C=CC(I)=C(F)C=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:25])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCOc1ccc(B(O)O)cc1F
Reactant: CCCCCCCCOc1ccc(-c2ccc(Br)cc2)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Fc1cc(Br)ccc1I
Product: CCCCCCCCOc1ccc(-c2ccc(Br)cc2F)cc1F

Procedure:
This was prepared using a similar method to that described for compound 8. The product is a low melting solid and was used without further purification. Quantities: 3-fluoro-4-octyloxyphenylboronic acid (6) (6.83 g, 0.026 mol), 1-bromo-3-fluoro-4-iodobenzene (6.92 g, 0.023 mol), tetrakis(triphenylphosphine)palladium(0) (1 g, 0.87 mmol).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH:29]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(CN2CCCCC2)cc1
Reactant: Nc1ccccc1
Product: O=C1NC(=O)c2ccc(Nc3ccccc3)cc2/C1=C/Nc1ccc(CN2CCCCC2)cc1

Procedure:
Using the procedure described for the preparation of example 118, the title compound is obtained as yellow solid (70% yield) from 6-bromo-4-[(4-piperidin-1-ylmethyl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione and aniline.
Reaction SMILES: CC([N:5]([C:9]([CH3:32])([CH3:31])[C:10]([NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][C:20]2[C:25]3[C:26]([CH3:30])([CH3:29])[CH2:27][O:28][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1)=[O:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:29][C:26]1([CH3:30])[C:25]2[C:20]([O:19][C:16]3[N:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[C:9]([CH3:32])([CH3:31])[NH2:5])=[CH:18][CH:17]=3)=[CH:21][CH:22]=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: CC1(C)COc2cccc(Oc3ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 1,1-dimethylethyl[2-({6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 74, 11 mg) in dry dichloromethane (2 ml), TFA (0.077 ml, 0.997 mmol) was slowly added at 0° C. and the reaction mixture was stirred for 2 hours at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified with an SCX cartridge. The cartridge was washed with 3 CV of methanol and then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). This afforded the title compound (8.5 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Sn](Cl)Cl>Cl>[Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1cc([N+](=O)[O-])c2ncccc2c1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Product: Cc1cc(N)c2ncccc2c1Cl
Yield: 61.5 %

Procedure:
In a similar fashion using route 1 general procedure 4, 5-chloro-6-methyl-8-nitroquinoline (Intermediate 39) (300 mg, 1.35 mmol), tin (II) chloride (760 mg, 4.05 mmol) and 6N HCl (4 drops) gave the title compound (160 mg, 62%) after purification by column chromatography with n-hexane/EtOAc (9:1) as the eluent.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[N+:11]([C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: OB(O)c1cccnc1
Reactant: O=[N+]([O-])c1cc(I)c2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=[N+]([O-])c1cc2c(c(-c3cccnc3)c1)OCC2
Temperature: 25 °C
Yield: 30.2 %

Procedure:
2,3-Dihydro-7-iodo-5-nitrobenzofuran (0.76 g, 0.0026 mole) and 3-pyridylboronic acid (0.32 g, 0.0026 mole) in 50% aqueous 1,2-dimethoxyethane (50 ml) were treated under argon with sodium carbonate (1.17 g, 0.011 mole) and tetrakis triphenylphosphine palladium (0) (0.06 g, 0.000052 mole) and heated under reflux for 18 hours. The mixture was allowed to cool to ambient temperature, diluted with deionised water, extracted into ethyl acetate, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 30% ethyl acetate/60-80° petroleum ether to afford the title compound (0.19 g, 30%) as a yellow solid.
Reaction SMILES: [C@H]12C[C@H](NC1)CN2.[ClH:8].C[CH:10]1[CH2:15][NH:14][CH2:13][CH:12]([CH3:16])[N:11]1[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[ClH:8].[N:22]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:11]1[CH2:10][C@@H:15]2[CH2:16][C@H:12]1[CH2:13][NH:14]2
Reactant: CC1CNCC(C)N1c1ncccn1
Agent: C1N[C@@H]2CN[C@H]1C2
Agent: Cl
Product: c1cnc(N2C[C@@H]3C[C@H]2CN3)nc1

Procedure:
Using (1S,4S)-2,5-diazabicyclo[2.2.1]heptane, reactions similar to those in Example 1 (2), (3) were successively performed to give (1S,4S)-2-pyrimidin-2-yl-2,5-diazabicyclo[2.2.1]heptane hydrochloride, then reactions similar to those in Example 1 (4) were performed to give the title compound (201 mg).
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:17].[N-:18]=[N+:19]=[N-:20].[Na+]>CS(C)=O>[N:18]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:17])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc2c(c1)CCC(Cl)C(=O)N2
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)CCC(N=[N+]=[N-])C(=O)N2
Temperature: 75 °C
Yield: 90.8 %

Procedure:
A solution of 3-chloro-7-carbomethoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 4 (3.50 g, 13.8 mmol) and NaN3 (1.08 g, 16.6 mmol) in DMSO (100 mL) was stirred at RT for 22 h, then heated at 75° C. for an additional 2 h. The resulting solution was poured into ice water (500 mL) and the resulting precipitate was filtered and dried under vacuum to give 5 (3.26 g, 91%). 1H NMR (250 MHz, CDCl3) δ 8.09 (1H, brs, H-1), 7.93 (2H, m, H-6,8), 7.10 (1H, d, j=6.5 Hz, H-9), 3.93 (3H, s, OCH3), 3.88 (1H, dd, j=8.0, 11.5 Hz, H-3), 3.01 (1H, ddd, j=8.0, 13.5, 13.5 Hz, H-5), 2.82 (1H, m, H-5), 2.59 (1H, m, H-4), 2.36 (1H , H-4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[CH:19]([CH2:20][CH2:21][OH:22])[CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1C(Cl)=O.[CH3:43][OH:44]>C(Cl)Cl>[C:38]1([C:43]([N:17]2[CH2:18][CH:19]([CH2:20][CH2:21][OH:22])[CH:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)[CH2:16]2)=[O:44])[C:39]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: OCCC1CNCC1CN1CCC(c2ccc(F)cc2)CC1
Reactant: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc2ccccc12)N1CC(CCO)C(CN2CCC(c3ccc(F)cc3)CC2)C1
Reaction time: 1.2 h

Procedure:
To a solution of 0.63 g (2.15 mmol) of 3-(RS)-(4-(4-fluorophenyl) piperidinylmethyl)-4-(SR)-hydroxyethylpyrrolidine and 0.6 mL (4.3 mmol) of Et3N in 20 mL of CH2Cl2 at 0° C. was added 0.32 mL (2.15 mmol) of 2-naphthoyl chloride and the reaction mixture was stirred for 1.2 h. To the reaction mixture was added 0.5 mL of MeOH and the reaction mixture was stirred 18 h at rt. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone: hexanes, 1:2 to 1:1) to give 0.63 g of the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[NH2:12][C:13]1[CH:18]=[C:17]([CH2:19][CH3:20])[N:16]=[C:15]([CH2:21][CH3:22])[C:14]=1[C:23](OC)=[O:24].[Na]>C(O)C>[CH2:21]([C:15]1[N:16]=[C:17]([CH2:19][CH3:20])[CH:18]=[C:13]2[C:14]=1[C:23]([OH:24])=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:3](=[O:5])[NH:12]2)[CH3:22]
Reactant: CCc1cc(N)c(C(=O)OC)c(CC)n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2c(CC)nc(CC)cc2[nH]c1=O
Temperature: 150 °C

Procedure:
Diethyl malonate (14.5 ml) and methyl 4-amino-2,6-diethylpyridine-3-carboxylate (21.3 g) was added to a solution of sodium (2.33 g) in ethanol (60 ml) and the resulting mixture was heated at 150° C. for 20 hours in an autoclave. The mixture was allowed to cool and then volatile material was removed by evaporation and the resultant semi-crystalline solid was triturated with ether. The solid was collected by filtration and dissolved in a minimum of water. The solution as acidified with 2M hydrochloric acid and the resulting precipitate was collected by filtration and washed with water. The solid was dried under vacuum to give ethyl 5,7-diethyl-4-hydroxy-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylate (B) (12.72 g); m.p. 240-242° C.; NMR (CDCl3): 1.34(dt, 6H), 1.52(t, 3H), 2.84(q, 2H), 3.36(q, 2H), 4.52(q, 2H), 6.87(s, 1H), 7.26(s, 1H), 11.41(broad, 1H); mass spectrum (CI, ammonia): 291 (M+H)+ ; microanalysis, found: C, 62.1; H, 6.2; N, 9.7%; C15H18N2O4 requires: C, 62.1; H, 6.3; N, 9.7%.