Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])OC(C)(C)C)[CH3:22])=[CH:15][C:14]=4[F:31])[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[N:34]1C=CC=C[CH:35]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:33]=[CH:32][C:9]3[N:10]=[C:11]([C:13]4[N:18]=[CH:17][C:16]([O:19][CH2:20][C@@H:21]([NH:23][C:24]([NH:34][CH3:35])=[O:30])[CH3:22])=[CH:15][C:14]=4[F:31])[O:12][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: c1ccncc1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC4)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Product: CNC(=O)N[C@@H](C)COc1cnc(-c2nc3ccc(OCC4CC4)cc3o2)c(F)c1

Procedure:
Using tert-butyl [(1S)-2-({6-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]-5-fluoropyridin-3-yl}oxy)-1-methylethyl]carbamate, and in the same manner as in Example 16, step A (using pyridine instead of triethylamine), the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:7][C@H:6](/[CH:8]=[CH:9]\[CH2:10][OH:11])[CH2:5][CH2:4][O:3]1.[C:13]([O:17][C:18](=[O:21])[CH2:19]Br)([CH3:16])([CH3:15])[CH3:14].O.[OH-].[Cs+]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1([CH3:12])[O:7][C@H:6](/[CH:8]=[CH:9]\[CH2:10][O:11][CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:21])[CH2:5][CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(C)OCC[C@@H](/C=C\CO)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)COC/C=C\[C@@H]1CCOC(C)(C)O1
Reaction time: 6 h
Yield: 96.7 %

Procedure:
To a round bottom flask charged with activated molecular sieves (6.0 g) was added a solution of substrate, (S,Z)-3-(2,2-dimethyl-1,3-dioxan-4-yl)prop-2-en-1-ol (9.0 g, 52.0 mmol) in acetonitrile (150 mL), followed by t-butylbromoacetate (9.90 mL, 67.2 mmol), tetrabutylammonium iodide (2.0 g, 5.2 mmol) and cesium hydroxide monohydrate (13.1 g, 78.0 mmol) at room temperature. The reaction was allowed to stir for 6 h. The solid was filtered out and the solvent was concentrated under vacuum; the residue was purified by flash column chromatography (5% ethyl acetate/hexanes) to afford 3 (14.4 g, 97% yield) as a colorless oil. Rf=0.57 (30% ethyl acetate/hexanes). [α]23D=+ 22.9 (c 1.29, CHCl3) 1H NMR (300 MHz, Chloroform-d) δ 5.72-5.51 (m, 2H), 4.77-4.65 (m, 1H), 4.26-4.09 (m, 2H), 4.01 (dd, J=17.3, 2.6 Hz, 1H), 3.93 (d, J=3.6 Hz, 2H) 3.82 (ddd, J=11.8 Hz, 5.4 Hz, 1.4 Hz, 1H), 1.79-1.65 (m, 1H), 1.48 (s, 3H), 1.46 (s, 10H), 1.37 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 169.5, 134.1, 127.7, 98.3, 81.5, 67.6, 66.8, 65.5, 59.5, 31.1, 29.9, 28.0, 19.1.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Br[C:20]1[CH:21]=[C:22]([O:34][CH2:35][CH3:36])[C:23]([O:30]COC)=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=1.C(OCC)(=O)C>C1(C)C=CC=CC=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>[C:26]([C:24]1[CH:25]=[C:20]([C:6](=[O:8])[CH3:7])[CH:21]=[C:22]([O:34][CH2:35][CH3:36])[C:23]=1[OH:30])([CH3:27])([CH3:28])[CH3:29]
Reactant: CCOc1cc(Br)cc(C(C)(C)C)c1OCOC
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1cc(C(C)=O)cc(C(C)(C)C)c1O
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
Tributyl(1-ethoxyvinyl)tin (7.77 g, 21.52 mmol) and Pd(PPh3)4 (1.18 g, 1.02 mmol) were added to a solution of the 5-bromo-1-(tert-butyl)-3-ethoxy-2-(methoxymethoxy)benzene (6.5 g, 20.4 mmol) in toluene (68 ml) and the mixture was stirred at 100° C. for 18 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added, the mixture was washed with 20% aqueous KF and filtered through celite, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A 1 N HCl aqueous solution (15 ml) was added to a solution of the residue in methanol (80 ml), and the mixture was stirred at room temperature for 2 hours. Saturated sodium hydrogencarbonate solution was added to be basic and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (3.17 g) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][NH:12]C(OCC2C=CC=CC=2)=O)=[CH:5][C:4]=1[F:23])#[N:2]>[Pd]>[NH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:23])[CH:5]=1
Reactant: N#Cc1ccc(CCCNC(=O)OCc2ccccc2)cc1F
Agent: [Pd]
Product: N#Cc1ccc(CCCN)cc1F
Yield: 96.4 %

Procedure:
Scheme IIIb, step B: N-[3-(4-Cyano-3-fluorophenyl)propyl](phenylmethoxy)carboxamide (2 g, 6.4 mmol) and 10% palladium on carbon (0.5 g, 25 mole %) combined and hydrogenation was carried out in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, 4-(3-aminopropyl)2-fluorobenzenecarbonitrile, (1.1 g, 96%) as a colorless oil. Electron spray M.S. 179 (M*+H).
Reaction SMILES: C1(=O)CCCC=C1.[CH2:8]([O:10][C:11](=[O:28])[CH:12]([CH:18]1[CH2:23][CH2:22][CH:21](CCC)[C:20](=[O:27])[CH2:19]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]>>[CH2:16]([O:15][C:13](=[O:14])[CH:12]([CH:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:27])[CH2:19]1)[C:11]([O:10][CH2:8][CH3:9])=[O:28])[CH3:17]
Reactant: CCCC1CCC(C(C(=O)OCC)C(=O)OCC)CC1=O
Agent: O=C1C=CCCC1
Product: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Yield: 88 %

Procedure:
Step 1 (3-Oxo-cyclohexyl)-malonic acid diethyl ester was prepared in 88% yield from cyclohexenone by the method described above for the synthesis of 2-(3-oxo-4-propylcyclohexyl)-malonic acid diethyl ester: 1H NMR (300 MHz, CDCl3) δ 4.44-4.12 (m, 4H), 2.88-1.22 (m, 16H).
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]1=O.[CH3:15][C:16]1(C)[CH2:20]C[CH2:18][C:17]1=O.N>CO>[CH3:15][C:16]1([CH3:20])[C:7]2=[N:2][CH:3]=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=[C:6]2[CH2:18][CH2:17]1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CC1(C)CCCC1=O
Agent: N
Solvent: CO
Product: CC1(C)CCc2cc([N+](=O)[O-])cnc21
Yield: 23.8 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (0.8 g, 4.0 mmol), 2,2-dimethyl-cyclopentanone (0.45 g, 4.0 mmol) and ammonia solution (2.0 M) in methanol (40 mL) was refluxed overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:10 v/v ethyl acetate-hexane) to give a yellow solid (0.183 g, 24% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1)[CH3:2].Br[C:11]1[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=[C:15]([Br:17])[CH:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:17][C:15]1[CH:16]=[C:11]([NH:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][CH3:2])[N:8]=2)[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CCc1nccc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 229a (246 mg, 2.0 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (534 mg, 2.0 mmol), Pd2(dba)3 (182 mg, 0.20 mmol), XantPhos (231 mg, 0.40 mmol), Cs2CO3 (1.30 g, 4.0 mmol), and 1,4-dioxane (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 229b as off-white solid (308 mg, 50%). MS-ESI: [M+H]+ 309.1
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][C:10]2[NH:19][C:18](=[O:20])[C:17]3[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][CH2:28][OH:29]>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[N:19]([CH2:26][CH2:27][CH2:28][OH:29])[C:18](=[O:20])[C:17]3[C:12](=[C:13]([O:21][CH3:22])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:23][CH:24]=1
Reactant: COc1cccc2c(=O)[nH]c(COc3ccc(Cl)cc3)nc12
Reactant: OCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc2c(=O)n(CCCO)c(COc3ccc(Cl)cc3)nc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (239 mg, 9.94 mmol) was added to a solution of 2-(4-chlorophenoxymethyl)-8-methoxy-3H-quinazolin-4-one (3000 mg, 9.47 mmol) in DMF (20 mL) at room temeprature. The reaction mixture was stirred for 30 min, then 3-bromopropanol (1448 mg, 0.94 mL, 10.42 mmol) was added. The reaction mixture was heated at 80° C. for 17 h, cooled to room temperature and diluted with EtOAc. The organic solution was washed with water, sat'd aq NaCl, dried and concentrated. The crude residue was purified using SiO2-gel chromatography (50% EtOAc/hexanes) to give 1.1 g of the desired N-alkylated product. API-MS: 375 (M+1). 1H NMR (300 MHz, CDCl3): d 7.82 (d, 1 H), 7.4 (t, 1 H), 7.2 (m, 3 H), 7.9 (d, 2 H), 5.2 (s, 2 H), 4.36 (t, 2 H), 4.0 (s, 3 H), 3.58 (t, 2 H), 2.0 (t, 2 H).
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[CH3:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Agent: Cl
Product: Cc1ccc(NC(=O)N2CCC(=O)N(CCCN3CCC4(CC4)[C@H](O)C3)C[C@H]2C)cc1C
Yield: 32 %

Procedure:
In analogy to the procedure described in example 58F, (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 58E) and 3,4-dimethylphenyl isocyanate (without addition of 0.1 eq. of 3,4-dimethylphenyl isocyanate) gave 0.035 g (32%) of the title compound as white foam. MS: 443.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:25]=[C:17]2[C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2ccccc2n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 4-nitrobenzyl bromide (1.85 g, 8.56 mmol), 1H-indole-2-carboxylic acid ethyl ester (1.62 g, 8.56 mmol) and potassium carbonate (4.17 g, 30 mmol) in 100 mL of acetone was refluxed for 1 day. After cooling to room temperature the reaction was quenched by addition of water and then partitioned between water and methylene chloride. The organic phase was dried over MgSO4, and concentrated to yield ethyl 1-(4-nitrobenzyl)-1H-indole-2-carboxylate as an off-white solid (2.0 g, 72%): 1H NMR (DMSO-d6) δ 1.27 (t, J=7.1 Hz, 3H), 4.26(q, J=7.1 Hz, 3H), 5.99(s, 2H), 7.18(t, J=7.0 Hz, 1H), 7.22 (d, J=9.0-Hz, 2H), 7.34 (t, J=7.0 Hz, 1H), 7.43 (s, 1H), 7.58 (d, J=13.8 Hz, 1H), 7.76 (d, J=13.8 Hz, 1H), 8.15 (d, J=9.0 Hz, 2H); MS (ESI) m/z 325 (MH+).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:21])[CH2:5]1.CS(O[CH2:27][C:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2)(=O)=O>CN(C=O)C>[C:28]12([CH2:27][N:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[N:7]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:6](=[O:21])[CH2:5][C:4]3=[O:3])[CH2:29][CH:30]3[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]3)[CH2:37]1)[CH2:35]2
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Reactant: CS(=O)(=O)OCC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1CC12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
Sodium hydride 80% dispersion in oil (0.07 g) was added portionwise to a solution of 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (0.5 g) in DMF (50 ml). The reaction mixture was stirred for 30 min, then a solution of 1-adamantylmethyl methanesulfonate (0.537 g) in DMF (3 ml) was added. The reaction mixture was stirred at 120° for 7 h and at 23° for 15 h, then concentrated. The residue was diluted with ethyl acetate (100 ml) washed with brine (2×30 ml) and water (50 ml), dried and concentrated "in vacuo". The crude product was purified by flash chromatography (eluting with CH-EA 1:1) to give the title compound as a white foam (0.15 g). T.l.c. CH-EA (1:1), Rf =0.42.
Reaction SMILES: [Li+].[CH3:2][Si:3]([N-:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])[CH3:4]>C1COCC1>[CH3:2][Si:3]([NH:6][Si:7]([CH3:10])([CH3:9])[CH3:8])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)N[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chloro intermediate XL (260 mg, 0.48 mmol) in THF (4 mL) was cooled to −78° C. under nitrogen. A solution of 1M LiHMDS solution in THF (0.5 mL, 0.5 mmol) was added slowly at −78° C. Upon completion of the addition, the reaction flask was allowed to warm to room temperature. After stirring at room temperature for 16 h, the reaction mixture was concentrated under vacuum and hexane (20 mL) was added. The precipitated lithium salts were filtered off through a Celite pad, rinsed with additional hexane and the combined filtrates were concentrated under vacuum to give crude bis(trimethylsilyl)amine product XLI.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:25])[N:15]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:16]4=[N:17][C:18]=3[CH:19]=2)[CH:5]=[CH:6][CH:7]=1.[O:26]1[CH2:30][CH2:29][CH:28](OS(C2C=CC=CC=2)(=O)=O)[CH2:27]1>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[C:14](=[O:25])[N:15]4[CH2:24][CH2:23][N:22]([CH:28]5[CH2:29][CH2:30][O:26][CH2:27]5)[CH2:21][CH2:20][C:16]4=[N:17][C:18]=3[CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CCNCC2
Reactant: O=S(=O)(OC1CCOC1)c1ccccc1
Solvent: CC#N
Solvent: O
Product: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CCN(C1CCOC1)CC2

Procedure:
A solution of 8-((3-fluorophenyl)ethynyl)-2,3,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazolin-11(1H)-one (100 mg, 0.3 mmol) and tetrahydrofuran-3-yl-benzenesulfonate (137 mg, 0.6 mmol) in acetonitrile (20 mL) was stirred at room temperature overnight. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI):404 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.25-8.22 (d, J=8.25 Hz, 1H), 7.77 (s, 1H), 7.58-7.55 (dd, J=8.25, 1.38 Hz, 1H), 7.40-7.34 (m, 2H), 7.28-7.26 (m, 1H), 7.13-7.06 (m, 1H), 4.61-4.32 (m, 2H), 4.02-3.95 (m, 1H), 3.90-3.70 (m, 3H), 3.25-3.22 (m, 3H), 2.89-2.74 (m, 4H), 2.09-1.86 (m, 2H). mGluR5 PAM EC50: ++.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.Br.Br[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[H-].[Na+]>CN(C=O)C>[CH3:7][N:6]1[CH:5]=[C:10]([C:2]2[CH:3]=[C:4]([O:11][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)[CH:9]=[N:8]1
Reactant: Oc1cc(Br)cn2nccc12
Reactant: BrCc1cccnc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(OCc3cccnc3)c3ccnn3c2)cn1
Reaction time: 1 h

Procedure:
6-bromopyrazolo[1,5-a]pyridin-4-ol (10.0 mg, 0.047 mmol), 3-(bromomethyl)pyridine hydrobromide (14.2 mg, 0.056 mmol), and NaH (6.7 mg, 0.168 mmol, 60 wt %) were suspended in DMF (1 ml) and stirred for 1 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride. The reaction mixture was diluted in ethyl acetate, then washed with water (5 mL) and brine (5 mL). The combined aqueous layers were extracted with ethyl acetate (2×10 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to afford 6-(1-methyl-1H-pyrazol-4-yl)-4-(pyridin-3-ylmethoxy)pyrazolo[1,5-a]pyridine.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14]O)=[NH:4].N[N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:29].[ClH:30]>>[ClH:30].[ClH:30].[OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14][N:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[N:19]=[C:18]1[NH2:29])=[NH:4]
Reactant: Cc1ccc(-c2cn(N)c(N)n2)cc1
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Agent: Cl
Product: Cc1ccc(-c2cn(N=C3CCc4c(C(=N)NO)cccc43)c(N)n2)cc1
Temperature: 110 °C

Procedure:
A mixture of 1.20 g (5.848 mmol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 1.10 g (5.844 mmol) of 1,2-diamino-4-(4-tolyl)-imidazole (Beyer H. et al., Chem. Ber. 101, 3151 (1968)) and 20 ml of 4N hydrochloric acid is heated at 110° C. for 22 hours, with stirring, and is then concentrated in vacuo to approximately half its original volume. The product that has crystallized out is filtered off, washed with isopropanol and recrystallized from a mixture of 15 ml of methanol and 30 ml of isopropanol, yielding the title compound in the form of the dihydrate, m.p. 225°-232° C. (decomp.), 1H-NMR (D2O): δ=8.04 (d, 1H); 7.74 (d, 1H); 7.55 (t, 1H); 7.30 (s, 1H); 7.26 (d, 2H); 7.07 (d, 2H); 3.17-3.23 (m, 2H); 2.98-3.04 (m, 2H); 2.07 (s, 3H).
Reaction SMILES: CS(C)=O.[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)C(C)C)(C)C.[CH3:27][O:28][C:29]([C:31]1[N:35]=[C:34]([CH2:36]Cl)[O:33][CH:32]=1)=[O:30]>C(OCC)(=O)C>[CH3:27][O:28][C:29]([C:31]1[N:35]=[C:34]([CH2:36][N:15]2[CH2:16][CH2:17][N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:11])[CH2:13][CH2:14]2)[O:33][CH:32]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1coc(CCl)n1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1coc(CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 8 h

Procedure:
A dimethyl sulfoxide (10 mL) solution of tert-butyl-1-piperazine carboxylate (1.06 g, 5.70 mmol) and N,N-diisopropylethylamine (2.98 mL, 17.1 mmol) was treated at room temperature with methyl (2-chloromethyl)oxazole-4-carboxylate (1.0 g, 5.70 mmol; portion-wise addition) and stirred overnight. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried on magnesium sulfate, filtered and concentrated to give the intermediate tert-butyl 4-((4-(methoxycarbonyl)oxazol-2-yl)methyl)piperazine-1-carboxylate (MS (ESI) m/z 325.7 [M+H]+. The intermediate was dissolved in dichloromethane (15 mL) at room temperature and treated with trifluoroacetic acid (5 mL) dropwise. The mixture was stirred for 4 hours and was then concentrated under vacuum to give the title compound (1.60 g). MS (ESI) m/z 226.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:11]([CH2:35][CH:36]([CH3:38])[CH3:37])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:42]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[NH2:42][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[C:19]2[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCCC(=O)O)cc23)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCCCCC(N)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
A mixture of 5-{[3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}pentanoic acid (0.8 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 g, 2.0 mmol), 1-hydroxy-1H-benzotriazole ammonium salt (0.24 g, 1.6 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from isopropyl ether to give tert-butyl {{6-[(5-amino-5-oxopentyl)oxy]-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl}methyl}carbamate (0.6 g, yield 77%) as crystals.
Reaction SMILES: [N+]([O-])(O)=O.S(=O)(=O)(O)O.[N+:10]([C:13]1[C:14]([N+:20]([O-])=O)=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1)([O-])=O>>[C:15]1([CH3:19])[CH:16]=[CH:17][CH:18]=[C:13]([NH2:10])[C:14]=1[NH2:20]
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: Cc1cccc(N)c1N

Procedure:
In a process for producing a meta-toluene diamine mixture wherein toluene is contacted with nitric acid in the presence of sulfuric acid under conditions for producing a reaction product containing primarily a dinitrotoluene isomer mixture, the dinitrotoluene recovered and then contacted with hydrogen in the presence of a hydrogenation catalyst, the resulting reaction product containing 2,4- and 2,6-toluene diamine formed into a liquid toluene diamine mixture, distilled in a column at elevated temperature to remove any water, ortho-toluene diamine and by-products, the substantially anhydrous meta-toluene diamine isomer mixture recovered from the bottom of the column, the improvement for preparing the resulting meta-toluene diamine isomer mixture for storage and/or transport which comprises:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>C(Cl)Cl>[CH3:26][O:27][CH2:28][O:16][C:3]1[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])=[CH:7][C:2]=1[Br:1]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(Br)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 45 °C
Yield: 95.4 %

Procedure:
To a solution of 2-bromo-4,6-di-t-butylphenol (Compound D 2.54 g, 8.88 mmol) and catalytic amount of BU4NI in 20 ml of dry CH2Cl2 at 0° C. was added diisopropylethylamine (9.51 ml, 53 mmol), followed by methoxymethyl chloride (2.02 ml, 26.6 mmol). The reaction mixture was heated to 45° C. for 12 hours. The reaction mixture was then washed with 10% citric acid, then NaHCO3 (sat.), brine, and dried over MgSO4. After filtration and removal of the solvent under reduced pressure, the residue was purified by column chromatography (pure hexane) to yield the title compound (2.79 g) as a colorless oil. 1H NMR δ 7.40 (d, J=2.44 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 9H).