Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=C(C)C(=O)c1ccc2c(C)cccc2c1
Yield: 58.1 %

Procedure:
1-methylnaphthalene (142 mg), methacryloyl chloride (110 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from −30° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (122 mg).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([OH:33])=[O:32])=[CH:24][C:18]=3[C:19]=2[C:20](=[O:23])[NH:21][CH3:22])=[CH:11][CH:10]=1>C(OCC)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:27]=[CH:26][C:25]([C:28]4[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=4)[C:31]([O:33][CH3:1])=[O:32])=[CH:24][C:18]=3[C:19]=2[C:20](=[O:23])[NH:21][CH3:22])=[CH:11][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)OC)c3)cc12
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Trimethylsilyldiazomethane (500 μL, 1.00 mmol, 2M in diethyl ether) was added to a stirring solution of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (100 mg, 0.257 mmol) in diethyl ether (2.5 mL) at 25° C. It was allowed to stir for 2 hours. The mixture was concentrated to afford the titled compound (100 mg, 97%). LC-MS retention time: 2.46 min; m/z (MH+): 404. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][Al](C)C.[F:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:7]=1[CH:8]1[O:10][CH2:9]1>CCCCCC>[F:5][C:6]1[C:7]([CH:8]([CH3:1])[CH2:9][OH:10])=[C:11]([F:18])[C:12]([F:17])=[C:13]([F:16])[C:14]=1[F:15]
Reactant: C[Al](C)C
Reactant: Fc1c(F)c(F)c(C2CO2)c(F)c1F
Solvent: CCCCCC
Product: CC(CO)c1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C

Procedure:
To a 10 ml of ice-cooled 1M solution of trimethylaluminum in hexane, was added dropwise a solution of 1.05 g of (+)-2,3,4,5,6-pentafluorostyrene oxide (over 95%ee) in 5 ml of hexane, to react for five hours at 0° C and for another one hour at room temperature. The similar work-up to Example 1 gave 1.10 g of (+)-2-(pentafluorophenyl)-1-propanol. The specific rotation was compared with that of Example 1, and the optical purity was determined to be 15%ee.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Br[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C=O)C>[CH:15]1([CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:10]#[N:11])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cccc(CC#N)c1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C#N)C2CCCC2)c1
Yield: 89.8 %

Procedure:
By working in a way similar to that described in example 16 but using 3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles), anhydrous DMF (30 ml), NaH (55-65%, 1.44 g, 36.3 mmoles) and bromocyclopentane (5.4 g, 36.3 mmoles), 5.8 g of the title compound were obtained (yield: 90%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25](B(O)O)=[CH:26][C:21]=2[CH2:20][CH2:19]1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:25]2[CH:24]=[CH:23][C:22]3[O:18][CH2:19][CH2:20][C:21]=3[CH:26]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc2c(c1)CCO2
Product: Cc1c2n(c3c(-c4ccc5c(c4)CCO5)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (80 mg, 91%), MS (ISP) m/z=353.5 [(M+H)+], mp 261° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 2,3-dihydro-benzofuran-5-ylboronic acid (53.3 mg, 0.325 mmol).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Br:13][C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:13][C:14]1[C:19]([CH2:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[O:22][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1ccc(F)c(C)c1
Reactant: CCc1cccc(O)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1cccc(Oc2ccc(C(=O)OC)cc2C)c1Br
Temperature: 130 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of methyl 4-fluoro-3-methylbenzoate (1.7 g, 10 mmol) and 2-bromo-3-ethylphenol (2.0 g, 10 mmol) in dimethyl sulfoxide (10 mL) was added potassium carbonate (2.8 g, 20 mmol). The reaction mixture was stirred at 130° C. for 3 hours. After the reaction, the mixture was poured into water (50 mL) and the solution was extracted with ethyl acetate (50 mL), washed with water (50 mL). The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure to give the pure product methyl 4-(2-bromo-3-ethylphenoxy)-3-methylbenzoate as colorless oil (2.10 g, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.Br[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>O.COCCOC>[N+:1]([C:4]1[CH:5]=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2ccncc2)c1
Yield: 74.1 %

Procedure:
A stirred mixture of 3-nitrophenylboronic acid (2.00 g), 4-bromopyridine hydrochloride (1.56 g), bis(diphenylphosphino)butanepalladium(II) chloride (0.48 g), sodium bicarbonate (2.69 g), water (30 ml) and 1,2 dimethoxyethane (100 ml) is heated under reflux for 3 hours. The cool mixture is added to water (300 nil) and extracted with chloroform (3×150 ml), and the combined organic extracts washed with water and brine, dried (MgSO4), charcoaled and filtered. The solvent is evaporated to give a residue which is purified by flash chromatography (silica, ether) to give 1.19 g of 4-(3nitrophenyl)pyridine, mp 109-110.5° C. (from acetone/hexane).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:12]2[NH:16][CH:15]([C:17]([OH:19])=[O:18])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:20](O)[CH3:21]>>[C:6]1([CH:12]2[NH:16][CH:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)C1CCC(c2ccccc2)N1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCC(c2ccccc2)N1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Ethyl (2RS,5SR)-5-phenylprolinate may be obtained as follows: 0.5 cm3 of concentrated sulphuric acid is added dropwise to a solution of 5.5 g of (2RS,5SR)-5-phenylproline in 50 cm3 of ethanol. The reaction mixture is then stirred at a temperature in the vicinity of 80° C. for five hours, then cooled to a temperature in the vicinity of 20° C. and concentrated under reduced pressure. The residue is taken up in 50 cm3 of water, brought to a pH in the vicinity of 9 by a normal aqueous sodium hydroxide solution and extracted with 3 times 100 cm3 of ethyl acetate. The combined organic extracts are washed with 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The residue is subjected to chromatography on silica [eluent cyclohexane/ethyl acetate (90/10 by volume)]. The fractions containing the expected product are combined and concentrated under reduced pressure. 2.16 g of ethyl (2RS,5SR)-5-phenylprolinate are thus obtained in the form of an oil, used as it is in subsequent syntheses.
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]=[CH:6][C:7]1[CH:35]=[CH:34][C:10]([CH2:11]NC(=O)C2C=CC(N3CCN(CC4C=NC=CC=4)CC3)=CC=2)=[CH:9][CH:8]=1)=[O:4].C(OC(=O)C=CC1C=CC(C[S:49](=[O:58])(=[O:57])[NH:50][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)=CC=1)C>>[OH:1][NH:2][C:3](=[O:4])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][S:49](=[O:58])(=[O:57])[NH:50][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)=[CH:34][CH:35]=1
Reactant: CCOC(=O)C=Cc1ccc(CS(=O)(=O)Nc2cccnc2)cc1
Reactant: O=C(C=Cc1ccc(CNC(=O)c2ccc(N3CCN(Cc4cccnc4)CC3)cc2)cc1)NO
Product: O=C(C=Cc1ccc(CS(=O)(=O)Nc2cccnc2)cc1)NO
Yield: 64 %

Procedure:
The titled compound was prepared as described in the process (1-3) using the compound from the process (9-3).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:14][CH:15]4[CH:19]([CH2:18][N:17]([C:28]([C:27]5[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=5[C:22]5[S:21][CH:25]=[CH:24][CH:23]=5)=[O:29])[CH2:16]4)[CH2:20]3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-c1cccs1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C27H24N4OS, 452.58; m/z found, 453.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH:9]3[O:13][CH:10]32)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[Cl-].[Na+].[OH-].[NH4+:18]>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@@H:9]([OH:13])[C@@H:10]2[NH2:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc2c(c1)C1OC1C2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H]1c2cc([N+](=O)[O-])ccc2C[C@H]1O
Temperature: 45 °C

Procedure:
A suspension of 6-nitro-1,2-epoxyindane in concentrated ammonium hydroxide (250 mL) was heated overnight in an oil bath at 45° C. The next day water was added and the basic aqueous layer was saturated with sodium chloride. The cloudy reaction mixture was extracted with tetrahydrofuran until no more product could be seen in the aqueous layer by TLC. The organic layers were combined, dried over magnesium sulfate, filtered, concentrated, and recrystallized from ethyl acetate to give 11.54 g of the title compound. (91% over two steps).
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:24][C@@H:25]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=2)(=[O:32])=[O:31])[CH2:26]1)(C)(C)C>>[Cl:46][C:45]1[C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[S:30]([N:27]2[CH2:28][CH2:29][C@@H:25]([OH:24])[CH2:26]2)(=[O:31])=[O:32])=[N:41][C:42]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:43][CH:44]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1cc2c(cc1N)CCN(C[C@H](C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@@H](O)C3)n1)CCN(C[C@H](C)O)CC2
Yield: 47 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (S)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and {2-[(R)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. The product was isolated as an off-white foam (55 mg, 47%). MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.58-7.52 (m, 2H), 7.25 (t, J=8 Hz, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.88 (m, 4H), 3.42 (m, 3H), 3.31 (d, 1H), 2.91-2.52 (m, 10H), 2.27 (m, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25].C([NH:31]C1C=CC(S(N=[N+]=[N-])(=O)=O)=CC=1)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:15][C:14](=[O:16])[C:13](=[NH:31])[C:12](=[O:17])[O:11]2)[CH:5]=[CH:4][C:3]=1[C:23]([CH3:27])([CH3:26])[C:24]#[N:25]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)C(=N)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-{2-chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile (0.5 g, 1.29 mmol) from step 5 of example B(22), and p-acetamidobenzenesulfonyl azide (0.46 g, 1.94 mmol) in THF (4 mL) under argon was added TEA (0.54 mL, 3.87 mmol). The resulting solution was stirred at 25° C. overnight. The solvents were removed and the residue was purified by flash column chromatography (25-60% % EtOAc in hexanes) to give the product as a yellow oil. ESIMS (MH+): 414.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: Cc1cccc2c1CCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4c(C)cccc43)c2cc1OC
Yield: 94 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 94% yield from 4-methyl-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 174°-175° C.; LC-MS: 322 (MH+); anal. RP18-HPLC RT: 4.85 min.).
Reaction SMILES: [C:1]([NH:18][CH2:19][C:20]([OH:22])=O)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:31]>ClCCl>[C:1]([NH:18][CH2:19][C:20]([F:31])=[O:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(F)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
FMOC-Glycine (5.02 g, 16.82 mmol) (Bachem) was dissolved in dichloromethane (85 mL). Pyridine (1.36 mL, 16.82 mmol) (Aldrich) and cyanuric fluoride (2.27 g, 16.82 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford FMOC-glycyl fluoride as a white powder. (Yield 3.67 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][O:8][CH2:9][CH:10]=O)=[CH:5][CH:4]=1.C(OCC1[N:20](C)[C:21]([CH:31]([CH3:33])[CH3:32])=[C:22](SC2C=CC=CC=2)[N:23]=1)(=O)N.N.C(O)(=O)C(O)=O>C(#N)C.C(OCC)(=O)C>[CH:31]([C:21]1[N:20]=[C:10]([CH2:9][O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=2)[NH:23][CH:22]=1)([CH3:33])[CH3:32]
Reactant: COc1ccc(COCC=O)cc1
Reactant: CC(C)c1c(Sc2ccccc2)nc(COC(N)=O)n1C
Agent: N
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(COCc2nc(C(C)C)c[nH]2)cc1
Reaction time: 96 h
Yield: 65.5 %

Procedure:
In 970 ml of acetonitrile was dissolved 175 g (0.968 mol) of p-methoxybenzyloxyacetaldehyde (2d), followed by addition of 150 g (0.968 mol) of 2,2-dichloro-3-methylbutyraldehyde (1). Then, 1300 ml of 28% aqueous ammonia was further added dropwise under ice-cooling. After completion of dropwise addition, the mixture was allowed to stand at room temperature for 4 days. This reaction mixture was concentrated under reduced pressure and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over MgSO4 and the solvent was distilled off under reduced pressure. The crude product was dissolved in ethyl acetate. To this solution was added a solution of oxalic acid (89.8 g, 0.968 mol) in ethyl acetate (70 ml) and the resulting oxalate was collected by filtration and rinsed with ethyl acetate. This oxalate was neutralized with 2N-sodiums hydroxide arid extracted with ethyl acetate. The organic layer was washed with water and dried over magnisium sulfate. The solvent was then distilled off under reduced pressure to provide 165 g (yield 69%) of 4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (3d) as oil.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=[C:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][N:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=[C:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26]
Reactant: O=c1c(CCc2ccccc2)nc2c(n1CCO)CCCC2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=c1c(CCc2ccccc2)nc2c(n1CCCl)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionylchloride (2.05 ml) was added dropwise under ice-cooling to compound 645 (6.49 g, 22.1 mM) dissolved in chloroform (25 ml), and stirred at room temperature for 2 hours. Dilute aqueous K2CO3 was added to the reaction mixture, which mixture was then extracted twice with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo to obtain compound 647, which was used without further purification in the following reactions.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2C=CC=CC=2)=[CH:24][CH:23]=1)[CH:17]1[CH:21]=[CH:20][O:19][NH:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCO.[Pd]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH:17]1[CH:21]=[CH:20][O:19][NH:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C[C@@H](c1ccc(OCc2ccccc2)cc1)C1C=CON1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(C[C@@H](c1ccc(O)cc1)C1C=CON1)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 90.3 %

Procedure:
Compound 9.1 (136 mg) and a catalytic amount of Pd/C in EtOH (2 mL) was stirred at room temperature under 1 atm of H2 for 2.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated to give 9.2 (100 mg). MS ESI (pos.) m/e: 395 (M+H).
Reaction SMILES: Cl.[CH:2]1(NN)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)[C:26](=[O:33])[N:25](CCO)[N:24]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23]2[C@H:32]3[C@H:27]([CH2:28][CH:29]=[CH:30][CH2:31]3)[C:26](=[O:33])[N:25]([CH:3]3[CH2:2][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4]3)[N:24]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNC1CCc2ccccc21
Agent: Cl
Product: COc1ccc(C2=NN(C3Cc4ccccc4C3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 2-indanylhydrazine hydrochloride as described for compound 35. Crystallized from methanol (2x). M.p. 163°-164° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[Na].Cl.[CH3:7][O:8][N:9]=[C:10]1[CH2:14][CH2:13][NH:12][CH2:11]1>CO>[ClH:1].[CH3:7][O:8][N:9]=[C:10]1[CH2:14][CH2:13][N:12]([C:3](=[NH:4])[CH2:2][Cl:1])[CH2:11]1
Reactant: CON=C1CCNC1
Reactant: N#CCCl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CON=C1CCN(C(=N)CCl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.63 ml of chloroacetonitrile was added to a solution of 23 mg of metallic sodium in 4 ml of absolute methanol, the mixture was stirred at room temperature for about 30 minutes, then 1.5 g of 3-methoxyiminopyrrolidine hydrochloride were added and the resulting mixture stirred for a further 2 hours. After completion of the reaction, the solvent was distilled off and the concentrate mixed with anhydrous ether. The crystals which separated out were collected by filtration and washed with ether, giving 2.2 g of 2-(3-methoxyiminopyrrolidin-1-yl)-2-iminoethylchloride hydrochloride.
Reaction SMILES: [OH2:1].[ClH:2].Cl.[CH3:4][N:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[CH:6]1[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8][CH2:7]1.CN(C1C=CC=C(C)C=1)C1CCN(CC2C=CC=CC=2)CC1.Cl.Cl.[H][H]>[Pd].CO>[OH2:1].[ClH:2].[ClH:2].[CH3:4][N:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)[CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: [H][H]
Reactant: Cc1cccc(N(C)C2CCN(Cc3ccccc3)CC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cccc(N(C)C2CCNCC2)c1
Yield: 60.9 %

Procedure:
A mixture of 9 parts of N-methyl-N-(3-methylphenyl)-1-(phenylmethyl)-4-piperidinamine dihydrochloride hemihydrate and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo and the filtrate was evaporated. The residue Was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, Yielding 1.5 parts (60.9%) of N-methyl-N-(3-methylphenyl)-4-piperidinamine dihydrochloride monohydrate; mp. 209.1° C. (intermediate 97).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2=[C:8]3[C:13](=[C:14]([NH2:16])[N:15]=[C:6]2[CH:5]=1)[N:12]=[CH:11][CH:10]=[CH:9]3)([O-])=O.C(Cl)[Cl:20]>[Ni].CCO>[Cl:20][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]([NH2:16])[N:15]=[C:6]3[CH:5]=[C:4]([NH2:1])[CH:18]=[CH:17][C:7]3=2)[N:12]=1
Reactant: ClCCl
Reactant: Nc1nc2cc([N+](=O)[O-])ccc2c2cccnc12
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)nc(N)c1nc(Cl)ccc12
Reaction time: 8 h

Procedure:
A mixture of 8-nitrobenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq) and Raney Nickel (wet, 10% wt) in EtOH was stirred under H2 balloon overnight. The reaction mixture was diluted with DCM. The insoluble solid was filtered off through celite, and the filtrate was concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-100% EtOAc/Hexanes to give 3-chlorobenzo[f][1,7]naphthyridine-5,8-diamine as a white solid. 1H NMR (methanol-d4): δ 8.75 (d, 1H), 8.08 (dd, 1H), 7.70 (d, 1H), 6.84-6.81 (m, 2H). LRMS [M+H]=245.1.