Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:17]1[C:22]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][CH:20]=[C:19]([I:27])[CH:18]=1.Cl>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][S:23]([C:22]1[CH:17]=[CH:18][C:19]([I:27])=[CH:20][CH:21]=1)(=[O:25])=[O:24])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a magnetically stirred solution of 2-amino-5-chlorobenzophenone (1.62 g, 7.0 mmol) in dry pyridine (30 mL) was added dropwise a solution of pipsyl chloride in toluene (12 mL) and the reaction was stirred at ambient temperature. The reaction was added to cold (ice bath) 6M hydrochloric acid with stirring and the mixture was extracted with ethyl acetate (3×50 mL). The extracts were washed with water and with saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered and concentrated to give a crystalline solid. The product was filtered, washed with hexane and dried (vacuum) to get white crystalline solid. 1H NMR (CDCl3) δ 9.63 (br s, 1H, NH), 7.75 (dm, 1H, J=8.8 Hz), 7.62 (tm, 1H, J=7.6 Hz), 7.56 (dm, 1H, J=7.6 Hz), 7.48 (m, 3H), 7.32 (m, 5H). MS: m/z 498.0 (M+1).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:23])[N:20]([OH:22])[CH3:21])[CH:9]=[CH:10]2)[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl[CH2:30][C:31]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:32]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:23])[N:20]([O:22][CH2:30][C:31](=[O:32])[N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH3:21])[CH:9]=[CH:10]2)[C:4]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)c1c2ccc(CC(=O)N(C)O)ccc-2c(C(=O)OCC)c1N
Reactant: O=C(CCl)N1CCCC1
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)N(C)OCC(=O)N3CCCC3)ccc-2c(C(=O)OCC)c1N
Yield: 77 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(N-methyl-hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and N-chloroacetyl-pyrrolidine the title compound is obtained in 77% yield as a wax.
Reaction SMILES: [CH3:1][C:2]([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)([CH3:6])[C:3]([OH:5])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]([NH2:36])([CH3:35])[CH3:34].O>O1CCCC1>[CH:33]([NH:36][C:3](=[O:5])[C:2]([CH3:1])([N:7]1[C:12](=[O:13])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[O:9][CH2:8]1)[CH3:6])([CH3:35])[CH3:34]
Reactant: CC(C)N
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)NC(C)C)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
To a solution of 2-methyl-2-(6-methyl-5-phenyl-2,3-dihydro-4-oxo-4H-1,3-oxazin-3-yl)-propionic acid (0.83 g) in 6 ml of tetrahydrofuran (THF) was added carbonyldiimidazole (0.59 g). After stirring at room temperature for 30 min., isopropylamine (0.23 g) was added and the reaction mixture was stirred at 60° C. for 5 h. Then it was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a silica gel column to get the captioned compound (0.38 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]#[N:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.CS(C)=[O:26].OO>[OH-].[Na+].CO>[Cl:1][C:2]1[C:3]([C:22]([NH2:23])=[O:26])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][OH:20])=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1
Reactant: CS(C)=O
Reactant: CCc1nc2cc(C#N)c(Cl)cc2n1-c1ccc(CCO)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCO)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carbonitrile (step 4, 2.4 g, 7.4 mmol), DMSO (0.7 mL, 8.8 mmol) and methanol (100 mL) was added 30% aqueous hydrogen peroxide (1.3 mL, 11 mmol) and 0.2 M aqueous NaOH (0.7 mL, 0.14 mmol). The mixture was stirred at 50° C. for 2 h. The solvent was removed and the resulting precipitates were collected by filtration. The precipitates were washed with water and dried under reduced pressure to give 1.9 g (76%) of the title compound as pale pink solids: 1H-NMR (DMSO-d6) δ 7.69 (1H, br.s), 7.61 (1H, s), 7.33–7.40 (4H, m), 6.95 (1H, s), 4.64 (1H, br.s), 3.59 (2H, t, J=6.4 Hz), 2.74 (2H, t, J=6.4 Hz), 2.62 (2H, q, J=7.4 Hz), 1.11 (3H, t, J=7.4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C([Sn](=O)CCCC)CCC.O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(O)cc1
Yield: 97.3 %

Procedure:
69.1 g (0.5 mole) of p-hydroxybenzoic acid, 216.2 g (2 moles) of benzyl alcohol and 1.4 g of dibutyltin oxide were fed into a four-necked glass flask, and reacted at 200° C. for 6 hours with stirring in an atmosphere of nitrogen. Water formed by the reaction and a small amount of phenol resulting from the decomposition of the p-hydroxybenzoic acid were distilled off from the reaction system. After the reaction, the excess of benzyl alcohol was evaporated under reduced pressure to give 111.0 g (yield 94.%) of crude benzyl p-hydroxybenzoate having a purity of 97.4%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[OH:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)CC)C>ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([O:24][C:33](=[O:35])[CH3:34])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:22][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(O)c3ccccc3)cc(OC)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(OC(C)=O)c3ccccc3)cc(OC)c21
Yield: 98.7 %

Procedure:
A solution of 136 mg (0.30 mmol) [2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-phenyl-methanol, 46 μl (0.66 mmol) acetyl chloride and 125 μl (0.90 mmol) triethylamine in 3 ml dichloromethane is stirred at room temperature for 1 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 140 mg of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][CH3:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]([CH3:17])[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNc1nc(C)c(C(=O)NCc2ccccc2)s1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(N(C)C(=O)c2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
To a solution of crude N-benzyl-4-methyl-2-(methylamino)thiazole-5-carboxamide (0.040 g, 0.15 mmol), 4-dimethylaminopyridine (catalytical amount) and triethylamine (64 μL, 0.45 mmol) in dichloromethane (5 mL) was added benzoyl chloride (19 μL, 0.17 mmol) at 0° C. and the reaction mixture was allowed to warm to ambient temperature over 18 h. The reaction was quenched by the addition of saturated soldium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (30/70 to 50/50) to afford the title compound (0.040 g, 0.11 mmol); 1H NMR (CDCl3, 400 MHz) δ 7.47-7.35 (m, 5H), 7.30-7.17 (m, 5H), 6.05 (s, 1H), 4.51 (s, J=5.6 Hz, 2H), 3.55 (s, 3H), 2.60 (s, 3H); MS (ES+) m/z 366 (M+1).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15](Br)[CH:16]=1)=[O:7].Cl>CN1C(=O)CCC1.O.[Cu]I>[CH3:4][O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15]([O:2][CH3:1])[CH:16]=1)=[O:7]
Reactant: C[O-]
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Temperature: 120 °C
Yield: 168.5 %

Procedure:
Freshly prepared sodium methoxide (500 mg in 5 mL methanol) was added to a stirred suspension of 6-bromo-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (500 mg, 1.68 mmol) and CuI (480 mg, 2.53 mmol) in NMP (8 mL) and then heated at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and acidified with 1N HCl. The reaction mixture was filtered through Celite and washed with EtOAc (5 mL). Separated the EtOAc layer from filtrate, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish the crude 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg), which was used in the next stage without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.44 (d, J=6.4 Hz, 6H), 3.84 (s, 3H), 4.80-4.76 (m, 1H), 6.87 (d, 1H), 7.33 (t, J=3.2 Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 12.65 (bs, 1H). LCMS (ES+): m/z=234.11 [M+H].
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH2:15][CH3:16])=[N+:2]=[N-:3].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:4]=1[N:1]1[CH:19]=[C:18]([C:17]([O:21][CH2:22][CH3:23])=[O:20])[N:3]=[N:2]1)[CH3:16]
Reactant: CCOc1cc(C(=O)OC)ccc1N=[N+]=[N-]
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(C(=O)OC)cc2OCC)nn1
Temperature: 25 °C

Procedure:
A solution of methyl 4-azido-3-ethoxybenzoate (1.0 g) obtained in Example 320b) and ethyl propiolate (0.92 ml) in toluene (10 ml) was stirred at 100° C. overnight. After the reaction solution was allowed to cool to room temperature, the resultant precipitate was collected by filtration to give the title compound as a white solid (0.76 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C>ClCCl>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:16]
Reactant: CCOC(=O)CBr
Reactant: COc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
The mixture of 3-methoxyaniline (3.7 g), ethyl bromoacetate (5 g) and triethylamine (4 g) in dichloromethane (30 mL) was stirred at room temperature for overnight. The mixture was washed with water (50 ml), dried over Na2SO4 and concentrated. The residue was purified with chromatography to give 1.7 g of (3-methoxy-phenylamino)-acetic acid ethyl ester. 1HNMR: δ 1.33 (3H), 3.796 (3H), 3.92 (2H), 4.26 (2H), 6.21 (1H), 6.29 (1H), 6.36 (1H), 7.13 (1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][N:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M74) (905 mg, 1.7 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (566 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17][CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.[OH-].[Na+]>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([C:11]2([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cncc3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cncc3ccccc23)CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
A mixture of 2.0 gm (6.1 mMol) 1-tert-butoxycarbon-yl-4-(isoquinolin-4-yl)-4-hydroxypiperidine, and 4 mL trifluoroacetic acid in 20 mL dichloromethane was stirred at room temperature for 18 hours. The reaction mixture was diluted with 2N sodium hydroxide and the phases were separated. The aqueous phase was extracted well with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 10% to 40% methanol and a trace of ammonium hydroxide Fractions containing product were combined and concentrated under reduced pressure to provide 0.793 gm (57%) of the title compound as a light yellow solid.
Reaction SMILES: [N:1]1([S:7]([CH2:10][C@H:11]([CH3:22])[C:12]([O:14]CC2C=CC=CC=2)=[O:13])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[N:1]1([S:7]([CH2:10][C@H:11]([CH3:22])[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@@H](CS(=O)(=O)N1CCCCC1)C(=O)OCc1ccccc1
Agent: [Pd]
Product: C[C@@H](CS(=O)(=O)N1CCCCC1)C(=O)O
Reaction time: 3 h

Procedure:
A 100 mL Fisher/Porter vessel was charged with 1 g of benzyl 3-(1-piperidinyl)sulfonyl-2(R)-methylpropionate 30 mL MeOH and a catalytic amount of 10% Pd—C. The reaction was hydrogenated at 50 psi for 3 hours. After filtration through Celite and concentration in vacuo of 3-(1-piperidinyl)sulfonyl-2(R)-methylpropionic acid was isolated in quantitive yield.
Reaction SMILES: [NH2:1][C:2]1([CH3:23])[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH2:13][CH2:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:31](=O)(O)[O-:32].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:1]([C:2]1([CH3:23])[CH2:3][CH2:4][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH2:13][CH2:14][C:15]=4[CH:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:6][CH2:7]1)=[C:31]=[O:32]
Reactant: CC1(N)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Reactant: O=C([O-])O
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(N=C=O)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Yield: 40 %

Procedure:
A solution of (1R)-1-[(4-amino-4-methyl-1-piperidinyl)methyl]-1,2,5,6-tetrahydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione (1.294 g, 4.09 mmol) in DCM (30 ml) under argon at rt was treated with triethylamine (0.684 ml, 4.91 mmol), then di-tent-butyl dicarbonate (1.045 ml, 4.50 mmol) and finally 4-dimethylaminopyridine (0.050 g, 0.409 mmol) and stirred at rt for 1 h. The reaction mixture was treated with aq sodium bicarbonate (100 ml) and extracted with DCM (3×200 ml). The combined organic fractions were dried (MgSO4), filtered and evaporated to give the crude product as a yellow solid which was then chromatographed (0-10% methanol/DCM, Rf=0.5 in 10% methanol/DCM) to give the product as a white solid (561 mg, 40%).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[OH-].[Na+]>CC(C)=O.O>[Br:14][C:12]1[CH:13]=[C:4]([CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1)[C:3]([OH:15])=[O:2]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1cc(Br)cc(C(=O)O)c1
Reaction time: 4 h
Yield: 89.5 %

Procedure:
Dimethyl-5-bromoisophthalate (3 g, 11.0 mmol) was dissolved in acetone-H2O (2:1 v/v, 60 mL) and NaOH (0.40 g, 11.0 mmol) was added. The reaction mixture was allowed to stir for 4 h. Acetone was removed under reduced pressure and the aqueous layer was washed with EtOAc, acidified to pH ˜2-3 using 1.5N HCl, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 3-bromo-5-(methoxycarbonyl)benzoic acid (2.55 g, yield 89%): 1H NMR (300 MHz, DMSO-d6) δ 13.75 (br s, 1H), 8.40 (d, J=1.0 Hz, 1H), 8.26 (d, J=1.4 Hz, 1H), 8.23 (d, J=1.0 Hz, 1H), 3.89 (s, 3H). MS (ESI) m/z: Calculated for C9H7BrO4: 257.95. found: 258.0 (M+H)+.
Reaction SMILES: [Na].C(O)C.[Br:5][C:6]1[CH:7]=[C:8]([N:12]2[CH:16]=[N:15][C:14]([OH:17])=[N:13]2)[CH:9]=[CH:10][CH:11]=1.Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CS(C)=O>[Br:5][C:6]1[CH:7]=[C:8]([N:12]2[CH:16]=[N:15][C:14]([O:17][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:25])=[N:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2cccc(Br)c2)n1
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2cccc(Br)c2)n1
Yield: 77.4 %

Procedure:
The process was carried out as described in Example 3, starting with 2.8 g of sodium, 50 ml of ethanol, 75 ml of dimethylsulfoxide, 29 g of 1-(3-bromophenyl)-3-hydroxy-1,2,4-1H-triazole and 21.9 g of ethyl 2-bromopropionate. The yield was 31.8 g of the desired product, m.p. 83°-85°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[O:15]1[CH2:29][CH:16]1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CC(C)=O>CO>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[OH:15][CH:16]([CH2:29][NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)NCCN)cc1
Reactant: COC(=O)c1ccccc1OCC1CO1
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1ccccc1OCC(O)CNCCNS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 2.15 g of N-(2-aminoethyl)-p-toluenesulfonamide (0.1 mole) and 2.08 g of methyl 2-(2,3-epoxypropoxy)benzoate (0.01 mole) in 100 ml of methanol was stored at 25° C. for 4 hours. The methanol was then removed under reduced pressure, leaving an oil (NMR indicated only mono-alkylated product). The oil was then dissolved in 50 ml of methanol and an equimolar quantity of oxalic acid was added to the solution. 50 Ml of acetone was added, and the product crystallized upon refrigeration. The product was recrystallized from acetone/methanol (1:1) to yield 1.4 g of product which had a melting point of 165°-166° C. The elemental analysis (CHN) and NMR spectrum were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[N:28]O)[NH2:27])=[CH:22][CH:21]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:8][N:7]=1)[CH:3]([CH3:5])[CH3:4].[C:30]([O:33][CH2:34][C:35](O)=[O:36])(=[O:32])[CH3:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:30]([O:33][CH2:34][C:35](/[N:28]=[C:26](/[NH2:27])\[C:23]1[CH:22]=[CH:21][C:20]([C:2]([CH3:1])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:8][N:7]=2)[CH:3]([CH3:5])[CH3:4])=[CH:25][CH:24]=1)=[O:36])(=[O:32])[CH3:31]
Reactant: CC(=O)OCC(=O)O
Reactant: CC(C)C(C)(c1ccc(C(N)=NO)cc1)c1ccc(OCc2ccccn2)cn1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)OCC(=O)/N=C(/N)c1ccc(C(C)(c2ccc(OCc3ccccn3)cn2)C(C)C)cc1
Reaction time: 0.75 h

Procedure:
Compound 3a (350 mg, 0.896 mmol) was added to a stirred solution of acetoxyacetic acid (126 mg, 1.07 mmol), EDC (205 mg, 1.07 mmol) and HOBt (157 mg, 1.16 mmol) in DCM (7.00 mL) at rt. After approximately 45 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic extracts were washed with water, brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound 3b, which was used without further purification in the subsequent reaction. m/z (ES) 491 (MH)+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH2:3]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:1][C@H:2]2[C@H:6]3[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]3[CH2:4][CH2:3]2)=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN2CC[C@@H](O)[C@H]2C1
Reactant: Clc1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2CC[C@@H](Oc3ccc(Cl)cn3)[C@H]2C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
(8R*,8aR*)-tert-Butyl 8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (Example 36A, 0.969 g, 4.0 mmol) and 2,5-dichloropyridine (0.651 g, 4.40 mmol) were treated with potassium tert-butoxide (0.987 g, 8.80 mmol) in dry tetrahydrofuran (5 mL). The mixture was heated to 80° C. and stirred for 16 hours. After the mixture cooled to room temperature, the mixture was purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=222 nm) to give the tert-butoxycarbonyl protected product, (8R*,8aR*)-tert-butyl 8-(5-chloropyridin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate. This tert-butoxycarbonyl compound was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated and then purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=220 nm) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.72-1.86 (m, 1H), 2.08-2.22 (m, 3H), 2.31-2.45 (m, 1H), 2.69-2.80 (m, 2H), 2.87-2.98 (m, 1H), 2.99-3.21 (m, 3H), 5.51 (ddd, 1H, J=7, 4, 2 Hz), 6.77 (d, 1H, J=9 Hz), 7.65 (dd, 1H, J=8, 2 Hz), 8.07 (d, 1H, J=2 Hz); MS (DCI) m/z 254 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].O.[OH-].[NH4+:22]>>[NH2:22][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: [NH4+]
Reactant: O=C(c1ccccc1)c1cccc(C(F)(F)F)c1F
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)c2ccccc2)cccc1C(F)(F)F
Temperature: 140 °C
Yield: 90 %

Procedure:
A suspension of (2-fluoro-3-trifluoromethyl-phenyl)-phenyl-methanone (0.5 g, 1.87 mmol) in 10 ml of ammonium hydroxide (28%) was sealed in a heavy-welled Pyrex tube. The sealed tube was heated at 140° C. overnight. The reaction was poured into water/saturated ammonium chloride solution and extracted with ethyl acetate. The combined organics was dried over MgSO4 and concentrated to give (2-amino-3-trifluoromethyl-phenyl)-phenyl-methanone as an oil (0.45 g, 90%). MS ESI (m/z) 266 ([M+H]+);