Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=2)[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:11]1=[O:31].Cl>CO>[OH:7][CH2:8][CH2:9][N:10]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[CH:21][CH:22]=2)[C:12]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[C:11]1=[O:31]
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)C1(CCNCC1)C(=O)N2CCOC1CCCCO1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc2c(c1)C1(CCNCC1)C(=O)N2CCO
Reaction time: 0.5 h

Procedure:
1-(Tetrahydropyran-2-yl-oxy-ethyl)-5-tert-butoxycarbonyl-spiro[indoline-3,4′-piperidin]-2-one (0.021 g, 0.05 mmol) was dissolved in methanol (2 mL). To the reaction mixture was then added at room temperature aqueous 1.0N HCl (80 μL) and the reaction mixture was stirred for 30 minutes. The reaction mixture was then partitioned with aqueous Na2CO3 and ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield the title compound as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:7]1([S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)c1ccccc1
Temperature: 42.5 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
(β-chloroethylsulfonyl)benzene (40.9 g, 200 mmol) was dissolved in 100 g of toluene, to this solution were added 30.7 g of 49% aqueous potassium carbonate solution (potassium carbonate 109 mmol) and 1.01 g (10 mmol) of triethylamine, and the mixture was stirred for 3 hours at from 40 to 45° C. Then, the mixture was washed with 70 g of water once, with 35 g of 5% aqueous sulfuric acid solution once and further with 35 g of water once, and the solvents were distilled off to obtain 33.1 g (yield 98.4%) of phenylvinylsulfone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][C:11]2[N:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[CH:19][C:14]3=[N:13][N:12]=2)[CH:7]=[CH:6][C:5]=1[NH2:26])([O-])=O.CN(C)C=O>CO.O1CCCC1.[Pd]>[C:20]1([C:17]2[CH:18]=[CH:19][C:14]3[N:15]([C:11]([CH2:10][C:8]4[CH:9]=[C:4]([NH2:1])[C:5]([NH2:26])=[CH:6][CH:7]=4)=[N:12][N:13]=3)[N:16]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(Cc2nnc3ccc(-c4ccccc4)nn23)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(Cc2nnc3ccc(-c4ccccc4)nn23)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
A mixture of 2-nitro-4-(6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-phenylamine (89 mg, 0.257 mmol) and 10% wt Pd/C (27 mg, 0.026 mmol) in methanol (4 mL), tetrahydrofuran (2 mL), and dimethylformamide (2 mL) was stirred at room temperature under hydrogen atmosphere for 4 h. Catalyst was filtered through celite and the filtrate was concentrated and dried in vacuo to provide 81 mg of the product as a beige solid. 1HNMR (DMSO) δ 4.30 (s, 2H), 4.32 (s, 2H), 4.43 (s, 2H), 6.43 (m, 2H), 6.50 (s, 1H), 7.60 (m, 3H), 7.93 (d, 1H), 8.11 (m, 2H), 8.39 (d, 1H); MS (m/z) 317 [M+H+]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18]O)(=[O:12])=[O:11].O=S(Cl)[Cl:22]>C(Cl)(Cl)Cl>[Cl:22][CH2:18][C:14]1[N:13]([S:10]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[CH3:9])(=[O:12])=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)c(S(=O)(=O)n2cccc2CO)c(C)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(S(=O)(=O)n2cccc2CCl)c(C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of [1-(2,4,6-Trimethyl-benzenesulfonyl)-1H-pyrrol-2-yl]-methanol (1.4 g, 5.0 mmol) in CHCl3 (25 ml) was cooled with an ice bath. SOCl2 (1.1 ml, 15 mmol) was added slowly. The solution was allowed to warm to rt, and held an additional 45 min. The solution was then concentrated under reduced pressure. 2-Chloromethyl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-pyrrole was obtained as a brown solid (1.5 g, 100%). 1H NMR (CDCl3) δ 7.28 (dd, 1H, J=3.3, 1.7 Hz), 6.98 (s, 2H), 6.38-6.34 (m, 1H), 6.19 (t, 1H, J=3.4 Hz), 4.58 (s, 2H), 2.50 (s, 6H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.CCN(CC)CC.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[N:29]1[CH2:30][CH2:31][N:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccccn2)CC1
Temperature: 25 °C

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of Et3N and 10 mL (66.0 mmol) of 1-(2-pyridyl)-piperazine. The reaction mixture was refluxed for five hours, cooled to rt. and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated NaHCO3, washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography using MeOH/chloroform as eluant and concentrated to dryness to give a quantitative yield of the desired mixture of isomers as a yellow oil. MS (ion spray) 312.2 (M+).
Reaction SMILES: [N:1]1[C:2]([C:10]([OH:12])=O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[N:1]=[C:5]4[N:6]=[CH:7][CH:8]=[CH:9][N:4]4[CH:3]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1cn2cccnc2n1
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2cccnc2n1
Yield: 46 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from Imidazo[1,2-a]pyrimidine-2-carboxylic acid (0.076 g, 0.466 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.1 g, 0.359 mmol). The product was purified by recrystallization from acetonitrile. Yield 46.0%. 1H-NMR (400 MHz; CDCl3): δ 1.32 (d, 3H), 4.33 (dd, 1H), 4.44 (dd, 1H), 4.57-4.67 (m, 1H), 6.57 (dd, 1H), 6.97 (dd, 1H), 7.50 (d, 1H), 7.59 (dd, 1H), 7.71 (dd, 1H), 7.80 (d, 1H), 8.08 (s, 1H), 8.47 (dd, 1H), 8.66 (dd, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:7]=[C:8]2[N:13]([CH:14]=1)[CH:12]=[CH:11][CH:10]=[CH:9]2>S(=O)(=O)(O)O>[CH3:5][C:6]1[C:7]([N+:1]([O-:4])=[O:2])=[C:8]2[N:13]([CH:14]=1)[CH:12]=[CH:11][CH:10]=[CH:9]2
Reactant: O=[N+]([O-])O
Reactant: Cc1cc2ccccn2c1
Agent: O=S(=O)(O)O
Product: Cc1cn2ccccc2c1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
Nitric acid (5 mL, 70%) was added slowly to a stirred solution of 2-methylindolizine 1 (see preparation of Example 1) (5 g, 38.2 mmol) in concentrated sulphuric acid (15 mL, 96%) at 0° C. After 5 minutes, the brown solution obtained was poured onto crushed ice. The orange precipitate formed was immediately isolated by filtration, washed with copious amounts of water and then dried under vacuum in the presence of P2O5 for a night to give 2-methyl-1-nitroindolizine 13 (3 g), m.p. 137-139° C. 1H NMR (DMSO-d6): δ 8.55 (dt, J=6.7, 1.0 Hz, 1H), 8.20 (d, J=9.1 Hz, 1H), 7.54-7.48 (m, 2H), 7.11 (dt, J=8.0, 1.2 Hz, 1H), 2.47 (d, J=1.0 Hz, 3H). 13C NMR (DMSO-d6): δ 132.2, 128.0, 127.7, 123.0, 122.8, 117.8, 115.0, 114.7, 12.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14]([CH3:19])=[N:15][N:16]([CH3:18])[CH:17]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[C:14]([CH3:19])=[N:15][N:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: Cc1nn(C)cc1N
Solvent: c1ccncc1
Product: Cc1nn(C)cc1NS(=O)(=O)c1ccc(Br)cc1
Yield: 91.6 %

Procedure:
Prepared from 4-bromobenzenesulfonyl chloride (396 mg, 1.55 mmol) and 4-amino-1,3-dimethyl-1H-pyrazole (228 mg, 1.55 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a white solid (469 mg, 1.42 mmol, 92%). OH (D-6 DMSO, 300K) 9.44 (1H, s), 7.79 (2H, d J 8.7 Hz), 7.57 (2H, d J 8.7 Hz), 7.39 (1H, s), 3.65 (3H, s), 1.70 (3H, s). m/z (ES+, 70V) 332.0 (MH+).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].CC(O)C.[Br:11][C:12]1[CH:13]=[C:14]([Cl:19])[C:15](Cl)=[N:16][CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([Cl:19])[C:15]([O:4][CH:2]([CH3:3])[CH3:1])=[N:16][CH:17]=1
Reactant: Clc1cc(Br)cnc1Cl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)Oc1ncc(Br)cc1Cl
Temperature: 95 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
Potassium tert-butoxide (25.7 g, 229 mmol) was added to 2-propanol (100 mL, 57.3 mmol) and the solution was stirred at 95° C. for 3 h, then 5-bromo-2,3-dichloropyridine (13 g, 57.3 mmol) was added. This reaction was refluxed overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with water and saturated brine, dried over sodium sulphate and evaporated in vacuo to afford the crude product 5-bromo-3-chloro-2-[(1-methylethyl)oxy]pyridine (D107) (14.5 g), which was used directly without further purification.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][CH2:16][C:17]1([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=3)[CH:26]=[C:25]2[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][CH2:16][C:17]1([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=3)[CH:26]=[C:25]2[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CNC(=O)OC(C)(C)C)CCOCC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CN)CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (60 mL) is added to a solution of crude diethyl 1-[(4-{[(tert-butoxycarbonyl)amino]methyl}tetrahydro-2H-pyran-4-yl)methyl]-1H-indole-2,6-dicarboxylate from the preceding step in CH2Cl2 (400 mL). The reaction mixture is stirred at room temperature for 2 h. Then the solvent is removed under vacuum and the residue is dissolved in EtOAc (300 mL) and washed with saturated NaHCO3 solution until the pH is about 7. The aqueous layer is separated and it is extracted with EtOAc (100 mL). The organic layers are combined, dried over Na2SO4 and concentrated to afford the crude title compound which is used in the next step without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:56]1([C@@H:62]([NH2:64])[CH3:63])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:64][C@H:62]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[CH3:63])=[O:22])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)O)(CC1)CC2
Reactant: C[C@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,4S)-1-[[N-Benzyloxycarbonyl-N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (40.0 mg) and 1-hydroxybenzotriazole (20.1 mg) were dissolved in N,N-dimethylformamide (0.8 mL). While the solution was chilled in an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41.9 mg) was added and the mixture was stirred at room temperature for 2 hours. Subsequently, (1S)-1-phenylethylamine (14.5 μL) was added and the mixture was further stirred at room temperature for 16.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in dichloromethane (2 mL). The dichloromethane solution washed sequentially with 0.1 mol/L hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine. The solution then was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The resulting residue was purified by a silica gel column (eluant:ethyl acetate) to give ((2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[N-[(1S)-1-phenyl-1-ethyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (51.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:30])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:15])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH3:30]
Reactant: O=C(O)c1ccc(C2CCCC2)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(C2CCCC2)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopentyl-pyridine-2-carboxylic acid (Example 106 e) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=426.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.[CH2:21]([Sn](CCCC)(CCCC)CCCC)[CH:22]=[CH2:23].[Li+].[Cl-].[NH4+].[OH-]>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.CC(=O)OCC.CN(C=O)C>[CH2:23]([C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2)[CH:22]=[CH2:21]
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1ccnc2ccc(OC)nc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A flask charged with trifluoro-methanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (2.50 g, 8.11 mmol; prepared according to WO 2007/107965), allyltributyltin (3.11 mL, 1.25 eq.) and DMF (20 mL) was degassed with 1\12. LiCl (1.29 g, 3.75 eq.) and Pd(PPh3)4 (234 mg, 0.025 eq.) were added and the mixture was stirred at 100° C. for 2 h. After cooling to rt the mixture was poured into 10% aq. NH4OH and EA, the aq layer was extracted with EA and the combined org. layers were washed with water (2×) and brine, dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 2:1) to afford the title intermediate as a yellow oil (1.59 g, 98% yield).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20](O)[CH2:19][N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:17]2=[O:30])=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[CH:19][N:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[C:17]2=[O:30])=[N:13][C:12]=1[CH3:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)CC2O)sc1C(=O)NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1nc(-n2ccn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1ccccc1
Yield: 64 %

Procedure:
To a solution of N-benzyl-2-(3-(4-fluorobenzyl)-5-hydroxy-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxamide (0.22 g, 0.50 mmol) in chloroform (10 mL) was added trifluoroacetic acid (10 mL) at ambient temperature. The resulting reaction mixture was heated to reflux for 8 hours. The solvent was removed in vacuo and the residue was purified by column chromatography to afford the title compound in 64% yield (0.12 g): mp 167-168° C.; 1H NMR (300 MHz, CDCl3) δ 7.34-6.96 (m, 10H), 6.30-6.29 (m, 1H), 6.12 (s, 1H), 4.76 (s, 2H), 4.55 (d, J=5.4 Hz, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.6, 162.0, 153.4, 152.9, 150.5, 131.4, 129.8, 128.8, 127.8, 117.7, 120.0, 116.1, 115.8, 113.0, 107.6, 46.7, 44.1, 17.2; MS (ES+) m/z 423.2 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:24][Si](C)(C)C)C#N)=[CH:17][CH:16]=1.[CH:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>COCCOC>[OH:36][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:24]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C(C#N)O[Si](C)(C)C)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: COCCOC
Product: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
According to the procedure in the literature [J. Chem. Soc. Perkin Trans. I, 1992, 2409-2417], dissolve 292 ml (2.08 mol) diisopropylamine in 3.6 litre 1,2-dimethoxyethane and cool to −78° C. Add 826 ml n-butyllithium solution (2.5 M in n-hexane, 2.066 mol) at a temperature below −60° C. Stir the mixture for a further 15 min at <−60° C. and then add a solution of 442 g (1.877 mol) (4-methoxyphenyl)[(trimethylsilyl)oxy]acetonitrile in 1.41 litre 1,2-dimethoxyethane dropwise at <−60° C. After further stirring for 30 min at −60° C., add a solution of 199.3 g (1.878 mol) benzaldehyde in 1.4 litre 1,2-dimethoxyethane in the space of 20 min at −60° C. Next, heat the reaction mixture slowly to RT in 4 h. Add 7 litre saturated ammonium chloride solution and extract with ethyl acetate. Wash the organic phase with saturated ammonium chloride solution, dry, and concentrate under vacuum. Take up the residue in 7 litre dioxan and 5 litre methanol, and add 6 litre 1 N hydrochloric acid. Stir the mixture for 3 h at RT, then add 3 litre saturated sodium chloride solution and extract the mixture with 6.5 litre ethyl acetate. Wash the organic phase with 1.0 litre 1 N sodium hydroxide solution and with saturated sodium chloride solution, dry, and concentrate under vacuum. Take up the residue in 2 litre diisopropyl ether, decant from the insoluble matter and seed with crystals. Stir the resultant suspension for 2 h at RT and then filter off the crystals with suction. Wash with 300 ml diisopropyl ether and petroleum ether and dry under vacuum. 236.8 g (47.8% of theor.) of the target compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]3[C:25]4[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=4[CH2:23][CH2:22][O:21]3)[C@@H:14]([CH3:31])[CH2:13]1)=[CH:7][CH:6]=[CH:5]2.N1C=CC=CC=1.Cl[C:39]([O:41][CH2:42][CH2:43]Cl)=[O:40]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]3[C:25]4[CH:26]=[CH:27][C:28]([N:30]5[CH2:43][CH2:42][O:41][C:39]5=[O:40])=[CH:29][C:24]=4[CH2:23][CH2:22][O:21]3)[C@H:14]([CH3:31])[CH2:13]1)=[CH:7][CH:6]=[CH:5]2
Reactant: O=C(Cl)OCCCl
Reactant: C[C@H]1CN(c2cccc3cc(F)ccc23)CCN1CC[C@@H]1OCCc2cc(N)ccc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CC[C@@H]1OCCc2cc(N3CCOC3=O)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S)-1-{2-[(2S)-4-(6-fluoro-1-naphthyl)-2-methyl-piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine (0.217 g, mmol) in dry DMF (5 mL) was added pyridine (0.05 mL, mmol) and 2-chloroethyl chloroformate (0.055 mL, mmol), and the reaction stirred at room temperature under nitrogen for 2 h. The reaction was quenched by addition of 2M sodium hydroxide (3 mL), diluted with water and extracted into dichloromethane. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by prep LCMS to yield 3-((1S)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]-ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one. M+H=490.
Reaction SMILES: N1C=CC=CC=1C(O)=O.S(=O)(=O)(O)O.N1C=CC=CC=1C(OC)=O.ClC1C=C(C=CC=1)C(OO)=O.P(Cl)(Cl)(Cl)=O.[Cl:41][C:42]1[N:47]=[C:46]([C:48](OC)=[O:49])[CH:45]=[CH:44][CH:43]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:41][C:42]1[N:47]=[C:46]([CH2:48][OH:49])[CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)c1cccc(Cl)n1
Agent: COC(=O)c1ccccn1
Agent: O=C(O)c1ccccn1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: OCc1cccc(Cl)n1

Procedure:
Scheme C depicts a general method for preparing compounds of Formula 1 in which L is —CH2O—. As shown in Scheme C, a picolinic acid derivative (CO is reacted with methanol and sulfuric acid at elevated temperature (e.g., about 65° C.). The resulting methyl picolinate derivative (C2) is activated via treatment with m-chloroperoxybenzoic acid in a compatible solvent (e.g., DCM) to give and N-oxide intermediate (C3) which is subsequently reacted with phosphoryl trichloride at elevated temperature (e.g., about 100° C.). The resulting methyl 6-chloropicolinate derivative (C4) is treated with sodium borohydride and methanol to give a (6-chloropyridin-2-yl)methanol derivative (CS) which is reacted with zinc cyanide in the presence of a palladium catalyst (e.g. Pd2(dba)3), an optional ligand (e.g., XPhos) and solvent (e.g., DMF, DMA, etc.) at elevated temperature (e.g., about 150-165° C.). The resulting 6-(hydroxymethyl)picolinonitrile derivative (C6) is reacted with tribromophosphine in a compatible solvent (e.g., THF) to give a brominated intermediate (C7) which is reacted with an alcohol (A2) in the presence of a base to give a nitrile (C8) in which L2 is —CH2O—. As in Scheme A, the nitrile (C8) is combined with ethyl hydrazinecarboxylate in a compatible solvent and is heated to give a triazolone intermediate (C9). Subsequent removal of the amine protective group and reaction with an acyl chloride (A7) in the presence of a nonnucleophilic base and a compatible solvent gives the desired compound of Formula 1B.