Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([C:35](=O)[C:36]([F:39])([F:38])[F:37])[C@H:30]([CH3:41])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.B.CSC>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([CH2:35][C:36]([F:37])([F:38])[F:39])[C@H:30]([CH3:41])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1C(=O)C(F)(F)F
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1CC(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of compound 316 (100 mg, 0.17 mmol) in tetrahydrofuran (5 mL) was added a solution of borane/dimethylsulfane (10 mol/L, 2 mL) dropwise at 0° C. After the addition was completed, the reaction mixture was stirred at that temperature for 30 min and then allowed to warm to 50° C. After stirred for another 1 hour the reaction mixture was quenched by adding 15 mL of methanol and 5 mL of 1 M HCl aqueous solution slowly. The mixture was stirred at room temperature for 2 hours before concentration to the residue. The mixture was treated with dichloromethane and water. The organic layer was concentrated to dryness and the crude was purified by pre-TLC (Hexanes/EtOAc=1:1) to afford 60 mg of 351. (Yield: 61%) 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1H), 7.51-7.46 (m, 1H), 7.09-6.97 (m, 4H), 6.45 (d, J=8.8 Hz, 1H), 4.18 (t, J=4.8 Hz, 2H), 3.84-3.80 (m, 2H), 3.27 (q, J=9.6 Hz, 2H), 3.07 (t, J=4.8 Hz, 2H), 2.84 (d, J=6.8 Hz, 2H), 2.57-2.51 (m, 2H), 1.22-1.34 (d, J=6.0 Hz, 6H). LC-MS (ESI): m/z=577 [M+H]+
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH3:15]O>Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCCCCCCCBr
Reaction time: 72 h

Procedure:
A mixture of 13.25 g of 11-bromoundecanoic acid, 100 mL of methanol and 10 drops of hydrochloric acid was stirred for 3 days in a closed flask. The solvent was removed in vacuo and the residual oil was redissolved in ether (100 mL). This solution was subsequently washed twice with 25 mL of a saturated NaHCO3 solution, once with water (25 mL) and once with brine (25 mL). Drying over sodium sulfate and removal of the solvents in vacuo gave 13.32 g of the product as a yellowish oil, which was sufficiently pure to use in the next step. 1H NMR (200 MHz, CDCl3): δ 3.65 (s, 3H); 3.39 (t, 2H); 2.28 (t, 2H); 1.90-1.78 (m, 2H); 1.70-1.50 (m, 2H); 1.50-1.21 (m, 12H) ppm. IR (neat, cm−1): 2928 (m); 2855 (m); 1741 (s).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-])=O)[CH:16]=2)=[CH:10][CH:9]=1)([O-])=O.[H][H]>CN(C)C=O>[NH2:25][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=1)[O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=[C:4]([NH2:1])[CH:5]=2)=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cc(Oc2ccc(Oc3cc([N+](=O)[O-])cc(C(F)(F)F)c3)cc2)cc(C(F)(F)F)c1
Reactant: [H][H]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(Oc3cc(N)cc(C(F)(F)F)c3)cc2)cc(C(F)(F)F)c1
Yield: 70.5 %

Procedure:
To a reducing apparatus equipped with a thermometer, reflux condenser and stirrer, 36.5 g (0.0747 mol) of 1,4-bis(3-nitro-5-trifluoromethylphenoxy)benzene, 250 mg of N,N-dimethylformamide and 1.8 g Pd-alumina were charged and reacted in a hydrogen atmosphere at 50° C. for 6 hours. After finishing the reaction, the catalyst was filtered and the filtrate was concentrated under reduced pressure to obtain 1,4bis(3-amino-5-trifluoromethylphenoxy)benzene as colorless crystals. The product was 36.5 g (70.5% yield) and had a melting point of 157.4°~158.0 ° C.
Reaction SMILES: O[C:2]1[C:11]2C(=C(C(F)(F)F)C=CC=2)N=C(C(O)CC)[C:3]=1C(NC1SC=CN=1)=O.[C:28]([OH:33])(=[O:32])[CH2:29][CH2:30][CH3:31]>>[C:28]([O:33][CH2:3][CH2:2][CH3:11])(=[O:32])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC(=O)O
Reactant: CCC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Product: CCCOC(=O)CCC

Procedure:
Using the procedure of Example5, 8 g of 4-hydroxy-2(1-hydroxypropyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide and 2 ml of butyric acid were reacted to obtain 7.8 g of 1-[4-hydroxy 3-[(2-thiazolylamino)-carboxyl]-8-trifluoromethyl)-2quinolinyl]-propyl butanoate melting at 203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=O)=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:28]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:28])=[O:24])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CCc1cc(Oc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Solvent: CO
Product: CCc1cc(Oc2ccc(CC(N)=O)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 64 %

Procedure:
Methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)phenyl)acetate (0.075 g, 0.20 mmol) and ammonia in methanol (7 M, 3 mL) were heated at 100° C. for 72 h. After this time, the crude reaction solution was cooled, evaporated, and purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.048 g, 64%) as a white solid. MW=367.83. 1H NMR (DMSO-d6, 500 MHz) δ 8.16-8.13 (m, 1H), 8.14-8.11 (m, 1H), 7.59-7.55 (m, 1H), 7.51 (t, J=7.9 Hz, 2H), 7.39-7.36 (m, 2H), 7.24-7.21 (m, 2H), 6.92 (s, 1H), 6.90 (s, 1H), 3.44 (s, 2H), 2.80 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H); APCI MS m/z 368 [M+H]+.
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:27])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[O:16])[C:11]([OH:13])=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:27][C@H:9]1[C@@H:10]([NH:14][C:15](=[O:16])[O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:11](=[O:13])[O:12]1
Reactant: Cc1ccc(CCOC(=O)N[C@@H](C(=O)O)[C@H](C)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(CCOC(=O)N[C@H]2C(=O)O[C@H]2C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
In a four necked round bottom flask, Et3N (7.3 mL, 52.5 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-({[2-(4-methylphenyl)ethoxy]carbonyl}amino) butanoic acid (4.85 g, 17.5 mmol) in dry CH2Cl2 (190 mL) under argon. After cooling at 0° C., HBTU (9.87 g, 26.2 mmol) was added and the mixture stirred 3 h at 0° C., then 3.5 h at rt. The obtained solid was filtered-off and the solvent removed under vacuum. The crude was purified by typical silica gel column chromatography, eluting with Cy/AcOEt (from 95:5 to 60:40). The resulting white solid (0.658 g) was further triturated with cyclohexane to afford the pure title compound (0.450 g, 10%), as white solid. MS (ESI) m/z: 262.21 [M−H]−. FTIR (cm−1): 3299, 3050, 2966, 2924, 2854, 1827, 1690, 1540, 1355, 1270, 1121, 1095, 1021, 844, 817. 1H-NMR (CDCl3): δ 1.42 (d, 3H); 2.33 (s, 3H); 2.90 (t, 2H); 4.31 (t, 2H); 4.81-4.88 (m, 1H); 5.39-5.46 (m, 2H); 7.08-7.13 (m, 4H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:40][CH2:39][N:30]2[C:31]3[CH:32]=[C:33](I)[CH:34]=[CH:35][C:36]=3[CH2:37][CH:29]2[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[CH3:41][S:42][Sn](CCCC)(CCCC)CCCC.O>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]([O:24][C:25]([N:27]1[CH2:40][CH2:39][N:30]2[C:31]3[CH:32]=[C:33]([S:42][CH3:41])[CH:34]=[CH:35][C:36]=3[CH2:37][CH:29]2[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)SC
Reactant: CC(C)(C)OC(=O)N1CCN2c3cc(I)ccc3CC2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc2c(c1)N1CCN(C(=O)OC(C)(C)C)CC1C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
Triphenylphosphine (28 mg) was added in 1 portion to a stirred solution of palladium(II) acetate (6 mg) in THF (2.5 mL) at room temperate under Ar. After stirring at room temperature under Ar for 10 min a solution of 2-tert-butoxycarbonyl-7-iodo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole (0.20 g, 0.5 mmol) in THF (5 mL) was added. The reaction was stirred at room temperature for 10 min then a solution of (methylthio)tributyltin (035 g, 1 mmol) in THF (2.5 mL) was added. The reaction was heated to reflux and stirred for 2 days. After allowing to cool to room temperature the mixture was poured into water (50 mL) and extracted. with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (r×50 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude oil. The oil was purified by flash column chromatography [SiO2; ethyl acetate-heptane (1:20)] to give the product as a yellow oil (0.08 g, 50%). NMR δH (400 MHz; CDCl3) 6.97 (1H, d, J 7.5 Hz), 6.56 (1H, dd, J 7.5, 1.5 Hz), 6.36 (1H, d, J 1l Hz), 3.94-4.26 (2H, m), 3.35-3.49 (2H, m), 2.78-2.96 (41, m), 2.49-2.55 (1H, m), 2.44 (311, s), 1.46 (9H, s).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)=[CH:29][CH:28]=2)O1>>[N:33]1([C:30]2[CH:31]=[CH:32][C:27]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]4[C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:4][CH:3]=3)=[CH:28][CH:29]=2)[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: CC1(C)OB(c2ccc(-n3ccnc3)cc2)OC1(C)C
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Product: COc1nn(-c2ccccc2)c2cc(-c3ccc(-n4ccnc4)cc3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 58 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole as the building block.
Reaction SMILES: Br.Br.[C:3]1([CH3:21])[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[C:24](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:3]1([CH3:21])[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17][N:18]([C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:19][CH2:20]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCNCCNCC2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2CCNCCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
From N-(p-toluenesulfonyl-1,4,7-triazacyclononane dihydrobromide (1.3.13.30), sodium hydride and trityl chloride.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([CH2:8]O)[O:6][CH:7]=1.O=S(Cl)[Cl:13]>ClCCl>[Cl:13][CH2:8][C:5]1[O:6][CH:7]=[C:2]([OH:1])[C:3](=[O:10])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1cc(CO)occ1O
Solvent: ClCCl
Product: O=c1cc(CCl)occ1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.96 %

Procedure:
To a stirred solution of 5-hydroxy-2-hydroxymethyl-pyran-4-one (1) (100.0 g, 703.68 mmol) in dichloromethane (750 mL) was added SOCl2 (102.0 mL) very slowly and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the solvent was evaporated to remove volatile compounds under reduced pressure to get a crude compound. It was then purified by hexane wash to get 2-chloromethyl-5-hydroxy-pyran-4-one (2) (70.0 g, 61.96%) as an off white solid.
Reaction SMILES: C(OC(N1C[C@H](OC(C)(C)C)C[C@H]1C(O)=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]([N:34]1[CH2:38][C@@H:37]([NH2:39])[CH2:36][C@H:35]1[C:40]1[O:41][CH:42]=[CH:43][N:44]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]([N:34]1[CH2:38][C@@H:37]([NH2:39])[CH2:36][C@H:35]1[C:40]1[O:41][C:42]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:43][N:44]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Product: N[C@H]1C[C@@H](c2ncc(-c3ccccc3)o2)N(C(=O)OCc2ccccc2)C1

Procedure:
(2S,4S)-4-amino-2-(5-phenyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4R)-4-tert-butoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester. MS calcd. for C21H22N3O3 [(M+H)+] 364, obsd. 364.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19]CC)=O)[CH2:13][CH2:12]1.[Cl:22][CH2:23]I.C[Li]>C1COCC1>[Cl:22][CH2:23][C:17]([CH:14]1[CH2:13][CH2:12][N:11]([C:3]2[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:16][CH2:15]1)=[O:19]
Reactant: ClCI
Reactant: CCOC(=O)C1CCN(c2cc(OC)c(Cl)cc2Cl)CC1
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1cc(N2CCC(C(=O)CCl)CC2)c(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
An oven-dried, 50-mL 2-neck round bottom flask containing a stir bar was fitted with an inert gas inlet and a rubber septum and placed under argon. The flask was charged with ethyl 1-(2,4-dichloro-5-methoxyphenyl)piperidine-4-carboxylate (233 mg, 0.701 mmol) and anhydrous THF (5 mL) and chloroiodomethane (0.102 mL, 1.403 mmol). The mixture was cooled to −70° C. (internal temperature). Once at the prescribed temperature, a solution of methyllithium (0.877 mL of 1.6 M in Et2O, 1.403 mmol) was added dropwise to the mixture via syringe over 5 min. At the conclusion of this period, the mixture was stirred at −70° C. (internal temperature) for 1.5 h and then quenched by adding saturated NH4Cl (2 mL). The pH of the mixture was adjusted to pH 7.5 by careful addition of 2 M HCl. Once at the prescribed pH, the mixture was extracted with EtOAc (25 mL). The aqueous phase was back-extracted with EtOAc and the combined extracts washed with brine, dried (MgSO4) and concentrated on a rotary evaporator to give 2-chloro-1-(1-(2,4-dichloro-5-methoxyphenyl)piperidin-4-yl)ethanone (242 mg). LC-MS: 336.24, [M+H]+; tR=3.84 min (b).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=2[C:27]([NH:29][CH2:30][CH3:31])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=2[C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)N(CC)CCN(CC)C3)ncc1Cl

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-benzamide in an analogous manner to example 712. Product was isolated as a tan solid (0.060 g, 53%); Mp 181-186° C.; LCMS (m/e) 494 (M); 1H-NMR (DMSO, 400 MHz) δ 11.56 (s, 1H), 9.30 (s, 1H), 8.81-8.74 (m, 2H), 8.21 (s, 1H), 7.75-7.77 (d, 1H, J=8.09 Hz), 7.44-7.48 (t, 1H, J=7.83 Hz), 7.23-7.25 (d, 1H, J=8.08 Hz), 7.14-7.16 (t, 2H, J=8.09 Hz), 6.99-7.01 (d, 1H, J=8.08 Hz), 3.60 (s, 2H), 3.05-3.07 (q, 2H, J=7.07 Hz), 2.92 (m, 2H), 2.77 (m, 2H), 2.39-2.41 (q, 2H, J=7.33 Hz), 1.18-1.09 (m, 6H), 1.06-1.00 (t, 3H, J=7.08 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+]>C(O)(C)C>[C:12]1([C:4]2[N:3]=[C:2]([NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([O:21][CH3:18])[CH:7]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: [K+]
Solvent: CC(C)O
Product: COc1cccc(Nc2nc(-c3ccccc3)nc3ccccc23)c1

Procedure:
4-Chloro-2-phenylquinazoline, 2 equivalents, 3-methoxyanilinyl, 2 equivalents, and potassium carbonate, 2 equivalents, were dissolved in 10 mL isopropanol and refluxed for 2 hours. The precipitated product formed was filtered and washed with water. Recrystallization from methanol provided the product as a white solid that was found to be homogenous by thin layer chromatography (TLC) and confirmed by EIMS.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)CS(C)(=O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:26]1([OH:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)Cl>[CH:26]1([O:31][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:15]2[CH2:16][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:18]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(C(CS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)C1
Reactant: OC1CCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(OC2CCCC2)c2ccc(Cl)c(Cl)c2)C1

Procedure:
Tertiary butyl 3-(1-(3,4-dichlorophenyl)-2-(methylsulfonyl)ethyl)azetidine-1-carboxylate (0.2 g, 0.49 mmol) and cyclopentanol (3.0 mL, 2.4 mmol) were stirred at 80° C. for one day. The reaction mixture was dissolved in methylene chloride (70 mL), and the organic layer was washed with saturated sodium carbonate (Na2CO3) and distilled water once, respectively, and dried over anhydrous magnesium sulfate to remove the solvent. Finally, a colorless liquid was obtained, and purified by flash chromatography (n-hexane:ethyl acetate (2:1, v/v)). The product was identified as a single compound by TLC (n-hexane:ethyl acetate (2:1, v/v)).
Reaction SMILES: [C:1]([N:8]([CH3:13])[CH:9]1[CH2:12][NH:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1>CC(O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH3:13][N:8]([CH:9]1[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=2)[CH2:10]1)[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: CN(C(=O)OC(C)(C)C)C1CNC1
Reactant: Cc1cc(Cl)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(N2CC(N(C)C(=O)OC(C)(C)C)C2)ccn1
Yield: 51 %

Procedure:
3-(Boc-methylamino)azetidine (2.74 mmol, 1.0 eq) and 4-chloro-2-methylpyridine HCl (8.21 mmol, 3.0 eq) were dissolved in 2-propanol (5 ml) and DI PEA (13.69 mmol. 5.0 eq) and refluxed for 24 hours. After monitoring by TLC, the reaction solution was diluted with ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was washed with ethyl acetate. The combined organic phases were washed 1× with sat. NaCl solution, dried over magnesium sulfate, concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate:ethanol 10:1+ammonia solution). Yield: 51%
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.S(Cl)([Cl:15])=O>>[Cl:15][CH2:2][CH2:3][N:4]([CH3:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: CN(CCCl)Cc1ccccc1

Procedure:
N-(2-hydroxyethyl)-N-benzyl-methylamine is a known compound and is described in literature (J. Am. Chem. Soc. 76, 4920-23, 1954). The reaction of this compound with thionyl chloride gives N-(2-chloroethyl)-N-benzyl-methylamine in a good yield. This compound can also be prepared by reacting N-benzyl-methylamine with 1-bromo-2-chloroethane, the yields, however, are poor and the dimeric 1,2-bis(N-benzylmethylamino)ethane, which is formed as a by-product, must be separated by chromatography.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].O1CCOCC1.Cl[C:19]1[CH:24]=[C:23]([CH:25]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[C:22]([Cl:42])=[CH:21][N:20]=1>C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[Cl:42][C:22]1[C:23]([CH:25]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])=[CH:24][C:19]([NH:10][CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[N:20][CH:21]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
In a small amount of a saturated aqueous solution of potassium carbonate was dissolved β-alanine t-butyl ester hydrochloride (1.5 g), followed by extraction with methylene chloride. The extract was dried and concentrated into 720 mg of β-alanine t-butyl ester in the free form. The resulting ester and a 1,4-dioxane (2.0 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (300 mg, 0.72 mmol) obtained in Example 54 was stirred at 120° C. for 4 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The diluted mixture was washed with water and brine, dried and then concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (79 mg, 16%) as an oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:11]([C:10]4[CH:9]=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2)CC1
Yield: 30 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (194 mg) described in Preparation Example 25 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (170 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 109, the title compound (95 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[CH3:13]C1C=CC(S(C)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(O)C>[CH3:11][C:6]1[CH:5]=[C:4]([O:12][CH3:13])[CH:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-dimethyl-4-nitrophenol (33.43 g), methyl p-toluene sulfonate (40.97 g) and K2CO3 (31.79 g) are stirred at reflux in 200 ml of acetone for four and one half hours and then stirred at R.T. overnight. The reaction mixture is filtered to give a dark amber filtrate. The filtrate is concentrated in vacuo to a yellowish brown solid which is dissolved in ethyl acetate washed with saturated aqueous sodium chloride, dried and concentrated in vacuo. The concentrate is distilled (87°-104° C./0.10 mm) to give a yellow waxy looking solid. The solid is dissolved in hot ethanol and recrystallized, M.P. 50°-52° C.