Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:3]=1.[CH:16]([N:19]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[N:35][CH:36]=[C:37](B4OC(C)(C)C(C)(C)O4)[CH:38]=3)=[CH:29][CH:28]=2)=[O:26])[CH2:21][CH2:20]1)([CH3:18])[CH3:17]>>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N:3]=[C:2]([C:37]2[CH:38]=[C:33]([C:30]3[CH:29]=[CH:28][C:27]([C:25]([N:22]4[CH2:21][CH2:20][N:19]([CH:16]([CH3:18])[CH3:17])[CH2:24][CH2:23]4)=[O:26])=[CH:32][CH:31]=3)[CH:34]=[N:35][CH:36]=2)[CH:7]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc(-c3cncc(B4OC(C)(C)C(C)(C)O4)c3)cc2)CC1
Reactant: Cc1cccc(-c2nc(Cl)cc(Cl)n2)n1
Product: Cc1cccc(-c2nc(Cl)cc(-c3cncc(-c4ccc(C(=O)N5CCN(C(C)C)CC5)cc4)c3)n2)n1

Procedure:
This compound is prepared from 4,6-dichloro-2-(6-methyl-pyridin-2-yl)-pyrimidine (Int. B) and (4-isopropylpiperazin-1-yl)(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)methanone (Int. I) analogously to Example 1: [M+H]+=513/515 as a brown solid.
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([NH:53][C@H:54]([C@H:59]([CH2:61][C:62]([O:64][CH3:65])=[O:63])[OH:60])[CH2:55][CH:56]([CH3:58])[CH3:57])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([NH:53][C@H:54]([C@H:59]([CH2:61][C:62]([O:64][CH3:65])=[O:63])[OH:60])[CH2:55][CH:56]([CH3:57])[CH3:58])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 56 mg of Z-Phe-His-OH, 60 mg of H-Leu-Val-Ala-Sta-OCH3.HCl, 18 mg of HOBT, 0.24 ml of ethyldiisopropylamine and 34 mg of DCCI, the title compound is obtained in the form of a colourless powder after flash chromatography (30 g of silica gel 60, 40-63 μm, system N8). Rf (N9)=0.33.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1.[CH2:13](Br)[CH:14]=[CH2:15]>CN(C=O)C>[CH2:15]([O:12][C@H:10]([C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH3:11])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: C[C@H](O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred suspension of sodium hydride (3.14 g, 55% dispersion in oil) in dry DMF (180 ml) under an argon atmosphere was added (S)-1-(4-fluorophenyl)-ethanol (8.41 g, CAS 101219-73-2). Allyl bromide (6.6 ml) was then added dropwise. The reaction mixture was stirred for 30 min at room temperature and was then quenched by addition of water. The mixture was extracted with ethyl acetate twice. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give 1-((S)-1-allyloxy-ethyl)-4-fluoro-benzene (8.66 g, 80%) as a colourless liquid. 1H NMR (300 MHz, CDCl3, δ ppm): 1.43 (d, J=6.6 Hz, 3H), 3.84 (m, 2H), 4.45 (q, J=6.6 Hz, 1H), 5.15 (dd, J1=10.5 Hz, J2=1.8 Hz, 1H), 5.22 (dd, J1=17.4 Hz, J2=1.8 Hz, 1H), 5.89 (m, 1H), 7.03 (m, 2H), 7.29 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH2:21]([O:14][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[Cl:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Clc1ccc(Nc2nccs2)cc1OCc1ccccc1
Yield: 53 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-chloro-5-(thiazol-2-ylamino)phenol (50 mg, 0.22 mmol) and Cs2CO3 (72 mg, 0.22 mmol) in acetone (4.4 mL) was treated with benzyl bromide (38 mg, 0.22 mmol) at RT. Reaction control by TLC showed full conversion after 2 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 53% yield (37 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][CH2:13]O.OS(O)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCO
Reactant: O=C(O)Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccccc1Cl
Temperature: 90 °C
Yield: 96.3 %

Procedure:
A solution of 2-chlorophenylacetic acid (10.12 g, 59.3 mmol) in EtOH (150 mL, 2576 mmol) in a 500 mL round bottom flask was treated with concentrated H2SO4 (0.700 mL, 8.28 mmol) and heated at 90° C. for 16 hours. The solution was concentrated in vacuo, diluted with 1N NaOH(aq) (200 mL), and extracted with EtOAc (2×200 mL). The combined organic layers were washed with 1N NaOH(aq) (200 mL), water (100 mL), and brine (100 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give ethyl 2-(2-chlorophenyl)acetate (11.344 g). MS m/e=217 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:16]([CH3:24])([CH2:17][CH2:18][C:19]=32)[C@@H:11]([C@H:12]([CH3:15])[CH:13]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:26])[CH3:25].[CH3:27][C:28]1([CH3:34])[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:27][C:28]1([CH3:34])[CH2:33][CH2:32][CH2:31][N:30]([CH2:15][C@H:12]([C@@H:11]2[C@:16]3([CH3:24])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:20]([C:19]=4[CH2:18][CH2:17]3)([CH3:23])[CH2:21][CH2:22][C@H:2]([OH:1])[C:3]5([CH3:26])[CH3:25])=[CH:9][CH2:10]2)[CH3:13])[CH2:29]1
Reactant: CC1(C)CCCNC1
Reactant: C[C@H](C=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@H](CN1CCCC(C)(C)C1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-al was treated with 3,3-dimethyl-piperidine and sodium tris(acetoxy)borohydride as described in Example 1h). (20S)-20-[(3,3-dimethylpiperidin-1-yl)methyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][C:28]([C:30]([NH:32][CH:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35])=[O:31])=[N:27][CH:26]=2)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[O:29][C:28]([C:30]([NH:32][CH:33]([CH:38]([CH3:40])[CH3:39])[C:34]([O:36][CH3:37])=[O:35])=[O:31])=[N:27][CH:26]=3)=[CH:21][CH:20]=2)=[C:4]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3Oc3ccccc3)cc2)o1)C(C)C
Yield: 79 %

Procedure:
The title compound was synthesized analogous to Example 1, using 4-chloro-1-isocyanato-2-phenoxybenzene and intermediate 1. Yield 79%; 1HNMR (DMSO-d6, 300 MHz): δ 9.61 (s, 1H), 8.99 (d, 1H), 8.74 (s, 1H), 8.4 (d, 1H), 7.8 (s, 1H), 7.77 (d, 2H), 7.6 (d, 2H), 7.44 (d, 2H), 7.22 (dd, 1H), 7.1 (d, 2H), 7.0 (dd, 1H), 6.85 (d, 1H), 4.3, (m, 1H), 3.67 (s, 3H), 2.28 (m, 1H), 0.95 (d, 6H); MS (ES+): m/z 563 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:22][CH3:23])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16]OS(C)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:41].C(OCC)(=O)C>C(#N)C>[F:41][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH:3]([O:22][CH3:23])[O:2][CH3:1]
Reactant: [F-]
Reactant: COC(COCCOCCOCCOCCOS(C)(=O)=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(COCCOCCOCCOCCF)OC
Temperature: 90 °C
Yield: 93 %

Procedure:
A mixture of the sulfonate (Compound 6) (75 mg, 0.21 mmol) and TBAF (1.1 M in THF, 573 μl, 0.63 mmol) in acetonitrile (8 ml) was heated at 90° C. for 30 minutes. TLC (ethyl acetate) monitoring showed the reaction was completed. After cooling to ambient and evaporation of the solvent the residue was flashed (Ethyl acetate) to afford the product (56 mg, 93%) as colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:13]O.C([O-])=O.[Na+]>C(O)=O>[C:4]([C:3]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=1[OH:1])#[N:13]
Reactant: NO
Reactant: COc1ccc(O)c(C=O)c1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: COc1ccc(O)c(C#N)c1
Yield: 51.5 %

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (4.00 g) in formic acid (30 ml) were added hydroxylamine hydrochloride (2.01 g) and sodium formate (3.22 g) at room temperature and the mixture was refluxed for 2 hours. The reaction mixture was concentrated. the residue was diluted with water and was extracted with t-butyl methyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with a mixture of t-butyl methyl ether and hexane to give the title compound (2.02 g) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[NH3:17]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:17])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Product: NS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 100 %

Procedure:
According to general procedure A, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and ammonia (10 mL, ca. 7N in methanol) were stirred together for 16 hours. 4-bromo-2-(trifluoromethoxy)benzenesulfonamide (0.33 g, 100%) was provided after purification. MS (ESI) m/z 320. HPLC purity 100.0% at 210-370 nm, 8.0 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: O=[C:2]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][C:16]1[C:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:23]=2[CH3:32])=[C:19]([NH2:33])[NH:18][N:17]=1>C(O)(=O)C>[CH3:15][C:16]1[C:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[C:23]=2[CH3:32])=[C:19]2[N:33]=[C:2]([CH:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[CH:3]=[C:4]([OH:6])[N:18]2[N:17]=1
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Reactant: Cc1n[nH]c(N)c1Cc1cccc(C(F)(F)F)c1C
Solvent: CC(=O)O
Product: Cc1nn2c(O)cc(C3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 140 °C
Reaction time: 8 h

Procedure:
To a suspension of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (98 mg, 0.49 mmol) in acetic acid (2 mL) was added 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine (125 mg, 0.46 mmol), prepared as described in Example 1, step a, in microwave reaction vessel. It was sealed and heated with microwave reactor at 140° C. for 40 minutes. The reaction mixture was cooled, diluted with acetic acid (2 mL) and stood for overnight. Precipitate was observed, filtered. Solid was washed with cooled methanol. Solid was dried. The titled compound was obtained. (75 mg, 38%) LC/MS: MS (ES+) m/e 406 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.80 (m, 4H) 2.05 (s, 3H) 2.46 (s, 3H) 2.75 (s, 1H) 3.37 (td, J=11.68, 2.40 Hz, 2H) 3.95 (d, J=14.40 Hz, 2H) 3.99 (s, 2H) 5.57 (s, 1H) 7.00 (d, J=7.33 Hz, 1H) 7.28 (t, J=7.45 Hz, 1H) 7.55 (d, J=7.58 Hz, 1H) 11.59 (d, J=1.01 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:3]1=[O:26].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]1=[O:26]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccccc2)C2(CCCNCC2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A diastereomeric mixture of tert-butyl 2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.6]undecane-8-carboxylate (step 4) (683.1 mg; 1.906 mmol) in DCM (6 ml) was treated with TFA (5.8 ml, 76 mmol) and stirred at RT for 10 minutes. The mixture was concentrated in vacuo and the crude product was dissolved in MeOH and applied to a 10 g pre-wetted (MeOH) SCX-2 cartridge. The column was washed with MeOH and the product was eluted with 2M NH3 in MeOH. The clean fractions were concentrated in vacuo to afford the title compound;
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:14]([O:16][CH3:17])=[O:15])[CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.CCOCC>[C:7]1([C@H:6]2[C@@H:5]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][CH2:3][CH2:2][NH:13]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(CCCCl)C(N)c1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)[C@H]1CCCN[C@H]1c1ccccc1
Yield: 78 %

Procedure:
3-(3'-Chloropropyl)-4-phenyl-1-(tert.-butyldimethylsilyl)azetidin-2-one (3.07 gm, 9.0 mmole) was dissolved in 10% methanolic sulfuric acid and refluxed for 16 hours. At the end of this period, the reaction mixture was cooled, the sulfuric acid was neutralized with sodium bicarbonate and the mixture was taken up in ether (2×200 ml). The ethereal solution was washed with water (2×50 ml) and dried (anhyd. magnesium sulfate). Evaporation afforded essentially pure 5-chloro-2-carbomethoxy-1-phenylpent-1-ylamine as an oil (2.11 gms). The 5-chloro-2-carbomethoxy-1-phenylpent-1-ylamine thus obtained was dissolved in the dimethylformamide ("DMF") (20 ml) and sodium iodide (2.11 gm) and sodium bicarbonate (2.11 gm) were added. The resulting mixture was refluxed for 15 min. At the end of this period, the reaction mixture was cooled and taken up in ether (200 ml). The ethereal solution was washed with water (2×50 ml) and dried (anhyd. magnesium sulfate). Evaporation of the ether afforded chromatographically pure cis-methyl 2-phenylpiperidine-3-carboxylate as an oil (1.54 gm, 78%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13]([O-:15])=[O:14])[CH:2]=1.[CH2:16](O)[CH3:17]>[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=1
Reactant: CCO
Reactant: O=C([O-])C=Cc1cnc2ccccc2c1
Agent: [Pd]
Product: CCOC(=O)CCc1cnc2ccccc2c1

Procedure:
3-quinolineacrylate (51.68 g) was dissolved in ethanol (170 ml) and hydrogenated at 37° and a pressure of 50 psi using 10% Palladium on charcoal to give ethyl 3-quinolinepropionate. p (iii) Ethyl 3-quinolinepropionate (47.99 g) and ethyl formate (16.3 g) were added over a period of 3 hours to a stirred mixture of sodium wire (4.8 g) and dry ether (150 ml) cooled by an ice-bath. The mixture was stirred for 20 hours at room temperature, evaporated to dryness and the residue was treated with thiourea (15.9 g) and ethanol (130 ml) and refluxed for 7 hours. The mixture was evaporated to dryness and the residue was dissolved in water and acetic acid added to pH 4. The mixture was filtered to give 5-(3-quinolinemethyl)-2-thiouracil, m.p. 281°-6° (decomp.) (ex. acetic acid-water).
Reaction SMILES: [C:1](OCC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:21]([OH:25])[CH:22]([CH3:24])[CH3:23]>>[C:1]([O:25][CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(C)CO
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)CC(=O)OCC(C)C

Procedure:
30 ml of ethyl acetoacetate were dissolved in 350 ml of i-butyl alcohol and a catalytic amount of p-toluensulphonic acid (PTSA) was added. The solution was refluxed for 18 h. The reaction mixture was evaporated in vacuo and the residue was dissolved in ether. The resulted solution was treated with s.s. NaHCO3. The organic layer was separated, dried over Na2SO4 and evaporated in vacuo. The crude oil was distilled at 66°-68° C./4 mmHg, to give 18.8 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=O)[NH:7][CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].S(Cl)(Cl)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[C:28]([C:34]([NH:36][NH2:37])=O)=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=2)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:38]([F:41])([F:40])[F:39]>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[C:28]([C:34]3[N:7]([CH:8]([CH3:10])[CH3:9])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:37][N:36]=3)=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=2)(=[O:24])=[O:25])=[CH:19][C:18]=1[C:38]([F:39])([F:41])[F:40]
Reactant: NNC(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)C(=O)NC(C)C
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1C(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 3.2 %

Procedure:
To a vial containing ethyl(isopropylcarbamoyl)formate (160 mg, 1.0 mmol) was added thionyl chloride (1.0 mL, 13.8 mmol). The vial was capped with a teflon coated septa and heated to 80° C. for 5 h. After cooling to room temperature, the volatiles were removed in vacuo. A solution of 4-chloro-N-(5-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide (342 mg, 0.80 mmol) in toluene (3 mL) was added. The mixture was stirred at 40° C. for 16 h. After cooling to room temperature, the toluene was removed in vacuo. Ethanol (9 mL) and triethylamine (1 mL) were added, and the solution heated to 90° C. for 4 h. After cooling to room temperature, the volatiles were removed in vacuo, and the resulting residue purified by flash chromatography on 4 g of silica gel (0→20% gradient of MeOH in DCM). The pure fractions were collected, and the solvent removed in vacuo to afford the title compound (14 mg, 3% yield). HPLC retention time=3.17 minutes. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=2.4, 1H), 8.19 (d, J=2.4, 1H), 8.04 (d, J=2.4, 1H), 7.89 (dd, J=2.0, 8.4, 1H), 7.53 (d, J=8.0, 1H), 5.66 (sept, J=7.0, 1H), 4.52 (q, J=7.4, 2H), 1.52 (d, J=7.0, 6H), 1.50 (t, J=7.4, 3H). MS (ES) [M+H]+ expected 552.0, found 552.0.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].OS(O)(=O)=O.[CH3:18]O>>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:18])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(C)=O)cc1

Procedure:
4-Acetylbenzoic acid (12.7 g., 0.077 mol) was dissolved in 750 ml. methanol. Concentrated H2SO4 (1.6 ml.) was added and the mixture heated at 70° for 8 hours, cooled, stripped solids, taken up in 400 ml. ether, washed 3×150 ml. saturated NaHCO3 and 1×150 ml. brine, dried over MgSO4 and stripped to yield title product, 12.9 g.; tlc Rf 0.46 (2:1 hexane:ethyl acetate).
Reaction SMILES: [C:1]([C:4](=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])(=O)[CH3:2].Cl.[C:27]([NH2:35])(=[NH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(=O)C.[Na+].C(OCC)(=O)C>CN(C=O)C>[C:11]1([CH2:10][CH2:9][CH2:8][NH:7][C:5]([C:4]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[N:34]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:35][C:1]=2[CH3:2])=[O:6])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)C(=Cc1ccc(Cl)c(Cl)c1)C(=O)NCCCc1ccccc1
Reactant: N=C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)NCCCc2ccccc2)C(c2ccc(Cl)c(Cl)c2)N=C(c2ccccc2)N1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
100 mg (0.266 mmol) of 2-acetyl-3-(3,4-dichlorophenyl)-N-(3-phenylpropyl)acrylamide was dissolved in 2 ml of DMF. 63.0 mg (0.400 mmol) of benzamidine hydrochloride and 26.0 mg (0.317 mmol) of sodium acetate were added to the obtained solution, and they were stirred at 60° C. overnight. Ethyl acetate was added to the reaction mixture and then the obtained mixture was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/3) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>N1C=CC=CC=1>[F:18][C:10]1[CH:9]=[C:8]([C:5]2[N:6]=[N:7][C:2]([NH:20][NH2:21])=[CH:3][CH:4]=2)[CH:17]=[CH:16][C:11]=1[C:12]([NH:14][CH3:15])=[O:13]
Reactant: NN
Reactant: CNC(=O)c1ccc(-c2ccc(Cl)nn2)cc1F
Solvent: c1ccncc1
Solvent: O
Product: CNC(=O)c1ccc(-c2ccc(NN)nn2)cc1F
Temperature: 65 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of 4-(6-chloro-pyridazin-3-yl)-2-fluoro-N-methyl-benzamide 34 g (128 mmol) in 500 mL of dry pyridine was cooled in an ice bath and 43.5 mL of hydrazine hydrate was added. The cooling was continued so as to keep the temperature below 30° C. at which time yellow needle separated. The mixture was then heated to 65° C. and stirred overnight. The mixture was filtered and the solid washed with water and Methanol to return the title compound (28.8 g, 84% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ (ppm): 8.27 (s, 2H), 7.96˜7.99 (d, 1H), 7.86˜7.92 (m, 2H), 7.69˜7.75 (m, 1H), 7.09˜7.12 (d, 1H), 4.42 (s, 2H), 2.78˜2.80 (d, 3H); MS (m/z): 262.1 [M++1].
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([O:11]C)=[CH:6][C:3]=1[CH:4]=[O:5].Br>C(O)(=O)C>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(C=O)c(Br)cc1F
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1cc(O)c(F)cc1Br
Yield: 64 %

Procedure:
A solution of 2-bromo-4-fluoro-5-methoxybenzaldehyde (1.19 g, 8.20 mmol), 48% HBr (57 mL) and glacier acetic acid (57 mL) were refluxed at 130° C. for 5 h. The glacier acetic acid was removed under reduced pressure. The solution was neutralized using sodium carbonate. Water was added and the mixture was extracted using ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 2-bromo-4-fluoro-5-hydroxybenzaldehyde (1.15 g, 64%).