Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[Si:6]([O:13][CH2:14][CH:15]([CH2:18][CH3:19])[CH:16]=O)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:9]([Si:6]([O:13][CH2:14][CH:15]([CH2:18][CH3:19])[CH:16]=[CH2:1])([CH3:8])[CH3:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: [Li]CCCC
Reactant: CCC(C=O)CO[Si](C)(C)C(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=CC(CC)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C

Procedure:
(Methyl)triphenylphosphonium bromide (59.1 g, 165 mmol) was suspended in tetrahydrofuran (330 mL). To the suspension, n-butyllithium (1.57 M hexane solution, 97.3 mL, 153 mmol) was gradually added with stirring at 0° C. The mixture was stirred at this temperature for 1 hour, and a tetrahydrofuran solution (110 mL) of 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)butanal (Tetrahedron 2004, 60, 9307) (27.6 g, 127 mmol) was then gradually added thereto. The mixture was stirred at 0° C. for 2 hours, and the reaction was then terminated by the addition of a saturated aqueous solution of ammonium chloride and water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water, and saturated saline and then dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (19.9 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:17]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[NH2:1][C:2]1[C:11]([CH3:17])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(I)c1N
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(F)(F)F)cc(C)c1N
Temperature: 130 °C
Yield: 96.1 %

Procedure:
A mixture of methyl 2-amino-3-iodo-5-(trifluoromethyl)benzoate (0.633 g, 1.83 mmoles), trimethylboroxine (0.56 ml, 3.66 mmoles), cesium carbonate (1.2 g, 3.66 mmoles) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.075 g, 0.09 mmoles) in 1,4-dioxane (15 mL) was heated in a microwave reactor at 130° C. for 1.5 h. The mixture was partitioned between water (30 ml) and ethyl acetate (2×30 ml). The combined organics were dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient. This gave the title compound 3 as an orange solid (0.41 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:30])[CH:16]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:17]O)[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:16]2[CH2:17][N:19]2[S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[O:30])[CH2:11][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)NC(CO)C(=O)N2CCN(c3cc(C)ccc3C)CC2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(S(=O)(=O)N2CC2C(=O)N2CCN(c3cc(C)ccc3C)CC2)cc1

Procedure:
In analogy to example 2, N-{2-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-1-hydroxymethyl-2-oxo-ethyl}-4-methyl-benzenesulfonamide was reacted with triphenylphosphine and diethylazodicarboxylate to give [4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-[1-(toluene-4-sulfonyl)-aziridin-2-yl]-methanone.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].[Cl:43][C:44]1[C:45]([CH2:50]Cl)=[N:46][CH:47]=[CH:48][CH:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[C:31](=[N:33][N:34]([CH2:50][C:45]3[C:44]([Cl:43])=[CH:49][CH:48]=[CH:47][N:46]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: ClCc1ncccc1Cl
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn(Cc3ncccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-chloro-2-(chloromethyl)pyridine and isolated as light brown gum. MS (m/e): 400.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[C:15]([N+]([O-])=O)[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.C([OH:25])C>[Fe].O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:25])[CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC(=Cc1ccc(OCc2ccc(Cl)cc2)cc1)[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Product: CC(=O)Cc1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
The starting material is prepared as follows: The mixture of 30.4 g of 1-[4-(4-chlorobenzyloxy)-phenyl]-2-nitropropene (Example 2), 80 g of iron powder, 3.2 g of ferric chloride, 40 ml of concentrated hydrochloride acid, 400 ml of ethanol and 1.2 lt of water is stirred vigorously at refux for ten hours, cooled and filtered. The residue is washed with methanol, the filtrate evaporated and the residue dissolved in hot isopropanol. The solution is treated with charcoal, filtered, the filtrate refrigerated, the precipitate collected, washed with petroleum ether and dried, to afford the 4-(4-chlorobenzyloxy)-phenylacetone melting at 76°-80°.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[S:10]([O-:13])([O-:12])=[O:11].[Na+:14].[Na+]>>[CH:3]1([CH2:2][S:10]([O-:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Na+:14]
Reactant: BrCC1CCCCCC1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Product: O=S(=O)([O-])CC1CCCCCC1

Procedure:
The subtitle compound was prepared by the method of Preparation 61 from 1-(bromomethyl)cycloheptane [Preparation 66] and sodium sulfite. The crude product was purified by recrystallisation from water to afford sodium cycloheptylmethanesulfonate as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[NH:26][CH:27]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=2)=[CH:20][CH:19]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.CC(O)=O>[Cl:16][C:13]1[S:12][C:11]([C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]4[NH:26][CH:27]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=4)=[CH:22][CH:23]=3)[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=2)=[CH:15][CH:14]=1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Cl
Reactant: COC(=O)c1c[nH]c(Cc2ccc(N)cc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Cc2nc(C(=O)OC)c[nH]2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A 8-mL vial was charged with 4-chloro-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidine (100 mg, 0.366 mmol, 1.05 eq.), methyl 2-[(4-aminophenyl)methyl]-1H-imidazole-4-carboxylate (81 mg, 0.348 mmol, 1 eq.), AcOH (0.8 ml). To the mixture was added 4N HCl in dioxane (4 drops using 1 ml of a syringe). The resulting mixture was stirred under 110° C. for 2 hrs. After cooling to room temperature, the mixture was added to sodium bicarbonate solution (20 ml). The precipitate was collected by filtration and washed with water then purified by chromatography on silica gel using 1˜1.5% of methanol in dichloromethane as eluent to give the title compound as a foam (79 mg, 48% yield).). MW=467.97. 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 4H), 7.30 (m, 2H), 6.93 (d, J=3.6 Hz, 1H), 6.54 (brs, 1H), 4.18 (s, 2H), 3.90 (s, 3H), 2.64 (q, J=6.8 Hz, 2H), 2.49 (s, 3H), 1.26 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:13](C=O)C>C1(C)C=CC=CC=1.S(Cl)(Cl)=O>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(N)=O)c(Br)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a suspension of 2-bromo-4-methylbenzoic acid (15.0 g, 69.8 mmol) in toluene (60 mL), thionyl chloride (10.3 mL) and DMF (0.10 mL) were added and stirred at 50° C. for 3 h. After cooling to room temperature, the excess thionyl chloride was removed in vacuo. The residue was dissolved in toluene (50 mL), and the mixture was added to the solution of ammonia (25%, 60 mL). The white precipitate was filtered over Celite and dried in vacuo to afford 2-bromo-4-methylbenzamide (14.8 g, 99%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24]([O:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[C:14]([CH:18]([O:20][C:21](=[O:23])[CH3:22])[CH3:19])[CH2:15][S:16](=O)[C@H:11]12)=[O:8].C(Cl)(=O)C>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:40](=[O:41])[N:12]2[C:13]([C:24]([O:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:25])=[C:14]([CH:18]([O:20][C:21](=[O:23])[CH3:22])[CH3:19])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S(=O)C1
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 105.8 %

Procedure:
Similarly, polar isomer B of diphenylmethyl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-3-cephem-4-carboxylate 1-oxide (69 mg) is reduced with stannous chloride dihydrate (66 mg) and acetyl chloride (0.28 ml) in N,N-dimethylformamide (2.1 ml) for 15 minutes to give stereoisomer B of diphenylmethyl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-3-cephem-4-carboxylate (71 mg). m.p. 72°-80° C. Yield: 83.4%. IR: νmaxCHCl 3 3396, 1787, 1731, 1687, 1508 cm-1. NMR: δCDCl 3 1.27d(6.5Hz) 3H, 1.88s3H, 3.40br-s2H, 3.83s2H, 4.95d(5Hz)1H, 5.72q(9;5Hz) 1H, 6.11q(6.5Hz)1H, 6.48d(9Hz)1H, 6.9-7.5m14H.
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][C:8]1[C:13]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=2)=[CH:12][N:11]=[C:10]([Cl:26])[CH:9]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[C:3]([N:7]1[C:8]2[CH:9]=[C:10]([Cl:26])[N:11]=[CH:12][C:13]=2[CH2:14][N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=2)[C:28]1=[O:30])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)Nc1cc(Cl)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)N1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
NaH (1.5 g, 36.6 mmol) was added portion wise to a solution of N-tert-butyl-2-chloro-5-((4-fluoro-3-nitrophenylamino)methyl)pyridin-4-amine (4.3 g, 12.2 mmol) in anhydrous dioxane (400 mL) at 0° C. and the resulting mixture was stirred at RT for 10 min. A solution of triphosgene (3.6 g, 12.2 mmol) in dioxane (30 mL) was added to the above mixture at 0° C. After the addition, the mixture was heated at 100° C. for 10 h. The cooled reaction was quenched with water and the pH was adjusted to pH>7 with saturated NaHCO3 solution. The dioxane was removed under reduced pressure and the residue was partitioned between water and EtOAc (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography provided 1-tert-butyl-7-chloro-3-(4-fluoro-3-nitrophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (3.5 g, 76% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1 H), 8.07 (m, 1 H), 7.71 (m, 1 H), 7.57 (m, 1 H), 7.32 (s, 1 H), 4.70 (s, 2 H) 1.57 (s, 9 H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:24][CH2:25][CH2:26][OH:27])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:28])[CH3:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:29][Mg]Br>C1COCC1>[OH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([N:12]2[CH2:17][CH2:16][C@:15]([CH2:24][CH2:25][CH2:26][OH:27])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:14][C:13]2=[O:28])[CH3:11])=[CH:8][CH:9]=1)([CH3:29])[CH3:2]
Reactant: CC(=O)c1ccc([C@H](C)N2CC[C@](CCCO)(c3ccccc3)OC2=O)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(C(C)(C)O)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 12.6 %

Procedure:
To a solution of (R)-3-((S)-1-(4-acetylphenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (40 mg, 0.1 mmol) in THF (10 mL) was added dropwise methylmagnesium bromide (3 M, 1 mL, 1 mmol) at −78° C. under N2. The mixture was stirred at rt for 2 days. The reaction was quenched with water, and the layers were separated. The aqueous layer was extracted with EtOAc (3×). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to give (R)-3-((S)-1-(4-(2-hydroxypropan-2-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (5 mg, 13%). 1H NMR (CDCl3): 1.31 (m, 1H), 1.44 (m, 3H), 1.64 (m, 1H), 1.93 (m, 2H), 2.11-2.25 (m, 3H), 2.82 (m, 1H), 3.51 (m, 2H), 5.58 (m, 1H), 6.81 (m, 2H), 7.14 (m, 2H), 7.27 (m, 5H). LC-MS Method 2 tR=1.141, min, m/z=420.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C@@H:6]([CH2:7][OH:8])[C:5]1([CH3:21])[C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:10]=1.[CH2:22](I)C>>[CH2:1]([O:2][CH2:3][CH:4]1[C@H:6]([CH2:7][OH:8])[C:5]1([CH3:21])[C:9]1[CH:10]=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:12]=[C:13]([CH:15]([CH3:16])[CH3:17])[CH:14]=1)[CH3:22]
Reactant: CCI
Reactant: COCC1[C@@H](CO)C1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CCOCC1[C@H](CO)C1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 77 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 39 but using Intermediate 38 as the starting material and ethyl iodide as alkylating reagent yielded the title compound (89 mg, 77% yield) as a colorless oil:
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](=O)([O:13][CH3:14])[O:11]C>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.S1(CCCC1)(=O)=O>[C:10]([O:13][CH3:14])(=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)OC
Reactant: O=C(Cl)c1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1ccccc1
Temperature: 150 °C
Reaction time: 22 h
Yield: 92.6 %

Procedure:
A mixture of 7.03 g (0.05 g mole) of benzoyl chloride, 4.5 g (0.05 g mole) of dimethyl carbonate, and 0.85 g (0.0025 g mole) of tetra-n-butyl phosphonium bromide (TBPB) in 25 ml of sulfolane was heated at 150° C. in a reaction flask equipped with reflux condenser. After 22 hours, the condenser was replaced by a distillation head and 6.3 g (93 percent yield) of methyl benzoate distilled at 83° C.-85° C./17 mm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][C:17]=2[Cl:19])=[CH:6][CH:5]=1)=[O:11]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1

Procedure:
4-Bromo-benzoic acid methyl ester (3 g) was dissolved in a mixture of toluene (20 mL) and ethanol (20 mL). 2,4-Dichloro-phenyl boronic acid (3 g) was added followed by 2 M Na2CO3 (20 mL). The mixture was stirred vigorously under N2 and (PPh3)4Pd (0.5 g) added. The mixture was refluxed with stirring for 3 hours under an atmosphere of N2. The solvent was removed under vacuum, the residue was dissolved in ethyl acetate, and washed with water and saturated NaCl solution. After drying (Na2SO4), the solvent was evaporated and the resultant oil purified by column chromatography to give a fluffy white powder, which was recrystallised from ethanol to give the title compound as long needles. 13C NMR (CDCl3): δ 52.3, 127.3, 129.5, 129.5, 129.6, 129.9, 131.9, 133.1, 134.4, 138.1, 142.8 and 166.8. 1H NMR (CDCl3): δ 3.93 (3H, s), 7.27 (2H, m), 7.47 (2H, d, J=8.5 Hz), 7.49 (1H, s) and 8.09 (2H, d, J=8.2 Hz).
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:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:21]([Cl:37])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[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: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)ccc2C1
Temperature: 100 °C

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine (0.105 g, 0.000407 mol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (0.140 g, 0.000403 mol), 10-camphorsulfonic acid (0.237 g, 0.0010 mol) and isopropyl alcohol (4 mL). The mixture was heated in a microwave at 100° C. for 20 min. After evaporation of the solvent, the residue was treated with a 10% sodium carbonate solution/DCM, separated, washed, dried and evaporated to give a solid. This material was chromatographed on a silica gel prep plate with DCM/10% ammonia/methanol (10-1) giving the product as a tan solid (0.084 g, 39%). Mp 88-91° C. LCMS (m/e) 530 (M); 1H-NMR (DMSO, 400 MHz) δ 9.41 (s, 1H), 9.31 (s, 1H), 8.68-8.56 (m, 1H), 7.82-7.80 (d, 1H, J=7.80 Hz), 7.70-7.66 (t, 1H, J=8.84 Hz), 7.37-7.33 (t, 1H, J=7.58 Hz), 7.14 (s, 2H), 7.00-6.98 (d, 1H, J=8.60 Hz), 3.59-3.42 (br, 2H), 3.06-2.89 (m, 5H), 2.76-2.68 (m, 2H), 2.65 (s, 4H), 2.47-2.38 (m, 4H), 1.09-1.03 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[F:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2[C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:26][CH2:25][C:24]1[C:19]([C:16]2[CH:17]=[N:18][C:13]([F:12])=[CH:14][CH:15]=2)=[N:20][CH:21]=[CH:22][CH:23]=1)=[S:11]
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: NCc1cccnc1-c1ccc(F)nc1
Product: Fc1ccc(-c2ncccc2CNC(=S)Nc2cccc(Cl)c2Cl)cn1
Yield: 72 %

Procedure:
The title compound was synthesized by general procedure 1 using 2,3-dichlorophenylisothiocyanate and C-(6′-fluoro-[2,3′]bipyridinyl-3-yl)-methylamine (Example 192F) to give 0.974 g (72%) of 1-(2,3-dichloro-phenyl)-3-(6′-fluoro-[2,3′]bipyridinyl-3-ylmethyl)-thiourea as a white powder. 1H NMR (DMSO-d6, 400 MHz) 4.74 (d, J=4.1 Hz, 2H), 7.31 (dd, J=2.5, J=8.2 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 7.49 (dd, J=4.7 Hz, J=7.9 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.87 (dd, J=1.5 Hz, J=7.9 Hz, 1H), 8.17 (dt, J=2.5 Hz, J=8.2 Hz, 1H), 8.39 (bs, 1H), 8.41 (d, J=2.5 Hz, 1H) 8.60 (dd, J=1.6 Hz, J=4.7 Hz, 1H), 9.49 (bs, 1H); RP-HPLC (Hypersil® HS C18, 5 μm, 100 Å, 25 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min), then 100% acetonitrile isocratic 2 minutes, Rt 10.30 min. (94.3%); MS: M+H+ 407.
Reaction SMILES: [CH3:1][C@:2]1([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[NH:25]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH2:3]1>CO.[Pd]>[CH3:1][C@:2]1([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[NH2:25])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)[CH2:3]1
Reactant: C[C@]1(N[C@@H]2CCCC[C@H]2NC(=O)OCc2ccccc2)CCCN(c2ccc(C(F)(F)F)cc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@]1(N[C@@H]2CCCC[C@H]2N)CCCN(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of benzyl ((1R,2R)-2-(((S)-3-methyl-1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)cyclohexyl)carbamate (420 mg, 0.858 mmol) in MeOH (4 mL) was added palladium on carbon (10%) (84 mg, 0.789 mmol) under nitrogen atmosphere. The resultant black color suspension was stirred under hydrogen balloon pressure at RT for 2 h. The reaction mass was filtered on Celite and the filter cake was washed with methanol (3×5 mL). The filtrate was concentrated and dried under vacuum to get (1R,2R)—N1-((S)-3-methyl-1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)cyclohexane-1,2-diamine (300 mg, 0.667 mmol, 78% yield) as off white solid. This was directly used for next reaction with out any further purification. Anal. Calcd. for C19H28F3N3 m/z 355.4, found: 490.4 (M+H)+; This was taken for next step with out any further characterization.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([OH:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[BH4-].[Na+]>CO.C(N(CC)CC)C>[CH2:30]([NH:1][CH2:2][CH2:3][C:4]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)([OH:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(OCC(O)(CCN)c2ccc(Cl)c(Cl)c2)cc1
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(OCC(O)(CCNCc2ccccc2)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2RS)-4-amino-2-(3,4-dichlorophenyl)-1-(4-methoxyphenoxy)butan-2-ol (6.7 g) in methanol (20 mL) were added magnesium sulfate (3.35 g), triethylamine (1.3 mL) and benzaldehyde (2.1 ml), and the mixture was stirred at room temperature for 1.5 hr. To the reaction mixture was added sodium borohydride (3.55 g), and the mixture was stirred at 0° C. for 10 min, and then stirred while warming to room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated. The concentrated residue was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-(benzylamino)-2-(3,4-dichlorophenyl)-1-(4-methoxyphenoxy)butan-2-ol (8.47 g). To a solution of 4-(benzylamino)-2-(3,4-dichlorophenyl)-1-(4-methoxyphenoxy)butan-2-ol (8.47 g) in THF (45 mL) were added triethylamine (2.85 mL) and chloroacetyl chloride (1.64 ml), and the mixture was stirred at 0° C. for 10 min, and then stirred while warming to room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (7.41 g).