Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[CH3:27][NH2:28]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:28][CH3:27])=[O:13])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 60 °C

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Example 5, Step E) (0.20 g, 0.44 mmol) in tetrahydrofuran was added methylamine (2.0 M solution in THF, 0.514 mL, 1.02 mmol), and the reaction mixture was heated to 60° C. for 90 minutes and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was triturated with ether, filtered, and dried to afford the title compound, a compound of the present invention, as a solid (40 mg), m.p. 162-164° C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]2[C:24]3[C:19](=[C:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:21]=[CH:22][CH:23]=3)[C:18]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)=[N:17][N:16]=2)[CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:38][C:34]1[CH:33]=[C:32]([NH:31][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:15]([C:13]3[CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=[N:11][CH:12]=3)=[N:16][N:17]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(-c2nnc(Nc3cccc(F)c3)c3c(-c4ccccc4)cccc23)c1
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cncc(-c2nnc(Nc3cccc(F)c3)c3c(-c4ccccc4)cccc23)c1
Temperature: 65 °C
Yield: 27.9 %

Procedure:
N-(tert-Butyl)-5-(4-((3-fluorophenyl)amino)-5-phenylphthalazin-1-yl)pyridine-3-sulfonamide (0.600 g, 1.14 mmol) was dissolved in TFA (10.0 mL, 130 mmol) and heated to 65° C. for 4 h. TFA was removed under reduced pressure and the resulting residue was diluted with saturated NaHCO3 (100 mL). The reaction mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by combiflash (REDISEP®, silica gel, 40 g, 0-6% MeOH/DCM) to afford 5-(4-((3-fluorophenyl)amino)-5-phenylphthalazin-1-yl)pyridine-3-sulfonamide (0.15 g, 27%) as an off-white solid. LCMS (Condition 38): retention time 2.12 min, [M+1]=472.2. HPLC (Condition 25): retention time=9.61 min, purity 99.78%. 1H NMR (400 MHz, DMSO-d6) δ 6.50 (dd, J=1.6 Hz, J=8.0 Hz, 1 H), 6.76 (td, J=2.0 Hz, J=8.4 Hz, 1 H), 7.19-7.25 (m, 2 H), 7.53-7.66 (m, 6 H), 7.76 (br s, 2 H), 7.90 (dd, J=1.2 Hz, J=7.2 Hz, 1 H), 7.95 (dd, J=1.2 Hz, J=8.0 Hz, 1 H), 8.05 (dd, J=7.2 Hz, J=8.0 Hz, 1 H), 8.54 (dd, J=2.0 Hz, J=2.4 Hz, 1 H), 9.15 (d, J=2.0 Hz, 1 H), 9.16 (d, J=2.4 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14][CH3:13])[CH:8]=2)[N:3]=1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2nc(NCc3ccccc3OC)ccc2c1

Procedure:
The title compound, MS: m/e=400.4 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline and 2-methoxybenzylamine.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].Cl.[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>ClCCl>[CH2:20]([O:27][C:28]([C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:16](=[O:18])[C@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:34])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Boc-D-α-phenylglycine (2 mmol), L-proline benzyl ester hydrochloride (2.2 mmol), and DIPEA (5 mmol) in dry dichloromethane (10 mL) was added TBTU (2.2 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was passed through a SCX-2 column and further chromatographied to yield compound 2a. 1H NMR (CDCl3, 400 MHz) δ (ppm) 1.40 (s, 9H), 1.76-1.82 (m, 1H), 1.92-2.07 (m, 3H), 3.09-3.15 (m, 1H), 3.70-3.77 (m, 1H), 4.47-4.51 (m, 1H), 5.16 (d, J=12.35 Hz, 1H), 5.23 (d, J=12.35 Hz, 1H), 5.43 (d, J=7.20 Hz, 1H), 6.12 (d, J=7.20 Hz, 1H), 7.27-7.41 (m, 10H); and MS (ESI, EI+) m/z=439 (MH+).
Reaction SMILES: [CH2:1]([CH:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C)C=O.C(Cl)(=O)C([Cl:35])=O>C(Cl)Cl>[CH2:1]([CH:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([Cl:35])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCC(CCCCCC)COc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCC(CCCCCC)COc1ccccc1C(=O)Cl
Reaction time: 2 h

Procedure:
36.0 g of the 2-(2-hexyldecyloxy)benzoic acid was dissolved in 100 ml of methylene chloride, 0.5 ml of N,N-dimethylformamide was added, and 13 ml of oxalyl chloride was added dropwise over about 30 min at room temperature with stirring. After the addition the stirring was continued for 2 hours further and it was concentrated, to obtain 2-(2-hexyldecyloxy)benzoic acid chloride.
Reaction SMILES: [BrH:1].N[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.N([O-])=O.[Na+]>O>[Br:1][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: Br
Reactant: Nc1ccc2c(C(F)(F)F)cc(=O)oc2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=c1cc(C(F)(F)F)c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of 48% HBr (4.5 g, 26.7 mmol) (3 mL) containing 7-amino-4-trifluoromethylcoumarin (Aldrich) (2.0 g, 8.8 mmol) at -10° C. was added NaNO2 (670 mg in 1 mL of H2O) then Cu powder 35 mg was added. The reaction mixture was stirred at r.t. for 30 min., then heated to 100° C. for 30 min.. The reaction mixture was cooled to 0° C. and H2O (25 mL) was added. The mixture was extracted with EtOAc (400 mL) and the combined organic phase was washed with brine (200 mL) dried over MgSO4 and evaporated. The crude solid was purified by chromatography on silica gel using hexane:EtOAc 8:2 as eluent, to give 1.5 g (58%) of the title compound as a white solid.
Reaction SMILES: [C:1]([CH2:14][C:15]([CH2:18][CH2:19]I)([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].S(=O)(=O)(O)[OH:22]>>[F:16][C:15]([F:17])([CH2:14][C:1]([F:3])([F:2])[C:4]([F:6])([F:5])[C:7]([F:9])([F:8])[C:10]([F:13])([F:12])[F:11])[CH2:18][CH2:19][OH:22]
Reactant: FC(F)(CCI)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(O)O
Product: OCCC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Fuming sulfuric acid (70 mL) was added slowly to 50 g of C4F9CH2CF2CH2CH2I and mixture stirred at 60° C. for 1.5 h. The reaction was quenched with ice-cold 1.5 wt % Na2SO3 aqueous solution and heated at 95° C. for 0.5 h. The bottom layer was separated and washed with 10 wt % aqueous sodium acetate, and distilled to provide 3,3,5,5,6,6,7,7,8,8,8-undecafluorooctan-1-ol (compound A6): bp 54-57° C. at 2 mmHg.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[Si:25]([O:32][C:33]1[C:41]2[O:40][C:39](CO)=[CH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl>[C:28]([Si:25]([CH3:27])([CH3:26])[O:32][C:33]1[C:41]2[O:40][C:39]([CH2:20][Cl:24])=[CH:38][C:37]=2[CH:36]=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2cc(CO)oc12
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2cc(CCl)oc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.5 g (9.5 mmol) of triphenylphosphine and 0.92 ml (9.5 mmol) of carbon tetrachloride are added to a solution of [7-(tert-butyldimethylsilanyloxy)-benzofuran-2-yl]methanol (14) (1.78 g, 6.4 mmol) in methylene chloride (9 ml), kept at 0° C. The reaction mixture is stirred at 0° C. for 1 hour and then the solvent is evaporated under reduced pressure. The residue is taken up in 30 ml of cyclohexane and stirred for 1 hour. The precipitate formed is filtered and the filtrate concentrated. The residue is purified by flash chromatography on silica gel (cyclohexane/ethyl acetate: 95/5). The title product is obtained in the form of a pale yellow liquid (1.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2OCCO2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[O:34]1[CH2:38][C:37](=[O:39])[NH:36][C:35]1=[O:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:38]2[O:34][C:35](=[O:40])[NH:36][C:37]2=[O:39])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: O=C1COC(=O)N1
Reactant: COc1cc(CCCCCCC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COc1cc(CCCCCCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 18, 2-[6-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]hexyl]-1,3-dioxolan was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[7-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]heptyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.109-111° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([F:14])=[C:4](Cl)[N:3]=1.[CH:16]([O:19][C:20]1[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=1)([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([F:14])=[C:4]([NH:25][C:22]2[CH:21]=[C:20]([O:19][CH:16]([CH3:18])[CH3:17])[NH:24][N:23]=2)[N:3]=1
Reactant: CN(c1nc(Cl)nc(Cl)c1F)S(C)(=O)=O
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(Cl)nc(N(C)S(C)(=O)=O)c2F)n[nH]1
Temperature: 70 °C
Yield: 46.2 %

Procedure:
To a solution of N-(2,6-dichloro-5-fluoro-pyrimidin-4-yl)-N-methyl-methanesulfonamide (Method 21, 440 mg, 1.6 mmol) in n-BuOH (3 ml) was added 5-isopropoxy-1H-pyrazol-3-ylamine (227 mg, 1.6 mmol) and DIPEA (207 mg). The mixture was heated at 70° C. overnight. LC/MS showed the completion of the reaction. The solvent was evaporated and the residue was dissolved in DCM, which was then washed by aqueous NaHCO3, dried and concentrated. Flash chromatography was performed with EtOAc/Hex (50%) as eluent. A colourless solid (280 mg) was obtained, yield 46%. 1H-NMR (300 MHz, CD3OD) 5.84 (s, 0.8H), 4.61 (m, 1H), 3.32 (s, 3H), 3.27 (s, 3H), 1.36 (d, J=6.0; 6H). MS (ES+) m/z 378.86, 380.86 [MH+]. MS (ES−) m/z 376.88, 378.87 [M−].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=2)[C@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: NC(=O)[C@@H]1CCCC[C@@H]1N(Cc1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 52 %

Procedure:
The titled compound (155 mg) was prepared in 52% yield from cis-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and 1-bromomethyl-4-trifluoromethyl-benzene according to the procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.80 (d, 2 H, J=8.6 Hz), 7.61 (m, 4 H), 7.49 (d, 2 H,J=8.0 Hz), 7.32 (s, 1 H), 6.66 (s, 1 H), 4.65 (AB2, 2 H, Δv=17, Jab=64 Hz), 3.88 (m, 1 H), 2.80 (s, 1 H), 2.44 (m, 1 H), 1.79 (m, 1 H), 1.65 (m, 2 H), 1.30 (m, 3 H), 0.92 (m, 1 H); MS m/e 475.01 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CN(C)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH:8][S:15]([CH3:14])(=[O:17])=[O:16])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N)ncc1Br
Agent: CN(C)C
Solvent: ClCCl
Product: Cc1cc(NS(C)(=O)=O)ncc1Br
Reaction time: 0.33 h

Procedure:
5-Bromo-4-methylpyridin-2-amine (1.56 g) was dissolved in DCM (40 ml), trimethylamine (1.4 ml) added, followed by methanesulfonyl chloride (1.9 g) and the mixture stirred for 20 min. The solution was washed with water, dried (MgSO4) and evaporated. The residue was dissolved in THF, treated with TBAF, stirred for 16 h and evaporated. The residue was purified by chromatography on silica eluting with 27% EtOAc/isohexane. Yield 1.3 g. Carried forward to step (ii) without characterisation.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]=[C:16]([CH3:25])[C:15]=1[CH3:26]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[N:17]=[C:16]([CH3:25])[C:15]=2[CH3:26])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)cc2[nH]ccc12
Reactant: Cc1nc2ccc(Cl)cc2c(Cl)c1C
Product: COc1cc(Br)cc2c1ccn2-c1c(C)c(C)nc2ccc(Cl)cc12

Procedure:
Prepared according to procedure U using 6-bromo-4-methoxy-1H-indole (0.05 g, 0.22 mmol) and 4,6-dichloro-2,3-dimethylquinoline (0.075 g, 0.33 mmol) to give 4-(6-bromo-4-methoxy-1H-indol-1-yl)-6-chloro-2,3-dimethylquinoline as a yellow solid: Mass Spectrum (ESI) m/e=415.0 [M+1 (79Br)] and 417.0 [M+1 (81Br)].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:7]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: Nc1nc2ccc(Br)cn2n1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2ccc3nc(N)nn3c2)cc1

Procedure:
N-(5-bromo-2-pyridinyl)-N′-carboethoxy-thiourea was prepared from 2-amino-5-bromopyridine (10.0 g, 0.0578 mol) in a manner analogous to Step 2a. The reaction product was isolated as a yellow solid and used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 12.14 (br s, 1H), 11.72 (br s, 1H), 8.67-8.55 (m, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.13 (dd, J=9.0, 2.5 Hz, 1H), 4.23 (q, J=7.0 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H). MS=304, 306 (MH)+. 36b) 6-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from N-(5-bromo-2-pyridinyl)-N′-carboethoxy-thiourea in a manner analogous to Step 2b. The reaction product was isolated as a white solid (7.84 g, 63%). MP=187-189° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.92 (d, J=1.9 Hz, 1H), 7.55 (dd, J=9.2, 1.9 Hz, 1H), 7.33 (d, J=9.4 Hz, 1H), 6.13 (br s, 2H). MS=213, 215 (MH)+. 36c) 6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (200.0 mg, 0.9388 mmol) and (4-methylsulfonylphenyl)boronic acid (210.0 mg, 1.050 mmol) in a manner analogous to Step 2c. The reaction product was isolated as an off-white solid (0.158 g, 58%). MP=301-303° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.08-9.05 (m, 1H), 8.06-7.97 (m, 4H), 7.86 (dd, J=9.2, 1.7 Hz, 1H), 7.48 (d, J=9.1 Hz, 1H), 6.15 (s, 2H), 3.26 (s, 3H). MS=289 (MH)+. 36d) 6-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 6-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (50.0 mg, 0.173 mmol) and 4-(4-bromo-phenyl)-morpholine (51.0 mg, 0.211 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (20.0 mg, 0.0366 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.011 g, 14%). MP=>300° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.41 (s, 1H), 9.28 (s, 1H), 8.09 (d, J=7.7 Hz, 2H), 8.03-7.96 (m, 3H), 7.64 (d, J=8.8 Hz, 1H), 7.59 (d, J=7.9 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 3.77-3.71 (m, 4H), 3.28 (s, 3H), 3.05-3.00 (m, 4H). MS=450 (MH)+.
Reaction SMILES: [C:1]([NH:14][C@H:15]([C:21]([OH:23])=O)[CH2:16][CH2:17][C:18](=[O:20])[NH2:19])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[C:1]([NH:14][CH:15]1[CH2:16][CH2:17][C:18](=[O:20])[NH:19][C:21]1=[O:23])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC(=O)NC1CCC(=O)NC1=O
Yield: 46.3 %

Procedure:
18.0 g of N-lauroyl-L-glutamine was dissolved in 52.6 mL of dimethylformamide, and 5.50 g of 1-hydroxybenzotriazole was added to it, then 6.90 g of diisopropylcarbodiimide was added thereto and reacted at 50° C. Dimethylformamide was concentrated under reduced pressure, then the reaction mixture was suspended in methanol, the insoluble matter was collected by filtration to obtain 7.88 g of 2-(lauroylamino)glutarimide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][C:22]1([CH3:34])[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[CH:30][C:31]([NH2:33])=[CH:32][C:23]1=2.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:33][C:31]2[CH:30]=[CH:29][C:24]3[NH:25][CH2:26][CH2:27][CH2:28][C:22]([CH3:34])([CH3:21])[C:23]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCCNc2ccc(N)cc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CC1(C)CCCNc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Yield: 17.2 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (112 mg, 0.330 mmol), 5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamine (76 mg, 0.399 mmol), 4 N HCl in dioxane (99 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 24 hours. Concentrated under reduced pressure and purified with normal phase chromatography to yield a brown solid, N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (28 mg, 17%). LCMS: m/z=493.30 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.25 (m, 2H), 7.06 (br s, 1H), 6.68 (d, 1H, J=8.1 Hz), 5.76 (br s, 1H), 5.42 (m, 1H), 3.82 (m, 1H), 3.75 (m, 2H), 3.53 (m, 2H), 3.21 (m, 1H), 3.03 (m, 2H), 2.78 (s, 3H), 2.16 (m, 2H), 1.88 (m, 2H), 1.79 (m, 2H), 1.64 (m, 2H), 1.40 (m, 6H), 1.33 (m, 4H).
Reaction SMILES: O[N:2]=[C:3]1[CH2:6][CH:5]([NH:7][C:8](=NO)[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:4]1([CH3:17])[CH3:16].C[OH:19]>N.[Ni]>[NH2:2][CH:3]1[CH2:6][CH:5]([NH:7][C:8](=[O:19])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:4]1([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=NO)NC1CC(=NO)C1(C)C
Reactant: CO
Agent: [Ni]
Agent: N
Product: CC(C)(C)OC(=O)NC1CC(N)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of tert-butyl (3-(hydroxyimino)-2,2-dimethylcyclobutyl)carbamate oxime (730 mg, crude) in MeOH and ammonia (12.5 mL and 2.5 mL) was added Raney-Ni (430 mg, crude). The reaction mixture was stirred at room temperature under hydrogen atmosphere overnight. The reaction was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (2-5% MeOH in DCM) to afford the title compound (490 mg, 2.29 mmol, 76% yield two steps). MS (ESI) m/z 215.2 [M+H]+.
Reaction SMILES: CO[C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1.[NH:16]([CH2:20][CH2:21][OH:22])[CH2:17][CH2:18][OH:19]>O>[OH:19][CH2:18][CH2:17][N:16]([C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1)[CH2:20][CH2:21][OH:22]
Reactant: OCCNCCO
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)cc1N(CCO)CCO
Temperature: 140 °C

Procedure:
3-Methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.0 g) was treated with diethanolamine (10 mL), and the mixture was heated to 140° C. for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. The solid was recrystallized from ethanol to give the title compound (53 mg); mp 204°-205° C.; NMR: 5.90 (s,1); MS: m/z=277(M+1). Analysis for C14H16NO4 : Calculated: C, 60.80; H, 5.84; N, 10.14; Found: C, 61.29; H, 5.29; N, 11.74.
Reaction SMILES: [C:1]1([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[SH-:13].[Na+]>CCO>[C:1]1([C:7]2([C:10](=[S:13])[NH2:11])[CH2:8][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [SH-]
Reactant: N#CC1(c2ccccc2)CC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=S)C1(c2ccccc2)CC1
Temperature: -20 °C

Procedure:
1-Phenylcyclopropanenitrile (1-1, 10.0 g, 69.8 mmol) and sodium hydrosulfide hydrate (0.98 g, 17.5 mmol) were mixed in a 350 mL glass bomb and dissolved in 50 mL anhydrous EtOH. The resulting solution was cooled to −20° C. and a stream of H2S was bubbled through the mixture for 30 min. The bomb was sealed and heated to 90° C. for 2 days. The dark mixture was cooled to −25° C. and N2 was bubbled through for 1 h. The reaction mixture was diluted with H2O (50 mL) and extracted with Et2O (3×50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated. The crude thioamide was triturated with hexanes to provide pure 1-phenylcyclopropanecarbothioamide (1-2) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1([CH3:18])[O:10][C:9]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=O)=[CH:14][C:8]=2[O:7]1)[CH3:2].[H][H]>[Ni]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1([CH3:18])[O:10][C:9]2[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:8]=2[O:7]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC1(C)Oc2ccc([N+](=O)[O-])cc2O1
Agent: [Ni]
Product: CCOC(=O)CC1(C)Oc2ccc(N)cc2O1

Procedure:
of ethyl(2-methyl-5-nitro-1,3-benzodioxol-2-yl)-acetate (prepared according to G. Sloof, Rec. Trav. Chim. 547, 995 (1935)) dissolved in 300 cc. of 95% alcohol are hydrogenated at room temperature and 2 atm. of hydrogen pressure in the presence of 6 g. of Raney nickel. After the theoretical absorption of hydrogen, the mixture is filtered and evaporated to dryness. The residual oil is purified by distillation, (b.p. 190°-200°C./0.4 mm.).