Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].C(N(C(C)C)CC)(C)C>C1COCC1>[Si:30]([O:29][CH2:28][CH2:27][CH:21]1[N:14]2[C:15]3[C:11]([CH:12]=[CH:13]2)=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:17][C:16]=3[CH2:18][NH:19][CH2:20]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCC1CNCc2cc(CCc3ccccc3)c(C(F)(F)F)c3ccn1c23
Temperature: 80 °C
Yield: 81.9 %

Procedure:
A mixture of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 100 mg, 0.26 mmol), 2-bromoethoxy t-butyl(dimethyl)silane (63 mg, 0.26 mmol) and diisopropylethylamine (0.09 mL, 0.53 mmol) in THF was heated at 80° C. for 5 h. The solvent was evaporated to yield 2-(2-((tert-butyldimethylsilyl)oxy)ethyl-6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (107 mg, MS m/z 503 (MH+)).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[C:15]([C:26]([F:29])([F:28])[F:27])=[CH:14][C:10]=2[C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.CN(C(O[N:47]1[N:55]=[N:54][C:49]2[CH:50]=[CH:51]C=N[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC(N)=CN=1>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[C:16]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[C:15]([C:26]([F:27])([F:29])[F:28])=[CH:14][C:10]=2[C:11]([NH:54][C:49]2[CH:50]=[CH:51][N:55]=[N:47][CH:48]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cc(C(F)(F)F)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccnnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccnnc1)c1cc(C(F)(F)F)c(C(=O)N2CCCCC2)cc1OCc1ccccc1
Reaction time: 0.08 h

Procedure:
2-[(Phenylmethyl)oxy]-4-(1-piperidinylcarbonyl)-5-(trifluoromethyl)benzoic acid (may be prepared as described in Description 58; 70 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (4 ml). Diisopropylethylamine (0.06 ml, 0.34 mmol) and HATU (131 mg, 0.34 mmol) were added. The mixture was stirred for 5 minutes then 4-pyridazinamine (32.7 mg, 0.34 mmol) was added. The solution was stirred for 90 minutes. The solvent was removed in vacuo and the residue purified by MDAP to give the title compound as a white solid. 30 mg.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]CC)[N:27]=1.C(N(CC)CC)C>C(#N)C>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:33]([NH:32][C:28]3[N:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[O:34])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Reactant: CCOC(=O)Nc1cccnn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cc3)c2)CC1
Temperature: 180 °C
Yield: 63.5 %

Procedure:
4-(3-(4-(Trifluoromethyl)phenoxy)benzylidene)piperidine hydrochloride (200 mg, 0.541 mmol, from Example 53, Step 5), ethyl pyridazin-3-ylcarbamate (99 mg, 0.595 mmol) and triethylamine (0.15 mL, 1.08 mmol) were combined in acetonitrile (4.5 mL) and heated in a microwave at 180° C. for 40 min. The reaction mixture was cooled to RT and concentrated. The residue was purified by silica gel chromatography (50-100% EtOAc in CH2Cl2) to provide the title compound (156 mg). MS APCI M+ 455.2, 375.2, 334.2 M− 454.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.46 (td, J=5.81, 0.84 Hz, 2H) 2.56 (td, J=5.81, 0.84 Hz, 2H) 3.55-3.61 (m, 2H) 3.65-3.70 (m, 2H) 6.44 (s, 1H) 6.91-6.99 (m, 2H) 7.06-7.14 (m, J=8.32 Hz, 3H) 7.35-7.43 (m, 1H) 7.59 (dd, J=9.13, 4.68 Hz, 1H) 7.61-7.66 (m, J=9.08 Hz, 2H) 8.12 (d, J=9.30 Hz, 1H) 8.78 (d, J=4.68 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: CCc1ccc(-c2c(CC(=O)OC)c(C)nc3sc4c(c23)CCC4)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(CC)cc1)CCC3
Yield: 60.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.120 g; 0.328 mmol), LHMDS 1N in THF (0.365 mL; 0.365 mmol), 1-iodopropane (0.052 mL; 0.533 mmol) in DMF (4.7 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.081 g (61%) of the title compound as a white solid.
Reaction SMILES: [H][H].[F:3][C:4]([F:34])([F:33])[C@H:5]([O:12][C:13]([CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25]CC3C=CC=CC=3)[CH:21]=2)[CH2:16]1)=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>[Pd].O1CCCC1>[F:3][C:4]([F:33])([F:34])[C@H:5]([O:12][C:13]([CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=2)[CH2:16]1)=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCCCC[C@@H](OC(=O)C1CCc2cc(OCc3ccccc3)ccc2C1)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC[C@@H](OC(=O)C1CCc2cc(O)ccc2C1)C(F)(F)F
Reaction time: 24 h
Yield: 100 %

Procedure:
Hydrogen gas was blown into a mixture of 8.19 g (18.3 mmol) of the 1,2,3,4-tetrahydro-6-benzyloxynaphthalene-2-carboxylic acid (R)-1-trifluoromethylheptyl ester obtained in the fourth stage, 3.6 g of 5% palladium/carbon as a catalyst and 50 ml of tetrahydrofuran with stirring at room temperature and ordinary pressure for 24 hours. The reaction mixture was filtered using Celite as a filter aid, and the filtrate obtained was concentrated to obtain 6.78 g (18.3 mmol) of 1,2,3,4-tetrahydro-6-hydroxynaphthalene-2-carboxylic acid (R)-1-trifluoromethylheptyl ester as a brown liquid.
Reaction SMILES: C(Cl)Cl.[Br:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>CCN(CC)CC>[Br:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccccc1Br
Reaction time: 0.42 h

Procedure:
DCM (670 Kg) and Et3N (76.4 Kg) were added to a 1000 L glass-lined reactor at 0° C. Then, 2-bromoaniline (3a) (100 Kg, 581 moles, 1.0 equiv.) was added with stirring. The resulting mixture was cooled to 0˜10° C. and pivaloyl chloride (77.1 kg, 640 moles, 1.1 equiv.) was added dropwise (5 kg/h) while maintaining the same temperature. The mixture was stirred at this temperature for 1 h 25 min and reaction progress monitored by HPLC. When it was deemed complete, the reaction was quenched by addition of a 5% aqueous solution of Na2CO3 (120 kg) at a rate of 2 kg/min. After addition, the mixture was stirred for 1.5 h and the pH value tested to be between 7 and 8. The reaction was allowed to stand for 20-30 min and the organic phase was separated out. The aqueous layer was extracted with DCM twice (60×2 kg). During each extraction, the bi-phasic mixture was stirred for 15-20 min and then held for 15˜20° C. to allow for layer separation. All the organic layers were combined and a 3% aqueous solution of HCl (251.8 kg) was added to adjust the pH value between 5 and 6. Then the aqueous layer was separated and the organic layer was washed with saturated NaHCO3 (150 L). During the washing, the bi-phasic mixture was stirred for 30 min and held for 30 min. The organic phase was separated and dried over NaSO4 (50 kg) with stirring for 13 h. The resulting slurry was filtered under vacuum using a 50 L vacuum filter. The filtration cake was washed with DCM twice (25 kg×2). The filtrate was concentrated by evaporation at T<50° C. under atmospheric pressure until no solvent distilled out. Then it was additionally concentrated by evaporation under vacuum (P≦MPa) at 65˜70° C. After concentration, the mixture was cooled to 55˜60° C. and THF was added (993 kg). Then the mixture was concentrated by evaporation again under the same conditions as above. The content of DCM was monitored by GC using method F until <0.1%. The mixture was cooled to 20˜30° C. under N2 and then filtered though silica gel (8 kg) under vacuum in order to dry it. The silica plug was washed twice with THF (20 kg×2) to give a solution of crude (3b) which was transferred into 200 L drums for the following step. Typical retention time for starting material (3a) is 8.0 min and for product (3b) is 8.9 min.
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:39])=[O:38])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:40])[CH2:6]1)C=C.[Cl:41]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:41][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:39])=[O:38])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:40])[CH2:6]1
Reactant: ClCl
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(S(C)=O)cc1)C(=O)C(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CS(=O)c1ccc(OC(C(=O)C(C)(C)C)=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)CC2Cl)cc1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
To a solution of 0.488 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-methylsulphinylphenoxy)-3-trimethylacetylthiopropenate in dichloromethane at -20°, was added dropwise a solution of 1.58 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 0.24 g of the title compound as a pale yellow foam (53% of the theoretical yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.[CH:24]([CH:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1)([CH3:26])[CH3:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH:24]([CH:27]1[CH2:32][CH2:31][CH:30]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:6]=[CH:5]3)[CH2:29][CH2:28]1)([CH3:26])[CH3:25]
Reactant: CC(C)C1CCC(O)CC1
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(Cc2ccc3cc(OC4CCC(C(C)C)CC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 486.7 %

Procedure:
Into a 25 mL round bottom flask was added ethyl 1-((6-hydroxynaphthalen-2-yl)methyl)piperidine-4-carboxylate (313 mg, 0.1 mmol, 2 eq), 4-isopropylcyclohexanol (284 mg, 0.2 mmol, 2 eq), PPh3 (562 mg, 0.2 mmol, 2 eq) and dry toluene (0.5 mL) under N2. Then DIAD (404 mg, 0.2 mmol, 2 eq) was quickly added in one portion at room temperature. The reaction mixture was stirred at rt for 0.5 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (PE:EA=4:1) to give ethyl 1-((6-(4-isopropylcyclohexyloxy)naphthalen-2-yl)methyl)piperidine-4-carboxylate (213 mg, yield: 51%) as slight yellow oil. ESI-MS (M+1)+: 438.1. 1H NMR (400 MHz, CDCl3) δ: 7.64-7.57 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.10-7.08 (m, 2H), 4.60-4.58 (m, 1H), 4.05 (q, J=7.2 Hz, 2H), 3.56 (s, 2H), 2.85-2.81 (m, 2H), 2.07-2.04 (m, 1H), 2.01-1.97 (m, 2H), 1.83-1.71 (m, 4H), 1.51-1.40 (m, 6H), 1.24-1.15 (m, 6H), 1.11-1.06 (m, 1H), 0.83 (d, J=6.4 Hz, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCSc1cccc2nccn12
Yield: 99.9 %

Procedure:
To a solution of 5-(2-hydroxy)ethylthioimidazo[1,2-a]pyridine (9.71 g, 50 mmoles) and triethylamine (10.5 ml, 75.3 mmoles) in methylene chloride (300 ml) was added methanesulfonyl chloride (4.26 ml, 55 mmoles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was washed in turn with aqueous saturated sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to obtain 13.6 g of the desired product (quantitative, brown oily product).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[O:16][C@@H:15]([CH3:17])[CH2:14][NH:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:12][C@H:11]([CH3:10])[O:16][C@H:15]([CH3:17])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C[C@@H]1CN(Cc2ccc(Br)cc2)C[C@H](C)O1
Temperature: 25 °C
Yield: 112.8 %

Procedure:
To a mixture of 4-bromobenzaldehyde (3.70 g, 20 mmol) and cis-2,6-dimethylmorpholine (2.52 g, 22 mmol) in DCE (100 mL) was added NaBH(OAc)3 (5.30 g, 25 mmol), followed by AcOH (0.5 mL). After addition, the resulting mixture was stirred O/N at rt. The reaction as quenched with sat. NaHCO3 (30 mL) and H2O (30 mL), and was extracted with DCM (30 mL×2). Concentration of the solvents afforded the crude title compound as a pale yellow liquid (6.41 g, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=7.2 Hz, 2H), 7.21 (d, J=7.2 Hz, 2H), 3.64-3.55 (m, 2H), 3.44 (s, 2H), 2.68 (d, J=11.6 Hz, 2H), 1.75 (t, J=11.0 Hz, 2H), 1.54 (d, J=6.0 Hz, 6H); MS ESI 284.0 [M+H]+, calcd for [C13H18BrNO+H]+ 284.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:17])[C:10]3[N:11]=[CH:12][CH:13]=[N:14][C:15]=3[CH:16]=2)[CH2:3][CH2:2]1.CS(O[C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30]2[N:35]=[CH:34][C:33]([Br:36])=[CH:32][N:31]=2)[CH2:25][CH2:24]1)(=O)=O>O1CCOCC1.CCOC(C)=O>[Br:36][C:33]1[CH:34]=[N:35][C:30]([NH:29][C@H:26]2[CH2:27][CH2:28][C@@H:23]([O:17][C:9]3[CH:8]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:16]=[C:15]4[C:10]=3[N:11]=[CH:12][CH:13]=[N:14]4)[CH2:24][CH2:25]2)=[N:31][CH:32]=1
Reactant: Oc1cc(N2CCOCC2)cc2nccnc12
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](Nc2ncc(Br)cn2)CC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Brc1cnc(N[C@H]2CC[C@@H](Oc3cc(N4CCOCC4)cc4nccnc34)CC2)nc1
Yield: 52.5 %

Procedure:
As shown in step 6-viii of Scheme 6, a solution of 7-morpholinoquinoxalin-5-ol (100 mg, 0.432 mmol), (trans)-4-((5-bromopyrimidin-2-yl)amino)cyclohexyl methanesulfonate (compound 1014, 303 mg, 0.865 mmol), and CsCO3 (282 mg, 0.865 mmol) in dioxane (1.0 mL was stirred for 16 hours at 105° C. After cooling, the reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0 to 5% MeOH/DCM gradient) to produce 5-bromo-N-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (compound 1020, 110 mg) as a yellow foam: 1H-NMR (400 MHz, CDCl3) δ 8.70 (d, J=2.0 Hz, 1H), 8.64 (d, J=1.9 Hz, 1H), 8.29 (s, 2H), 6.98 (d, J=2.5 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 5.29 (d, J=8.3 Hz, 1H), 4.81 (s, 1H), 4.04-3.84 (m, 4H), 3.42-3.31 (m, 4H), 2.22 (s, 2H), 1.92 (d, J=4.9 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][OH:23].[CH2:24](N(S(F)(F)F)CC)[CH3:25].C(O)C>O1CCCC1>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:21])[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH2:22][O:23][CH2:24][CH3:25]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2CO
Solvent: CCO
Solvent: C1CCOC1
Product: CCOCN1CCc2c(F)c(F)cc3c(=O)c(C(=O)OCC)cn1c23
Reaction time: 4 h

Procedure:
65 mg of the compound (177) obtained in Example 54 was suspended in 5 ml of tetrahydrofuran, and 270 μl of diethylaminosulfurtrifluoride was added to the solution. The solution was stirred for 4 hours, and 1 ml of ethanol was added to the solution. The deposited solid matter was filtered off and washed with ether to obtain 28 mg of the subject compound (181).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])(C)(C)C.C(O[C:30](=[O:53])[CH2:31][C:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[S:40][C:41]([CH2:44][O:45]C3CCCCO3)=[N:42][N:43]=2)[CH:34]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:45][CH2:44][C:41]1[S:40][C:39]([C:35]2[CH:34]=[C:33]([C:32]3[CH2:31][C:30](=[O:53])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)=[N:43][N:42]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nnc(COC3CCCCO3)s2)c1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3nnc(CO)s3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J35) and 3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,3,4]thiadiazol-2-yl]-phenyl}-propionic acid tert-butyl ester (0.23 g) (Example K30) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.02 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:21]([CH2:29][CH3:30])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18](O)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:64][C@:65]1([C:70]([NH:72][S:73]([CH:76]2[CH2:78][CH2:77]2)(=[O:75])=[O:74])=[O:71])[CH2:67][C@H:66]1[CH:68]=[CH2:69]>ClCCl>[CH:76]1([S:73]([NH:72][C:70]([C@@:65]2([NH:64][C:18]([C@@H:13]3[CH2:14][C@@H:15]([OH:17])[CH2:16][N:12]3[C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[C@H:21]([CH2:29][CH3:30])[CH2:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=[CH2:27])=[O:19])[CH2:67][C@H:66]2[CH:68]=[CH2:69])=[O:71])(=[O:75])=[O:74])[CH2:78][CH2:77]1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Reactant: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of (2S,4R)-1-((2S,3R)-2-(tert-butoxycarbonylamino)-3-ethyl-5-methylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.3 g, 3.05 mmole) in dichloromethane (50 mL) was added HATU (1.15 g, 3.05 mmole) followed by DIPEA (1.6 mL, 9.13 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide (1.22 g, 3.05 mmole) was added to the reaction mass and the mixture was stirred at room temperature for 1 h. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4; filtered; then concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (6% methanol in chloroform) to get 1.7 g (87%) of tert-butyl (2S,3R)-1-((2S,4R)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-hydroxypyrrolidin-1-yl)-3-ethyl-5-methyl-1-oxonon-8-en-2-ylcarbamate as a white solid. MS: MS m/z 639.55 (M++1).
Reaction SMILES: [Cl:1]Cl.[C:3]([NH2:13])(=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>O>[Cl:1][NH:13][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: ClCl
Reactant: CCCCCCCCC(N)=O
Solvent: O
Product: CCCCCCCCC(=O)NCl
Temperature: 20 °C
Reaction time: 0.42 h
Yield: 97.4 %

Procedure:
Gaseous chlorine is introduced at a speed of 95 g/h into a suspension of 194 g of 98.15% pure pelargonamide (1.21 mol) in 1400 ml of water. The introduction of chlorine is discontinued after 60 min and the suspension is still left under stirring for 20-30 min at 20° C. The solid is filtered off, is washed with water until all HCl has disappeared (300 cc. of water) and the chlorinated derivative is dried. 226 g of N-chloropelargonamide (yield 97.4%) having an active chlorine titer of 17.6% (theory 18.5%) are thus obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:32]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: COc1cccc(C(=O)NCCc2ccc(-c3ccc(C(C)CNS(=O)(=O)C(C)C)cc3)cc2)c1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 18 mg (0.11 mmol) 3-methoxybenzoyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [Mg].II.ClC(C)C.[CH3:8][O:9][Si](OC)(OC)OC.CO.C([Si:22]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[O:23][CH3:24])(C)C>COC(C)(C)C>[CH:25]([Si:22]([CH:28]([CH3:30])[CH3:29])([O:9][CH3:8])[O:23][CH3:24])([CH3:27])[CH3:26]
Reactant: CO[Si](OC)(OC)OC
Reactant: CO[Si](C(C)C)(C(C)C)C(C)C
Agent: CC(C)Cl
Agent: II
Agent: [Mg]
Solvent: CO
Solvent: COC(C)(C)C
Product: CO[Si](OC)(C(C)C)C(C)C

Procedure:
Under an inert gas, 24.2 g magnesium chips (1.0 mol) were combined with about 20 ml methyl-tert-butylether, an iodine crystal and 3.1 g 2-chloropropane (0.04 mol). To start the reaction a solution of 61.9 g tetramethoxysilane (0.41 mol) and 75.4 g 2-chloropropane (0.96 mol) in 140 ml methyl-tert-butylether was added dropwise, with stirring, to the first mixture at a rate to maintain a moderate reflux. After addition of the solution, the reaction was allowed to reflux for six more hours. After cooling the reaction mixture, 6.0 g methanol (0.19 mol) was added, the mixture was stirred for a few minutes and then the resulting precipitate was removed by filtration. After washing the filter cake with several portions of methyl-tert-butylether, the solvent was distilled from the combined filtrates. The remaining residue consisted of 70.5 g diisopropyldimethoxysilane (98% of the theoretical yield) which had a purity of 98% according to GC. Triisopropylmethoxysilane was not detected by GC.