Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[N:19][N:18]=[C:17]2[CH2:21][N:22]2[C:26](=[O:27])[C:25]3=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]3[C:23]2=[O:32])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Cl:33]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:17]([CH2:21][N:22]3[C:26](=[O:27])[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=[O:32])=[N:18][N:19]=[C:20]2[Cl:33])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1cc(Br)ccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
5-Bromo-2-[3-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]-benzophenone (0.01 mole) and N-chlorosuccinimide (0.013 mole) in benzene is stirred and refluxed under a nitrogen atmosphere for 7 hours to give 5-bromo-2-[3-chloro-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[C:11]=2[Cl:13])[NH:6][CH:5]=1)#[N:2].N1[CH2:20][CH2:19][CH2:18][CH2:17]1>CO.[Ni]>[N:2]1([CH2:1][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[C:11]=3[Cl:13])[NH:6][CH:5]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc2[nH]cc(CC#N)c2c1Cl
Reactant: C1CCNC1
Agent: [Ni]
Solvent: CO
Product: COc1ccc2[nH]cc(CCN3CCCC3)c2c1Cl

Procedure:
3-Cyanomethyl-4-chloro-5-methoxyindole (2.0 g, 9.1 mmol) was reductively aminated with pyrrolidine (32 ml) in methanol (100 ml) over Raney nickel for 21/2 hours at 30 p.s.i. pressure, at room temperature. After removal of the catalyst, the solvent was removed and the crude mixture purified by chromatography (SiO2 ; CHCl3 /MeOH) to give 3-(2-Pyrrolidinylethyl)-4-chloro-5-methoxyindole (1.26 g) as a solid. Part of this product (250 mg) was dissolved in methanol (10 ml) and treated with a solution of fumaric acid (150 mg) in methanol (5 ml), then ether to give the product as the hemifumarate salt (244 mg), m.p. 217°-8° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>CO.O.[Fe]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(F)c(Cl)c1Nc1ccccc1
Temperature: 90 °C
Yield: 80.8 %

Procedure:
To a mixture of (2-chloro-3-fluoro-6-nitrophenyl)phenylamine (1.28 g, 4.8 mmol) in MeOH (45 mL) and water (15 mL) were added NH4Cl (1.48 g, 28.8 mmol) and iron powder (1.07 g, 19.2 mmol) and the reaction mixture heated at 90° C. for 2 h. After cooling to RT, the crude mixture was filtered through a pad of Celite® and the filtrate concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% DCM in cyclohexane) to afford the title compound (918 mg, 81%). LCMS (Method C): RT 3.46 min [M+H]+ 237.1/239.1.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([O:23]C)=[C:17]([CH2:25][CH3:26])[CH:16]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl>[CH2:1]([C:8]1[O:9][C:10]([CH3:28])=[C:11]([CH3:27])[C:12]=1[C:13]([C:15]1[CH:16]=[C:17]([CH2:25][CH3:26])[C:18]([OH:23])=[C:19]([CH2:21][CH3:22])[CH:20]=1)=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1O
Yield: 38.1 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 3 using (2-benzyl-4,5-dimethyl-furan-3-yl)-(3,5-diethyl-4-methoxy-phenyl)-methanone (19.3 g, 51.2 mmol) and 1M boron tribromide/CH2Cl2 (36.8 mL) in CH2Cl2. Purification on Biotage KP-Sil eluting with a 2 & 5% EtOAc/hexane step gradient gave 7.07 g (37%) of the title compound. 1H NMR (DMSO-d6) δ1.08 (t, 6 H), 1.79 (s, 3 H), 2.17 (s, 3 H), 2.57 (q, 4 H), 3.81 (s, 2 H), 7.06 (dd, 2 H), 7.16-7.18 (m, 1 H), 7.22-7.26 (m, 2 H), 7.37 (s, 2 H), 9.10 (s, 1 H). mass spectrum (EI), m/z 362 (M+).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:30])=[N:25][CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cnc(N)c(-c2ccc(OC3CCCCC3)nc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(OC3CCCCC3)nc2)=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 238 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.375 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-[6-(cyclohexyloxy)pyridin-3-yl]-5-methylpyrazin-2-amine (338 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 1 day. The mixture was quenched with water at 0° C. carefully. EtOAc and THF were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from MeCN-THF/IPE to give the title compound (84.5 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[O:3][C:4]([CH3:7])=[N:5][N:6]=1.C([Mg]Cl)(C)C.[CH3:13][C:14]([CH3:24])([CH3:23])/[CH:15]=[N:16]/[S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18]>C1COCC1.C1(C)C=CC=CC=1>[CH3:13][C:14]([CH3:24])([CH3:23])[CH:15]([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:2]1[O:3][C:4]([CH3:7])=[N:5][N:6]=1
Reactant: Cc1nnc(Br)o1
Reactant: CC(C)(C)/C=N/S(=O)C(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nnc(C(NS(=O)C(C)(C)C)C(C)(C)C)o1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 2-bromo-5-methyl-1,3,4-oxadiazole (CAN 864750-58-3, 0.473 g, 2.91 mmol) in dry THF (8 ml) cooled down to −15° C. under an argon atmosphere was added isopropyl magnesium chloride, lithium chloride complex (2.23 ml, 2.91 mmol). (During the addition the temperature was kept below −12° C.). The reaction was then stirred at −15° C. for 30 minutes followed by slow addition of a solution of (NE)-N-(2,2-dimethylpropylidene)-2-methyl-propane-2-sulfinamide (CAN 917104-90-6, 500 mg, 2.64 mmol) in dry toluene (8 ml). The reaction was allowed to warm up to room temperature overnight. The reaction was quenched by addition of water. The reaction medium was diluted with ethylacetate and the organic phase was extracted with a saturated aqueous solution of ammonium chloride. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (462 mg, 64%). MS (ESI, m/z): 274.5 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:54][C:55]1[CH:56]=[C:57]([C:61]2[N:70]=[C:69]([NH:71][C:72]3[CH:73]=[C:74]4[C:78](=[CH:79][CH:80]=3)[N:77]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[N:76]=[CH:75]4)[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[N:62]=2)[CH:58]=[CH:59][CH:60]=1>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]([NH:54][C:55]2[CH:56]=[C:57]([C:61]3[N:70]=[C:69]([NH:71][C:72]4[CH:73]=[C:74]5[C:78](=[CH:79][CH:80]=4)[N:77]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[N:76]=[CH:75]5)[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]=3)[CH:58]=[CH:59][CH:60]=2)=[O:11])[CH2:6][CH2:7]1
Reactant: CN1CCN(CC(=O)O)CC1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CC(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-(4-methylpiperazin-1-yl)acetic acid (34 mg, 0.22 mmol), PyBOP® (11 mg, 0.22 mmol), DIEA (300 μL, 1.72 mmol) in CH2Cl2 (0.5 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (100 mg, 0.22 mmol) and CH2Cl2 (1 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 1 equivalent of the acid as described above and it was once again added to the reaction mixture. Stirred for 16 h, diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo to give the desired product tert-butyl 5-(2-(3-(2-(4-methylpiperazin-1-yl)acetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:22]([O:24][C:25](=[O:28])[CH2:26]Br)[CH3:23].OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][N:15]1[C:16](=[O:19])[CH2:17][CH2:18][N:12]([C:10](=[O:11])/[CH:9]=[CH:8]/[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14]1)[CH3:23]
Reactant: O=C1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCN1
Reactant: CCOC(=O)CBr
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.5 %

Procedure:
A solution of 4.33 g (15.53 mmol) of 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 3A) in 80 ml of DMF was treated at 0° C. with 0.75 g (17.09 mmol) of NaH (55% in oil) in two portions and after 30 min with 1.89 ml (17.09 mmol) of bromo-acetic acid ethyl ester in 1 ml of DMF. The reaction was stirred for 5 h at RT, cooled (0° C.) and treated again with 0.20 g (4.66 mmol) of NaH (55% in oil) and after 20 min with 0.34 ml (3.11 mmol) of bromo-acetic acid ethyl ester. The reaction was warmed up to RT over night, cooled and neutralized with cold aqueous 10% KHSO4 and extracted with Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (EtOAc/n-heptane 1:1 to 9:1) to yield 2.92 g (52%) of the title compound as light yellow viscous oil. MS: 365.0 (MH+, Cl).
Reaction SMILES: [N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([OH:45])=O)=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl.CN(C)CCCN=C=NCC.[NH2:58][CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCN(CC)CC>[N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:58][CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])=[O:45])=[O:39])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of (C18H37)2NCOCH2OCH2COOH (1.0 g, 1.5 mmol) in CH2Cl2 (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.31 g, 1.6 mmol) and the reaction was stirred at room temperature. After 0.5 h, Gly-OCH2Ph.TsOH (0.53 g, 1.5 mmol) and Et3N (0.6 mL) were added and the mixture was stirred overnight. The reaction mixture was washed with water (20 mL), 0.5 M aqueous HCl (20 mL), water (20 mL), 10% aqueous Na2CO3 (20 mL), and brine (20 mL) then dried over MgSO4, evaporated and the residue crystallized from MeOH yielding (C18H37)2NCOCH2OCH2CO-Gly-OCH2Ph as a deliquescent white solid (0.86 g, 70%), mp 38–40° C. 1H-NMR (300 MHz, δ, CDCl3) 0.86 (6H, t, J=6.9 Hz), 1.24 (64H, m), 1.50 (4H, bs), 3.06 (2H, t, J=7.5 Hz), 3.28 (2H, t, J=7.5 Hz), 4.10 (2H, s), 4.12 (2H, s), 4.25 (2H, s), 5.15 (2H, s), 7.33 (5H, m), 8.20 (1H, t, J=5.7 Hz). 13C-NMR (75 MHz, 6, CDCl3): 14.2, 22.7, 26.9, 27.1, 27.6, 29.0, 29.39, 29.44, 29.5, 29.6, 29.7, 29.8, 32.0, 40.8, 46.3, 47.0, 67.1, 69.7, 71.8, 128.5, 128.6, 128.8, 135.3, 168.5, 169.8, 170.6.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.[CH2:24](I)[CH3:25]>>[CH2:24]([N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:23])[CH2:5][CH2:6]1)[CH3:25]
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCNCC1
Reactant: CCI
Product: CCN1CCC(N2C(=O)Nc3ccccc3C2c2ccccc2)CC1

Procedure:
In similar way as in Preparation Example 31, the title compound was synthesized from 3-(piperidin-4-yl)-4-phenyl-3,4-dihydro-2(1H)-quinazolinone and ethyl iodide.
Reaction SMILES: Cl.O.[CH:3]1([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:27](OC)[O:28]C)[CH:19]=3)[CH:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C1COCC1>[CH:3]1([CH2:9][NH:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:19]=2)[CH:27]=[O:28])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(OC)c1cc(Oc2cccc(NCC3CCCCC3)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(Oc2cccc(NCC3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12N HCl (2 mL) and H2O (4 mL) were added to a mixture of cyclohexylmethyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-amine (0.0055 mol) in THF (17 mL), and the reaction mixture was stirred overnight at room temperature. H2O was added, and the mixture was extracted with diisopropyl ether. The organic layer was washed with a 10% NaHCO3 solution, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by short column chromatography (eluent: 100% CH2Cl2). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([N:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:56](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([N:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([CH3:56])[CH2:20][CH2:19]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(OC3CCNCC3)c2)n1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCC(Oc2cc(-n3nc(C(C)(C)C)cc3NC(=O)N[C@H]3CC[C@@H](Oc4ccc5nnc(N6CCCCC6)n5c4)c4ccccc43)ccc2Cl)CC1
Reaction time: 3 h
Yield: 53.7 %

Procedure:
To a stirred solution of Example 68 (605 mg, 0.82 mmol) in DCM (8 mL) was added formaldehyde solution (37 wt % in H2O, 610 μL, 8.19 mmol), followed by acetic acid (47 μL, 0.82 mmol), and then sodium triacetoxyborohydride (347 mg, 1.64 mmol) and the reaction stirred at RT under a N2 atmosphere. After 3 h, the reaction was partitioned between H2O and DCM, and passed through a phase separator cartridge. The organics were concentrated in vacuo and subjected to FCC, eluting with 0-7.5% 2M NH3 in MeOH/DCM, and the product purified further by HPLC (XBridge C18 column, 45-85% MeCN in H2O, 0.1% NH4OH, 20 min gradient, 18 mL/min) to afford the title compound (331 mg, 54%). LCMS (Method 5): Rt 3.61 min, m/z 752, 754 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.58-1.65 (2H, m), 1.65-1.77 (6H, m), 1.80-1.97 (4H, m), 2.11 (3H, s), 2.12-2.23 (4H, m), 3.14 (4H, t, J=5.1 Hz), 4.45-4.55 (1H, m), 4.76-4.83 (1H, m), 5.55 (1H, t, J=4.3 Hz), 6.33 (1H, s), 7.04 (1H, broad d, J=8.4 Hz), 7.08 (1H, dd, J=2.3, 8.6 Hz), 7.15 (1H, dd, J=2.2, 9.7 Hz), 7.22-7.36 (4H, m), 7.36-7.41 (1H, m), 7.52-7.56 (1H, m), 7.59-7.65 (2H, m), 8.13 (1H, s).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[C:17]1([C:23](OC)=[O:24])[CH2:22][CH2:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.O>[C:1]([NH:5][C:23]([C:17]1[CH2:22][CH2:21][CH:20]=[CH:19][CH:18]=1)=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1=CC=CCC1
Reactant: CC(C)(C)N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)NC(=O)C1=CC=CCC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 33471.2 %

Procedure:
t-Butylamine (2.38 g, 0.033 mmol) was dissolved in THF (20 ml), 1.6M solution of n-butyl lithium in hexane (20 ml, 0.032 mol) was added thereto at 0° C. and the mixture was stirred as it was for 40 minutes. A solution of methyl 1,3-cyclohexadiene-1-carboxylate (3 g, 0.0217 mol) synthesized in Example 12 in THF (3 ml) was added dropwise and the solution was further stirred for 30 minutes. The reaction mixture was poured in water, extracted with methylene chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (silica gel 60 g, ethyl acetate:hexane=1:5) to obtain 1,3-cyclohexadiene-1-carboxylic acid t-butylamide (1.98 g, 5 1%). This compound has the following NMR spectrum.
Reaction SMILES: C(O)=O.[CH:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23]3[CH:38]=[CH:37][C:26]([CH2:27][CH2:28][NH:29]C(=O)OC(C)(C)C)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C([Si]([O:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH:65]2[CH2:67][O:66]2)=[CH:59][CH:58]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:4]1([CH2:10][CH2:11][CH2:12][NH:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23]3[CH:38]=[CH:37][C:26]([CH2:27][CH2:28][NH:29][CH2:67][C@H:65]([OH:66])[CH2:64][O:63][C:60]4[CH:61]=[CH:62][C:57]([OH:56])=[CH:58][CH:59]=4)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(NC2CCN(C(=O)NCCCC3CCCCC3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=CO
Solvent: CO
Product: O=C(NCCCC1CCCCC1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 36 %

Procedure:
tert-Butyl 4-[(1-{[(3-cyclohexylpropyl)amino]carbonyl}-4-piperidinyl)amino]phenethylcarbamate formate (0.35 g, 0.809 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.327 g, 0.809 mmol) according to Procedure G (eluant: 20:1 going to 10:1 chloroform-methanol) to give the title compound (0.23 g, 0.291 mmol).
Reaction SMILES: [C:1](Cl)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C.Cl.[CH3:15][O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=[O:24])[CH2:22][NH2:23])=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[C:1]([NH:23][CH2:22][C:21]([C:20]1[CH:25]=[CH:26][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:24])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COc1ccc(C(=O)CN)cc1
Reactant: CCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)NCC(=O)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
To a solution of 22.0 g (108 mM) of undecanoyl chloride in 185 ml of pyridine, 22.2 g (110 mM) of 4-methoxyphenacylamine hydrochloride was gradually added in 30 minutes under cooling and stirring below -5° C., followed by stirring for 30 minutes below -5° C. and heat-refluxing of 1 hour under stirring. After the reaction, the reaction mixture was cooled to room temperature and poured into 1 liter of cool water to precipitate a crystal. The crystal was recovered by filtration, washed with water and recrystallized from ethanol to obtain 13.9 g of decanoyl-4-methoxyphenacylamine (Yield: 38.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:31](OCC)(=[O:33])[CH3:32].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[C:31]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N:12]([CH2:22][P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)(=[O:33])[CH3:32]
Reactant: CCOC(C)=O
Reactant: CCOP(=O)(CN(c1ccc2[nH]ccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOP(=O)(CN(c1ccc2c(ccn2C(C)=O)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C

Procedure:
100 mg diethyl {[(3,5-dichloro-phenylsulphonyl)-(1H-indol-5-yl)-amino]-methyl}-phosphonate are dissolved in 1 ml acetic anhydride and refluxed overnight. After cooling to ambient temperature the mixture is divided between ethyl acetate and ice water. Then it is neutralised by the addition of saturated sodium hydrogen carbonate solution. The phases are separated and the organic phase is washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (petroleum ether/ethyl acetate 1:2 to 1:3).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:19].[CH3:20][N:21]1C(=O)CCC1>>[C:20]([C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:19])#[N:21]
Reactant: O=C(N1CCc2ccc(Br)c(O)c2CC1)C(F)(F)F
Reactant: CN1CCCC1=O
Product: N#Cc1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Temperature: 150 °C
Yield: 86 %

Procedure:
Add copper nitrile (2.6 g, 28 mmol) to a solution of 7-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (2.4 g, 7.0 mmol) in anhydrous NMP (45 mL), degas and purge with nitrogen and heat to 150° C. for 18 h. Allow the reaction mixture to cool to ambient temperature and then dilute with EtOAc/heptane (2:1) and filter through a silica pad. Dilute the filtrate with water, and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc/heptane (1:4 to 1:1) to obtain the desired intermediate as an orange oil (1.7 g, 86%). MS (ES−) m/z: 283 (M−H)−.