Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:9]=[C:10]([CH3:23])[C:11]([NH:14][C:15](=O)[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:12][CH:13]=1.[OH-].[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH3:23])[C:11]([NH:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:12][CH:13]=1
Reactant: Cc1cc(Br)cnc1NC(=O)CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cc(Br)cnc1NCCN1CCCC1
Reaction time: 3 h

Procedure:
Under an argon atmosphere 2 mL of a 1 M solution of LiAlH4 in THF are slowly added dropwise to a solution, cooled to 0° C., of 800 mg (2.68 mmol) N-(5-bromo-3-methyl-pyridin-2-yl)-2-pyrrolidin-1-yl-acetamide (Example 15b) in 10 mL THF and the reaction mixture is stirred for 3 h at this temperature. 20% NaOH is slowly added dropwise, solid K2CO3 is added to the suspension and this is stirred vigorously. The precipitate is filtered off, the filtrate is evaporated down and the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 80:20:2).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][CH:5](C(OCC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].O.[Cl-].[Li+]>CS(C)=O>[Br:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(Cc1c(Cl)cccc1Br)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCc1c(Cl)cccc1Br

Procedure:
Diethyl 2-(2-bromo-6-chlorobenzyl)malonate (13.0 g, 35.7 mmol), water (1.29 mL, 71.5 mmol) and lithium chloride (3.03 g, 71.50 mmol) in dimethylsulfoxide (75 mL) were heated to +185° C. for 1 h. The solution was allowed to cool. 75 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with water and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered and the solvent was removed by rotary evaporation to give the title compound. Yield: 7.34 g, 70%. 1H NMR (500 MHz, CDCl3) δ ppm 1.27-1.30 (m, 3H) 2.55-2.61 (m, 2H) 3.27-3.33 (m, 2H) 4.16-4.21 (m, 2H) 7.02 (t, 1H) 7.31-7.35 (m, 1H) 7.45-7.50 (m, 1H). MS m/z 293.0 [M+H]+.
Reaction SMILES: [F:1][S:2]([C:5]([F:10])([F:9])[C:6](F)=[O:7])(=[O:4])=[O:3].Cl.[C:12]([O:17][CH2:18][CH2:19][NH2:20])(=[O:16])[C:13]([CH3:15])=[CH2:14].N1C=CC=CC=1.Cl>C(Cl)Cl>[C:12]([O:17][CH2:18][CH2:19][NH:20][C:6](=[O:7])[C:5]([F:10])([F:9])[S:2]([F:1])(=[O:4])=[O:3])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)OCCN
Reactant: O=C(F)C(F)(F)S(=O)(=O)F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCNC(=O)C(F)(F)S(=O)(=O)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
A 500 ml flask was charged with CH2Cl2 (80 ml) under nitrogen stream and stirred for 10 min at 0° C. and then 2-(fluorosulfonyl)difluoroacetyl fluoride (29.9 g, 166.0 mmol, 1.5 equivalent (eq.)) was added. After 25 minutes, a CH2Cl2 (160 ml) solution of 2-aminoethyl methacrylate hydrochloride (18.4 g, 111.0 mmol, 1.0 eq.) and pyridine (17.5 g, 221.0 mmol, 2.0 eq.) was added drop wise to the mixture over 50 minutes. The mixture was allowed to warm to room temperature (RT) and stirred for 3 hours at RT. 1N HCl was added to the final reaction mixture and the lower layer was separated and washed with 1N HCl and Brine. The solution was dried over anhydrous MgSO4, filtrated and then CH2Cl2 was removed by an evaporator. The crude product was purified by recrystallization (hexane/CHCl3). The target compound was obtained as a white solid (20.4 g) in 64% yield. 1H-NMR (400 MHz, CDCl3); delta=1.93 (dd, J=1.1, 1.2 Hz, 3H), 3.73 (td, J=5.4, 5.2 Hz, 2H), 4.35 (dd, J=5.1, 5.0 Hz, 2H), 5.63 (dq, J=1.4, 1.5 Hz, 1H), 6.12-6.14 (m, 1H), 7.09 (brs, 1H). 19F-NMR (376 MHz, CDCl3, C6F6 as standard); delta=40.68 (t, J=5.1 Hz, 1F), −105.91 (d, J=4.8 Hz, 2F).
Reaction SMILES: [Cl:1][C:2]1[C:10](C(F)(F)F)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5].ClC1C=C([F:25])C=CC=1C(O)=O.ClC1C(C(F)(F)F)=CC=CC=1C(O)=O>>[Cl:1][C:2]1[CH:10]=[C:9]([F:25])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:6])=[O:5]
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: O=C(Cl)c1ccc(F)cc1Cl

Procedure:
The title compound was prepared in a manner analogous to Intermediate 12 substituting 2-chloro-4-fluorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:19]2[S:20][CH:21]=[C:22](Br)[CH:23]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@@H:6]([CH3:25])[CH2:5]1)[CH:2]=[CH2:3].C([Li])CCC>>[CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@@H:6]([CH3:25])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N([C@H](c2cccc(O)c2)c2cc(Br)cs2)C[C@H]1C
Agent: [Li]CCCC
Product: C=CCN1C[C@H](C)N([C@H](c2cccc(O)c2)c2cccs2)C[C@H]1C
Yield: 74.1 %

Procedure:
(-)-3-((R)-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)(4-bromo-2-thienyl)methyl)phenol (0.53 g, 1.3 mmol, Example 66) was debrominated with n-butyllithium as in Example 9. The crude product was recrystallized from acetonitrile to give 0.33 g (77%) of (-)-3-((R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(2-thienyl)methyl)phenol as beige crystals, mp 176°-178° C., [α]D20 =-23.3° (ethyl acetate, c=1.5). HPLC on β-cyclodextrin with methanol:0.1M aqueous ammonium acetate/1:1 gave one peak at tR =8.5 min. Calc. for C20H26BrN2OS 0.25 H2O: C, 69.23; H, 7.70; N, 8.07; S, 9.24. Found: C, 68.86; H, 7.47; N, 8.27; S, 9.06. The product (0.30 g, 0.87 mmol) was treated with ethanolic hydrogen chloride as in Example 42 to give 0.201 g (61%) of the monohydrochloride salt. Calc. for C20H26BrN2OS HCl 0.75 H2O: C, 61.21; H, 7.32: N, 7.12; S, 8.17; Cl, 9.03. Found: C, 61.35; H, 7.01; N,7.30; S, 8.16; Cl, 9.11. [α]D20 =-11.9° (ethanol, c=1.05).
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[N:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:8][CH:9]=1.[N+:15]([C:18]1[CH:22]=[N:21][NH:20][N:19]=1)([O-:17])=[O:16].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[N+:15]([C:18]1[CH:22]=[N:21][N:20]([CH2:4][C:5]2[N:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:8][CH:9]=2)[N:19]=1)([O-:17])=[O:16]
Reactant: CCOC(=O)c1nc(CCl)cs1
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Cn2ncc([N+](=O)[O-])n2)cs1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of ethyl 4-(chloromethyl)thiazole-2-carboxylate (WO 2009077990 A1) (2.16 g, 10.5 mmol) in DMF (15.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (T. E. Eagles et al. Organic preparations and procedures 2 (2), 117-119, 1970; P. N. Neuman J. Heterocycl. Chem. 8, 51-56, 1971) (8.0 g of a 10% solution in DMF, 7.01 mmol) in DMF (15.0 mL) pre-treated for 30 min with DIPEA (1.82 mL, 2.33 mmol) and the reaction mixture was stirred overnight at 50° C. Water (50 mL), followed by EA (50 mL) was added. The layers were separated and the aq. layer was washed with water (50 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA)) gave the title compound as a yellow oil. TLC: rf (7:3 hept-EA)=0.36. LC-MS-conditions 07: tR=0.76 min, [M+H]+=284.28.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][P:14](=[O:25])([O:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][P:14](=[O:25])([O:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:26][CH:27]=1
Reactant: CCCCOP(=O)(Cc1ccc(OCc2ccccc2)cc1)OCCCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCOP(=O)(Cc1ccc(O)cc1)OCCCC

Procedure:
To a solution of dibutyl 4-benzyloxybenzylphosphonate (4.07 g) in ethyl acetate (60 ml) is added 10% palladium on carbon (0.41 g) and the mixture shaken under 25 psi of hydrogen for about 20 hours. The mixture is filtered, concentrated in vacuo, and the residue purified by HPLC, eluting with a gradient of 50-65% ethyl acetate in hexane, to give dibutyl 4-hydroxybenzylphosphonate.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]([O:14][CH3:15])[NH:8][CH:9]=[C:10]([C:11]([NH2:13])=O)[C:5]=2[N:4]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.O>C1COCC1>[Br:1][C:2]1[C:6]2[CH:7]([O:14][CH3:15])[NH:8][CH:9]=[C:10]([C:11]#[N:13])[C:5]=2[N:4]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]=1
Reactant: COC1NC=C(C(N)=O)c2c1c(Br)cn2C1CCCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: O
Solvent: C1CCOC1
Product: COC1NC=C(C#N)c2c1c(Br)cn2C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of 3-bromo-1-cyclopentyl-4-methoxy-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxamide (654 mg) in THF (8 mL) was added Burgess reagent (1152 mg at 0° C.), and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (522 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([CH:28]4[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]4)=[O:27])[CH2:22][CH2:21]3)=[N:18][CH:19]=2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38].IC1C=CC(NC(C2C=CC(N3CCC(C(NS(C(C)(C)C)(=O)=O)=O)CC3)=NC=2)=O)=CC=1C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:13])[C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([CH:28]4[CH2:33][CH2:32][CH:31]([C:34]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:35])[CH2:30][CH2:29]4)=[O:27])[CH2:22][CH2:21]3)=[N:18][CH:19]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS(N)(=O)=O
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)C4CCC(C(=O)O)CC4)CC3)nc2)c1
Agent: Cc1cc(NC(=O)c2ccc(N3CCC(C(=O)NS(=O)(=O)C(C)(C)C)CC3)nc2)ccc1I
Product: CCS(=O)(=O)NC(=O)C1CCC(C(=O)N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)CC1

Procedure:
N-(3-tert-Butyl-phenyl)-6-[4-(4-ethanesulfonylaminocarbonyl-cyclohexanecarbonyl)-piperazin-1-yl]-nicotinamide was prepared from 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclohexanecarboxylic acid and ethyl sulfonamide in a manner similar to the one described in the synthesis of 4-(2-methyl-propane-2-sulfonylaminocarbonyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carboxylic acid (4-iodo-3-methyl-phenyl)-amide above. The product was isolated after silica gel purification with 0-3% MeOH in CH2Cl2 gradient. HRMS m/z calcd for C30H41N5O5S [M+H]+: 584.2901. Found: 584.2902.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([OH:9])=O.[CH3:13][N:14]([CH3:30])[CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:16]1>>[CH3:13][N:14]([CH3:30])[CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH:29][C:7](=[O:9])[CH:6]=[CH:5][C:4]4[CH:10]=[CH:11][CH:12]=[C:2]([F:1])[CH:3]=4)[CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:16]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)/C=C/c1cccc(F)c1
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4cccc(F)c4)cc3s2)C1
Yield: 16.9 %

Procedure:
Prepare according to Method B, using trans-3-fluorocinnamic acid (98 mg, 0.590 mmol) and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (162 mg, 0.618 mmol) to afford the title compound (41 mg, 16%). mass spectrum (m/e): 411.2 [M+H], 409.2 [M−H].
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.[CH3:17][O-:18].[Na+].[C-]#N.[Na+].C(Cl)Cl>CO>[Cl:7][C:5]1[N:6]=[C:2]([O:18][CH3:17])[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[Cl:8]
Reactant: C[Si](C)(C)CCOCn1c(Br)nc(Cl)c1Cl
Reactant: C[O-]
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Yield: 67 %

Procedure:
A solution of 2-bromo-4,5-dichloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole (0.12 g, 0.35 mmol), sodium methoxide (0.12 mL of a 25% solution in methanol, 0.53 mmol) and CuBr (0.010 g, 0.07 mmol) in methanol (0.5 mL) was heated at 100° C. for 6 h. Dilute aqueous NaCN and CH2Cl2 were added and the solution was stirred for a few minutes. The solution was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and purified by silica gel chromatography (0-40% EtOAc/hex) to afford the title compound (0.070 g, 67%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.11 (s, 2H) 4.02 (s, 3H) 3.51-3.63 (m, 2H) 0.88-0.97 (m, 2H) −0.01 (s, 9H).
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:16])=[N:7]2.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN(C=O)C>[O:20]1[CH2:21][CH2:22][N:17]([C:2]2[C:11]([F:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([CH3:16])=[N:7]3)[CH2:18][CH2:19]1
Reactant: C1COCCN1
Reactant: Cc1ccc2c(Br)c(F)cc([N+](=O)[O-])c2n1
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCOCC3)c(F)cc([N+](=O)[O-])c2n1
Temperature: 70 °C
Reaction time: 6.5 h
Yield: 35.9 %

Procedure:
5-Bromo-6-fluoro-8-nitroquinaldine (9.0 g) and morpholine (13.7 g) were dissolved in 90 ml of DMF and the solution was stirred at an internal temperature of 70° C. for 6.5 hours. Excessive morpholine and DMF were distilled off under reduced pressure and n-hexane was added to the residue followed by sufficient stirring. Then, isopropanol was added to the solution to precipitate solids which then were collected by filtration. The solids were dissolved in water and the aqueous solution was rendered alkaline with an aqueous sodium hydroxide solution to precipitate solids, which were collected by filtration to give 3.3 g of 5-morpholino-6-fluoro-8-nitroquinaldine.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[NH:3]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([N:3]2[C@@H:2]([CH3:1])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C@H:4]2[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: C[C@H]1Cc2ccccc2[C@@H](c2ccc(C(=O)O)cc2)N1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(C(=O)O)cc2)N1C(=O)Nc1ccc(F)cc1
Reaction time: 5 h

Procedure:
To a solution of 4-((1R,3S)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoic acid (22 mg, 82 μmol) in CH2Cl2 (0.5 mL) at RT was added 1-fluoro-4-isocyanatobenzene (28 mg, 206 μmol). The reaction was stirred 5 h and directly purified by HPLC to give 4-((1R,3S)-2-((4-fluorophenyl)carbamoyl)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoic acid as a white solid. MS (ESI pos. ion) m/z: 405 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[N:40]1([C:45]2[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[N:41]1>>[N:40]1([C:45]2[CH:53]=[CH:52][C:48]([C:49]([O:1][CH:2]3[CH2:20][CH:19]4[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]5[C:16]([C:22]([NH:24][S:25]([CH:28]6[CH2:30][CH2:29]6)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]4=[O:21])[CH2:15]5)[CH2:3]3)=[O:50])=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[N:41]1
Reactant: O=C(Cl)c1ccc(-n2cccn2)cc1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(-n4cccn4)cc3)CN2C1=O
Yield: 7.7 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-(1-pyrazolyl)benzoyl chloride (183 mg, 0.88 mmol). The final trituration (diethyl ether/hexane) and filtration gave 10 mg (7.7%) of 18-(4-[1-pyrazolyl]benzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.9% pure (HPLC), MS m/z 737 (M−H)−, HRMS: calcd. 739.3125 and found 739.3109 (M+H)+, mp 167-169° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([C:32]2[N:33]=[CH:34][CH:35]=[C:36]3[CH:40]=[CH:39][N:38]([CH3:41])[C:37]=23)[C:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[N:25][N:26]([CH3:31])[C:27]=3[C:28]([OH:30])=[O:29])=[CH:19][CH:18]=2)=[O:16])[CH2:9]1)=O)(C)(C)C.[ClH:42]>O1CCOCC1>[ClH:42].[CH3:31][N:26]1[C:27]([C:28]([OH:30])=[O:29])=[C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:15](=[O:16])[N:14]([C:32]3[N:33]=[CH:34][CH:35]=[C:36]4[CH:40]=[CH:39][N:38]([CH3:41])[C:37]=34)[C@@H:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:22][CH:21]=2)[CH:24]=[N:25]1
Reactant: Cn1ncc(-c2ccc(C(=O)N(c3nccc4ccn(C)c34)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2)c1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc(-c2ccc(C(=O)N(c3nccc4ccn(C)c34)[C@@H]3CCCNC3)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the compound from Step 3 (R)-4-(4-((1-(tert-butoxycarbonyl)piperidin-3-yl)(1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)carbamoyl)phenyl)-1-methyl-1H-pyrazole-5-carboxylic acid (0.18 g, 0.17 mmol) in 1,4-dioxane (10 mL) was added HCl in 1,4-dioxane (10 mL, 4 N). The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo. The resulting residue was triturated with EtOAc to deliver the hydrochloride salt of the title compound (0.12 g, 70% over 2 steps) as a brown solid. 1H NMR (400 MHz, DMSO-d6, T=80° C.) δ 9.38 (br s, 1H), 9.11 (br s, 1H), 8.11 (d, 0.75H), 8.08 (d, 0.25H), 7.57 (d, 1H), 7.52-7.46 (m, 2H), 7.28-7.17 (m, 4H), 6.61 (d, 0.25H), 6.49 (d, 0.75H), 4.02 (s, 3H), 3.98-3.94 (m, 1H), 3.90 (s, 3H), 3.76-3.67 (m, 1H), 3.61-3.50 (m, 1H), 3.28-3.15 (m, 1H), 2.86-2.64 (m, 2H), 1.90-1.69 (m, 3H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH2:6])[C:4]#[CH:5].[CH3:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>O>[CH2:3]([NH:6][S:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH3:7])[CH:9]=1)(=[O:16])=[O:15])[C:4]#[CH:5]
Reactant: C#CCN
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCNS(=O)(=O)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.7 %

Procedure:
Sodium hydroxide (0.60 g, 15 mmol) was dissolved in 10 ml of water and 0.66 g of propargylamine (12 mmol) was added thereto. Under ice-cooling, 1.91 g of 3-methylbenzenesulfonyl chloride (10 mmol) was added dropwise to the solution. The reaction temperature was raised again to room temperature and the mixture was stirred for 3 hours. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated to obtain N-propargyl-3-methylbenzenesulfonamide (2.17 g). NMR spectrum of this product was as follows.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:19][Si:20]([C:23]#[C:24][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)([CH3:22])[CH3:21]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#C[Si](C)(C)C)cc2)CC1

Procedure:
10.00 g (32.36 mmol) of 1-bromo-4-(trans-4-pentylcyclohexyl)benzene, 3.89 g (35.60 mmol) of trimethylsilylacetylene, 0.45 g (0.65 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.062 g (0.32 mmol) of copper(I) iodide are heated for 6 hours at the reflux temperature in 100 ml of diisopropylamine. The solvent is subsequently stripped off, and the soluble constituents of the residue are chromatographed on silica gel using n-hexane, giving 7.32 g of 1-(trimethylsilylethynyl)-4-(trans-4-pentylcyclohexyl)benzene, ##STR5## which is stirred for 1 hour at room temperature in 220 ml of methanol with 1.38 g (24.70 mmol) of potassium hydroxide. Work-up by evaporation of the solvent, partitioning between ether and water, drying and evaporation of the organic phase gives 4.95 g of 1-ethynyl-4-(trans-4-pentylcyclohexyl)benzene. ##STR6##
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.C(OCC)(=[O:28])C.O>>[OH:28][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N:12]3[C:20]4[CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][C:16](=[O:23])[C:15]=4[C:14]([CH3:24])=[CH:13]3)=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1cn(-c2ccc3c(N)ncnc3c2)c2c1C(=O)CC(C)(C)C2
Agent: Cl
Solvent: O
Product: Cc1cn(-c2ccc3c(O)ncnc3c2)c2c1C(=O)CC(C)(C)C2
Yield: 60 %

Procedure:
1-(4-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.2 g 0.62 mmol) is microwaved at 80 degrees Celsius for 300 seconds in the presence of excess 36% HCl. The crude product is taken up in ethyl acetate/water. The organic phase is dried over magnesium sulfate, filtered, concentrated and chromatographed to afford 1-(4-hydroxyquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one as a solid (0.12 g, 60%). LC/MS m/z=322 [M+H]+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[NH:14][C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]=2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][O:29][CH2:28]1>CN(C=O)C>[CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:25][CH2:26][C@@H:27]2[CH2:31][CH2:30][O:29][CH2:28]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: BrCC[C@@H]1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CC[C@@H]3CCOC3)c2n1
Temperature: 60 °C
Yield: 79.6 %

Procedure:
N2-Butyl-8-(methyloxy)-3H-purine-2,6-diamine (157 mg, 0.447 mmol) was heated in dry DMF (3 ml) with potassium carbonate (232 mg, 1.675 mmol) at 60° C. for one hour. (3S)-3-(2-Bromoethyl)tetrahydrofuran (100 mg, 0.558 mmol) in dry DMF (2 ml) was added and the mixture stirred and heated to 60° C. under nitrogen for 4 hours. The mixture was cooled to room temperature, quenched into water (40 ml) and extracted with ethyl acetate (3×25 ml). The organic extracts were combined, dried by passage through a hydrophobic frit and concentrated under vacuum. The residue was dissolved in 1:1 MeOH:DMSO and purified by mass directed autopreparation. The desired fractions were combined and concentrated using a nitrogen blowdown unit to give the title compound as a white solid (119 mg).