Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH2:2][CH2:3][CH3:4].[NH4+:32].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)Cl>ClCCCl>[NH2:32][C:9]1[C:8]2[N:18]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (3.68 g, 8.60 mmol) in 100 mL of 1,2-dichloroethane was heated to 80° C. and treated with 10 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (1.87 g, 9.81 mmol) over a 10 min period. The reaction mixture was then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CH2Cl2. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (3×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 3.68 g of tert-butyl 2-[2-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.CO.[C].[Pd]>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][N:21]4[CH2:22][CH2:23][CH2:24]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:28]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(CN2CCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCC4)CC3)c2)c(F)c1
Reaction time: 5 h
Yield: 97.7 %

Procedure:
4-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]amide (33 mg) was dissolved in tetrahydrofuran (1 ml) and methanol (1 ml), and then 10% palladium carbon (17 mg) was added thereto, followed by stirring under a hydrogen atmosphere for 5 hrs. The reaction mixture was filtered to remove the catalyst, and the catalyst was washed with methanol. The filtrate was concentrated under reduced pressure to give a crude product of 4-(azetidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (30 mg) as a pale yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH3:26])[CH:18]=2)[S:6]1(=[O:16])=[O:15]
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(N2c3ccccc3CN(CCCCl)S2(=O)=O)c1

Procedure:
In an analogous manner to Example 1 step 7, 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (408 mg) was coupled to m-tolylboronic acid to provide 3-(3-chloropropyl)-1-(3-methylphenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (39 mg):
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[O:43]=[C:44]1[NH:48][CH2:47][CH:46]([C:49](O)=[O:50])[CH2:45]1>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([CH:46]3[CH2:45][C:44](=[O:43])[NH:48][CH2:47]3)=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: O=C1CC(C(=O)O)CN1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)C2CNC(=O)C2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and 5-oxopyrrolidine-3-carboxylic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.04 minutes; C30H35ClN6O4 (579.10); mass spectrum: (M−H)−=578.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]([NH2:13])=[N:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24]N[CH2:22][CH2:21]1.[CH:26](N(CC)C(C)C)(C)C.CS(C)=O>Cl.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:2][C:3]1([CH3:26])[CH:18]=[C:7]2[NH:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[N:11]=[C:12]([N:13]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[C:6]2=[CH:5][CH2:4]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc2c(c1)Nc1ccccc1N=C2N
Reactant: CN1CCNCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN1CCN(C2=Nc3ccccc3NC3=CC(C)(C)CC=C32)CC1
Temperature: 110 °C
Reaction time: 48 h
Yield: 39.5 %

Procedure:
Combine 3-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (636.4 mg, 2.85 mmol), N-methylpiperazine (444.2 mg, 3.08 mmol), N,N-diisopropylethylamine (856.5 mg, 8.55 mmol), DMSO (2.0 ml), and toluene (4.0 ml). Stir and heat the mixture at 110° C. After 48 hours, add one drop of 5N HCl. After 72 hours, cool the mixture to ambient temperature and then dilute it with ethyl acetate. Wash the organic layer with DI H2O and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 362.9 mg (42%) of a tan foam: mp 84°, dec; mass spectrum (ion spray): m/z=307.1 (M+1).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH2:9][CH2:8][C:7]3[S:10][C:11]([NH:13][C:14]([C:16]45[CH2:23][CH:22]6[CH2:24][CH:18]([CH2:19][CH:20]4[CH2:21]6)[CH2:17]5)=[O:15])=[N:12][C:6]=3[C:5]=12.[CH3:25][O:26][CH2:27][CH2:28]Br>>[CH3:25][O:26][CH2:27][CH2:28][N:12]1[C:6]2[C:5]3=[N:1][O:2][N:3]=[C:4]3[CH2:9][CH2:8][C:7]=2[S:10]/[C:11]/1=[N:13]\[C:14]([C:16]12[CH2:17][CH:18]3[CH2:24][CH:22]([CH2:21][CH:20]1[CH2:19]3)[CH2:23]2)=[O:15]
Reactant: COCCBr
Reactant: O=C(Nc1nc2c(s1)CCc1nonc1-2)C12CC3CC(CC1C3)C2
Product: COCCn1c2c(s/c1=N\C(=O)C13CC4CC(CC1C4)C3)CCc1nonc1-2

Procedure:
The product from Example 71B and 2-bromoethyl methyl ether were processed according to the method of Example 1B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44-1.70 (m, 4H), 1.70-1.87 (m, 4H), 2.14 (d, J=11.2 Hz, 2H), 2.29 (s, 2H), 2.59 (t, J=6.8 Hz, 1H), 3.13 (t, J=7.1 Hz, 2H), 3.21-3.30 (m, 5H), 3.63-3.85 (m, 2H), 4.69 (t, J=5.8 Hz, 2H); MS (ESI+) m/z 401 (M+H)+; Anal. Calculated for C20H24N4O3S: C, 59.98; H, 6.04; N, 13.99. Found: C, 59.90; H, 6.09; N, 13.95.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25]([NH2:29])(=[O:28])[CH:26]=[CH2:27]>CN(C)C=O>[C:25]([CH2:26][CH2:27][N:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:20])[CH2:15][CH2:16]1)(=[O:28])[NH2:29]
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: C=CC(N)=O
Solvent: CN(C)C=O
Product: NC(=O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Temperature: 140 °C
Yield: 49.7 %

Procedure:
A mixture of 3.31 g (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid and 4.2 g (0.058 mole) of acrylamide in 50 ml of dimethylformamide is heated at 140° C. for 6 hours. The suspension is concentrated under a high vacuum and the residue is stirred with water and recrystallised from glycol monomethyl ether. 2 g (50% of theory) of 7-[4-(2-carbamoylethyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of decomposition point 283° to 286° C. are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH3:25][N:26]([NH2:28])[CH3:27]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:28][N:26]([CH3:27])[CH3:25])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: CN(C)N
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NN(C)C
Yield: 83.8 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.9 ml (0.025 mol) of unsym-dimethylhydrazine in 30 ml of DMF were reacted affording a residue which was recrystallized in hot hexane to give 4.57 g (83.8%) of product as a yellow solid; mp 97°-98° C.
Reaction SMILES: [C:1]([S:5][CH2:6][C@@:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])([CH3:4])([CH3:3])[CH3:2].CO.S(=O)(=O)(O)[OH:18].C(O)(C)C.OO.O>[Cl-].[Na+]>[C:1]([S:5]([CH2:6][C@@:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)SC[C@@]1(C)NC(=O)NC1=O
Reactant: O=S(=O)(O)O
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(C)S(=O)C[C@@]1(C)NC(=O)NC1=O
Yield: 50 %

Procedure:
(5S)-5-[(Tert-butylthio)methyl]-5-methylimidazolidine-2,4-dione (1.00 eq, 46.2 mmol, 10.0 g) was charged to a vessel followed by methanol (2.64 mol, 107 mL, 84.5 g). The resulting clear solution was stirred and a solution of sulfuric acid, 4.40% w/w in iso-propanol (6.22 mmol, 13.9 mL, 13.9 g) was added. To this mixture was then added a solution of hydrogen peroxide, 11.68M, 35% w/w in water (107 mmol, 9.13 mL, 10.4 g) in one portion without external cooling (an exotherm from 22° C. to 41° C. over 10 min was noted). Hplc analysis of the reaction mixture approximately 1.5 h after the addition of the hydrogen peroxide revealed complete consumption of the starting material and the appearance of two new peaks (diastereoisomeric sulfoxides). The mixture was diluted with saturated aqueous sodium chloride solution (231 mL) and extracted with dichloromethane (2×250 mL). The combined organic phases were extracted with water (2×200 mL). The aqueous phase was evaporated to dryness under reduced pressure (water bath temperature 40° C.) to give (5S)-5-[(tert-butylsulfinyl)methyl]-5-methylimidazolidine-2,4-dione as white crystals (0.497 eq, 23.0 mmol, 5.34 g) in 50% yield as a 71:29 mixture of diastereoisomers (by comparison of 1H NMR integrals).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](O)[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>N1C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([SH:14])[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: Nc1nc(O)c2cccnc2n1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Nc1nc(S)c2cccnc2n1

Procedure:
2-Amino-4-hydroxypyrido[2,3-d]pyrimidine (8.1 gm) is heated to boiling for ten hours with phosphorus pentasulfide (25 gm) in pyridine (125 ml). After the solvent has been distilled off, the residue is triturated with water, made alkaline with sodium hydroxide solution, and purified with activated charcoal, and the filtrate is acidified with acetic acid. The yellow fine crystalline powder precipitate is washed with water and dried.
Reaction SMILES: CI.[C:3]([O-])([O-])=O.[K+].[K+].[O:9]=[C:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>CC(C)=O>[CH3:3][CH:11]([C:10](=[O:9])[CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CC(=O)C(C)C(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 55.5 %

Procedure:
Methyl iodide (6.86 mL, 1.1 eq) and K2CO3 (17.97 g, 1.3 eq) were added to an acetone (400 mL) solution of tert-butyl 3-oxobutanoate (15.82 g, 100 mmol) at room temperature. After 15 h, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate (300 mL), washed with water (30 mL) and brine (300 mL), dried (MgSO4) and concentrated. The crude residue was purified by silica gel chromatography (5-10% EtOAc-hexanes) to give tert-butyl 2-methyl-3-oxobutanoate as a colorless oil (9.56 g, 56%). MS found: (M+Na)+=195.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(O)(=O)C.O[C@@H:10]1[C@@:34]2([CH3:35])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13][C@@H:12]([OH:37])[CH2:11]1.[OH-].[K+].C(O)(=O)C.O>C(OCC)C.CO>[C:1]([O:4][C@@H:10]1[C@@:34]2([CH3:35])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13][C@@H:12]([OH:37])[CH2:11]1)(=[O:3])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC(=O)O[C@H]1C[C@H](O)CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@]21C
Yield: 107.8 %

Procedure:
A solution of 600 mg of 1α-hydroxycholesterol diacetate (16) in 1.6 ml of diethyl ether was cooled to ice-bath temperature and 1.6 ml of 0.1 N KOH in methanol was added slowly with stirring. After stirring for 2.5 hours, acetic acid (0.25 ml) and water was added, the mixture was extracted with ether (3×), combined extracts were dried (Na2SO4) and evaporated to dryness to give 0.55 g of 1α-acetoxycholesterol (17), homogeneous on tlc. nmr (CDCl3) δ5.55 (1H, broad, C-6), 5.00 (1H, m, C-1), 3.62 (1H, m, C-3), 2.10 (3H, s, OAc).
Reaction SMILES: [F:1][C:2]([F:33])([CH:30]([F:32])[F:31])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][N:15]3[CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[F:33][C:2]([F:1])([CH:30]([F:32])[F:31])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][C@@H:16]3[CH2:18][C@H:13]2[CH2:14][N:15]3[CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3Cc2ccc(OCC(F)(F)C(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN2C[C@@H]3C[C@H]2CN3Cc2ccc(OCC(F)(F)C(F)F)cc2)cc1
Yield: 52.9 %

Procedure:
Methyl 4-[[(1S,4S)-5-[[4-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate (177 mg, 0.38 mmol) was stirred with 1.9 mL aqueous sodium hydroxide solution (2 M) in 3.9 mL methanol overnight at room temperature, and then concentrated under reduced pressure. The residue was diluted with water, adjusted to pH 8 with 1 M aqueous hydrochloric acid, and extracted with butanol. The combined organic layers were concentrated under reduced pressure. Flash chromatography gave 91 mg of 4-[[(1S,4S)-5-[[4-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoic acid; 1H NMR (300 MHz, CD3OD) δ7.92 (d, 2H), 7.41 (d, 2H), 7.40 (d, 2H), 7.02 (d, 2H), 6.32 (tt, 1H), 4.45 (tt, 2H), 3.98 (d, 2H), 3.88 (d, 2H), 3.69 (br s, 1H), 3.64 (br s, 1H), 3.17 (d, 1H), 3.12 (d, 1H), 2.90 (dd, 1H), 2.85 (dd, 1H), 2.02 (s, 2H) ppm.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(C1C=CC=CC=1)C.C1COCC1.[CH3:22][Si:23]([CH3:40])([CH3:39])[CH2:24][CH2:25][O:26][CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[N:30]=[CH:29]1.[Cl:41][C:42]1[CH:59]=[CH:58][C:45]([CH2:46][N:47]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]([CH:56]=[O:57])=[CH:48]2)=[CH:44][CH:43]=1>C1COCC1>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:46][N:47]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]([CH:56]([C:29]3[N:28]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:40])([CH3:39])[CH3:22])[CH:32]=[C:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[N:30]=3)[OH:57])=[CH:48]2)=[CH:58][CH:59]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccccn2)c1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(-c2ccccn2)nc1C(O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Lithium diisopropylamide (2 M solution in petane/ethylbenzene/THF, 57 uL, 0.12 mmol) was added to a stirred solution of 2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridine (10.5 mg, 0.038 mmol) in dry THF (3 mL) at −78° C. under N2. After 1 hour at this temperature, a solution of N-4-chlorobenzylindole-3-carboxaldehyde (31 mg, 0.12 mmol) in dry THF (1 mL) was then added through a cannula. The resultant clear solution was stirred at −78° C. for 2 hours. The temperature was then allowed to rise to room temperature and the reaction was quenched by the addition of saturated aqueous NH4Cl (5 mL), extracted with dichloromethane (3×10 mL). The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure. Flash silica gel chromatography (4:1 hexane/ethyl acetate then 2:1 ethyl acetate/hexane then 4:1 ethyl acetate/MeOH) provided the product [1-(4-Chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol as a light yellow syrup (18 mg, 87%). 1H NMR δ−0.05 (s, 9H), 0.81 (t, 2H, J=7), 3.38 (t, 2H, J=7), 5.05-5.35 (m, 5H), 6.30 (s, 1H), 6.95-7.30 (m, 9H), 7.45 (d, 1H, J=6), 7.65 (s, 1H), 7.71 (t, 1H, J=6), 8.05 (d, 1H, J=6), 8.60 (d, 1H, J=4)ppm; ESMS calcd for (C30H33ClN4O2Si): 544.2; found: 545.2 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[OH2:12]>>[CH:8]1([O:12][CH2:1][CH2:2][C:3]#[CH:4])[CH2:7][CH2:6][CH2:11][CH2:10][CH2:9]1
Reactant: O
Reactant: CCCCCC
Reactant: [Li]CCCC
Product: C#CCCOC1CCCCC1
Temperature: 25 °C
Yield: 71 %

Procedure:
Furthermore, to a solution of 4-cyclohexyloxy-1,1-dibromobut-1-ene (12.6 g, 40.4 mmol) obtained above in tetrahydrofuran (130 ml) was added a 1.5M solution of n-butyllithium in hexane (54 ml, 81.0 mmol) at −78° C. with stirring under a nitrogen atmosphere, and the resulting mixture was stirred at −78° C. for 1 hour. After stirring, the reaction temperature was raised slowly to room temperature with stirring, and the reaction mixture was stirred furthermore at room temperature for 50 minutes. After stirring, water was added to the reaction mixture with stirring under ice-cooling to quench the reaction, and then the resulting mixture was extracted with ether. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (100:1–50:1) as the eluent to afford the title compound (4.35 g, yield: 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:30]1[CH2:34][CH2:33][CH:32]([CH2:35]O)[CH2:31]1.[K+].[Br-].Cl>>[O:30]1[CH2:34][CH2:33][CH:32]([CH2:35][O:24][C:23]([C:18]2([C:20]([O:22][CH2:35][CH:32]3[CH2:33][CH2:34][O:30][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:31]1
Reactant: OCC1CCOC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC1CCOC1)(C(=O)OCC1CCOC1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and tetrahydrofuran-3-ylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 1.03 (d, J=6.37 Hz, 3H, CH3), 1.5 (m, 2H, CH2), 1.9 (m, 2H, CH2), 2.6 (m, 3H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 3.6-3.7 (m, 6H, CH2), 4.1-4.15 (m, 6H, CH2), 5.09 (m, 1H, CH), 6.36 (brs, 1H, OH), 6.86 (m, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.38-7.42 (m, 3H, Ar--H), 7.47 (s, 1H, Ar--H), 8.84 (brs, 2H, NH, NH); IR (KBr, cm-1) 3300 (OH), 2900 (NH), 1760 (CO); MS m/e 590 (M+H)+ ; Analysis for: C30H36ClNO9 ×HCl: Calc'd: C, 57.51; H, 5.95; N, 2.24; Found: C, 57.80; H, 6.30; N, 2.21.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:44]1([S:48]([NH2:51])(=[O:50])=[O:49])[CH2:47][CH2:46][CH2:45]1>CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:51][S:48]([C:44]3([CH3:45])[CH2:46][CH2:47]3)(=[O:50])=[O:49])=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)C1CCC1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2(C)CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Yield: 53.6 %

Procedure:
Prepared from 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid etherate (114 mg, 0.192 mmol) and cyclobutanesulfonic acid amide (34 mg, 0.25 mmol) as described in the general procedure above. Flash chromatography (2% methanol/methylene chloride) gave 73 mg (58%) of [18-(isoquinolin-1-yloxy)-4-(1-methyl-cyclopropanesulfonylaminocarbonyl)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: LC-MS (Method A, retention time: 3.55 min), MS m/z 710 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.[NH:10]1[CH2:16][CH:15]([OH:17])[CH2:14][NH:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>CCO>[Br:1][C:2]1[C:3]([N:10]2[CH2:16][CH:15]([OH:17])[CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][C:5]([I:8])=[CH:6][CH:7]=1
Reactant: OC1CNCCNC1
Reactant: Fc1nc(I)ccc1Br
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: OC1CNCCN(c2nc(I)ccc2Br)C1
Yield: 87.2 %

Procedure:
A solution of 3-bromo-2-fluoro-6-iodopyridine (1.00 g, 3.4 mmol), 1,4-diazepan-6-ol (510 mg, 4.4 mmol), and DIPEA (2 mL) in EtOH (6 mL) in a sealed tube was stirred at 100° C. for 20 hours. The reaction mixture was concentrated under reduced pressure to give a residue (1.18 g), which was used for the next step without further purification. MS (ESI) m/z: 398 [M+H]+.