Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([Si](C)(C)C)=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[K+].[Br-:24].CO.ClN1C(=O)CCC1=O>C(O)(=O)C>[Br:24][C:16]1[CH:17]=[CH:18][C:13]([C:2]2([OH:1])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]2)=[CH:14][CH:15]=1
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc([Si](C)(C)C)cc2)C1
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(Br)cc2)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
A mixture of tert-butyl 3-hydroxy-3-(4-(trimethylsilyl)phenyl)azetidine-1-carboxylate (Preparation 3, 45 g, 0.14 mol) and KBr (25 g, 0.21 mol) in acetic acid (10 and MeOH (100 mL) was heated at 60° C. for 20 minutes. Then N-chlorosuccinimide (22.4 g, 0.17 mol) was added to the reaction mixture and stirred at 60° C. for 2 hours. LC/MS indicated the reaction was complete (only product peak). After cooling to ambient temperature, the mixture was poured into ice-water (1 L). The mixture was extracted with CHCl3 (2×800 mL). The combined organics were washed with 3M NaOH (2×600 mL), water (600 mL), dried over sodium sulfate, filtered and concentrated. The crude product was washed with ether to afford the desired product (35 g, 76% yield). 1H NMR (CDCl3) δ 7.5 (d, 2H), 7.4 (d, 2H), 4.2 (s, 4H), 3.4 (s, 1H), 1.4 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:18]=[C:17]([OH:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:21]1([C:24]2[C:29]([CH2:30]O)=[CH:28][N:27]=[C:26]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)[N:25]=2)[CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:18]=[C:17]([O:19][CH2:30][C:29]2[C:24]([CH:21]3[CH2:23][CH2:22]3)=[N:25][C:26]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=3)=[N:27][CH:28]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: CCOC(=O)C(C)(C)Oc1cc(O)c2ccccc2c1
Product: CCOC(=O)C(C)(C)Oc1cc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)c2ccccc2c1

Procedure:
A] In analogy to the procedures described in example 4D] and 4E], 2-(4-hydroxy-naphthalen-2-yloxy)-2-methyl-propionic acid ethyl ester (example 17D]) was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol (example 9D]) to give 2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-naphthalen-2-yloxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Li]C(C)(C)C.CN([CH:20]=[O:21])C.Cl>C1COCC1.C(OCC)C>[CH:8]([C:6]1[CH:5]=[CH:4][C:3]([CH3:11])=[C:2]([CH:7]=1)[CH:20]=[O:21])([CH3:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(C)C)cc1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C(C)C)cc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-4-isopropyl-1-methyl-benzene (863 mg, 4.0 mmol) in 10 mL of THF is added a solution of t-BuLi (1.7 M in pentane, 4.7 mL) dropwise at below −70° C. After addition, the reaction mixture is stirred at −78° C. for one hour. A solution of DMF (0.46 mL) in 1 mL of THF is added at the same temperature and stirred for additional one hour. The reaction mixture is allowed to warm to room temperature then poured into a mixture containing ice (50 g) and concentrated HCl (2 mL) and stirred for 15 minutes. To the mixture, ethyl ether (20 mL) is added. The organic layer is separated and the aqueous layer is extracted with ethyl ether. The organic solutions are combined, washed with brine, dried and concentrated to give 600 mg of 5-isopropyl-2-methyl-benzaldehyde. 1H NMR: (CDCl3) 10.27 (s, 1H), 7.66 (d, 1H), 7.34 (d, 1H), 7.17 (d, 1H), 2.94 (m, 1H), 2.63 (s, 3H), 1.24 (d, 6H).
Reaction SMILES: Cl[CH:2]([O:4][CH2:5][CH3:6])[CH3:3].[CH2:7]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([O-:30])=[O:29])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:7]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH:2]([O:4][CH2:5][CH3:6])[CH3:3])=[O:29])=[CH:31][CH:32]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Reactant: CCOC(C)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)OCC)cc1
Reaction time: 3 h

Procedure:
A mixture of 22.0 g. of ethyl 1-chloroethyl ether, 77.0 g. of sodium 4-(hexadecylamino)benzoate and 250 ml. of hexamethylphosphoramide is stirred at 20° C. for 24 hours. After slow addition of water to the crystallization point and standing for 3 hours, the acetal ester is collected on a filter.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][C@@H:6]([CH:9]([CH3:11])[CH3:10])[C@H:5]([O:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18]Cl)[CH3:16])[CH2:4]1.C(O)(C)C.[CH:24]([NH2:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:2][C@@H:3]1[CH2:8][CH2:7][C@@H:6]([CH:9]([CH3:11])[CH3:10])[C@H:5]([O:12][CH2:13][CH2:14][N:15]([CH2:17][CH2:18][NH:27][CH:24]([CH3:26])[CH3:25])[CH3:16])[CH2:4]1
Reactant: CC(C)N
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCCN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)NCCN(C)CCO[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Yield: 100 %

Procedure:
5 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclohex-3-yloxy)ethyl]-N-(2-chloro ethyl)-N-methylamine hydrochloride were added to a mixture of 50 ml isopropanol and 50 ml water. 1.9 g of isopropylamine and 7.7 g of potassium carbonate were then added, and the reaction mixture was heated under reflux for 5 hours. The reaction mixture was worked up by diluting it with 100 ml of water and extracting the solution with ethyl acetate. The organic phase was worked up as described in Example 1 C). 4.78 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcyclo hex-3-yloxy)ethyl]-N-[2-(isopropylamino)ethyl]-N-methylamine were obtained. The free base was then converted into the corresponding hydrochloride analogously to Example 1 D). 5.1 g of N-[2-((1R,3R,4S)-1-methyl-4-isopropylcycl ohex-3-yloxy)ethyl]-N-[2-(isopropylamino)ethyl]-N-methylamine dihydrochloride having a melting point of 156° C.-158° C. were obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A150) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:30][CH:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:28]1>CN(C1C=CN=CC=1)C.CC#N>[C:34]([O:33][C:32](=[O:38])[NH:31][CH:29]1[CH2:30][N:27]([S:23]([C:21]2[CH:20]=[CH:19][C:8]3[N:9]([CH2:10][CH:11]4[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]4)[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:22]=2)(=[O:25])=[O:24])[CH2:28]1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)C1
Yield: 74 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.41 g, 1.0 mmol), tert-butyl azetidin-3-ylcarbamate (0.17 g, 1.0 mmol) and DMAP (0.37 g, 3.0 mmol) in MeCN (20 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 0.40 g (74%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.33 (s, 9 H), 1.48-1.62 (m, 2 H), 1.64 (s, 9 H), 1.67-1.87 (m, 4 H), 1.98-2.15 (m, 2 H), 2.19-2.35 (m, 1 H), 3.62 (t, J=7.03 Hz, 2 H), 3.96 (t, J=8.11 Hz, 2 H), 4.05-4.16 (m, 1 H), 4.51 (d, J=7.42 Hz, 2 H), 7.86 (dd, J=9.18, 1.17 Hz, 1 H), 7.98 (d, J=8.79 Hz, 1 H), 8.14 (d, J=1.56 Hz, 1 H); MS (ESI) (M+H)+=541.3; Anal. Calcd for C26H38F2N4O4S+1.00 TFA+0.20 EtOAc (674.72): C, 51.62; H, 6.07; N, 8.30. Found: C, 51.73; H, 5.94; N, 8.27.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([CH2:2][CH2:3][NH:4][C:5]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][C:7]([O:9][CH3:10])=[O:8])(=[O:26])=[O:25]
Reactant: COC(=O)C=C(CC(=O)OC)NCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C=C(CC(=O)OC)NCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
The solution of dimethyl 3-(2-hydroxyethylamino)-2-pentenedioate was cooled to 0° C., and triethylamine (235 mL, 170.6 g, 1.69 mol) was added in one portion. Methanesulfonyl chloride (168.8 g, 1.47 mol) was added dropwise via an addition funnel over 3.75 hours, with the temperature rising to 5°-7° C. The medium-yellow slurry darkened to yellow-orange as the last 10 mL methanesulfonyl chloride was added. The mixture was stirred at 0° C. for an additional 2 hours, and water (250 mL) added. The organic phase was washed with water (4×500 mL) and brine (250 mL), and dried overnight over anhydrous magnesium sulfate. After filtration, the solvents were evaporated on a rotary evaporator under reduced pressure at 50° C. to afford 310.0 g (93% yield) of dimethyl 3-(2-methanesulfonylethylamino)-2-pentenedioate as a red oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[CH3:15])[CH2:2][CH2:3][CH3:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[Br:39]N1C(=O)CCC1=O>O>[CH2:1]([O:5][C:6]1[C:7]([CH2:15][Br:39])=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc([N+](=O)[O-])cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCCOc1ccc([N+](=O)[O-])cc1CBr
Reaction time: 8 h

Procedure:
To a stirred and gently refluxing mixture of 256 parts of butyl (5-nitro-o-tolyl)ether, 1 part of benzoyl peroxide and 4800 parts of anhydrous carbon tetrachloride is added, over a one-day period, a mixture of 213.6 parts of N-bromosuccinimide and 1 part of benzoyl peroxide. Upon completion, stirring at gentle reflux is continued overnight. The reaction mixture is cooled and water is added. The organic layer is separated, washed with water, dried, filtered and evaporated. The oily residue is crystallized on standing overnight in 2-propanol, yielding 189.7 parts of (α-bromo-5-nitro-o-tolyl) butyl ether; mp. 64° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1.[CH3:17][NH2:18]>O1CCOCC1>[CH3:17][NH:18][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[CH:8]=[C:7]3[O:14][CH2:15][O:16][C:6]3=[CH:5][C:4]=2[N:3]=1
Reactant: CN
Reactant: O=Cc1cc2cc3c(cc2nc1Cl)OCO3
Solvent: C1COCCO1
Product: CNc1nc2cc3c(cc2cc1C=O)OCO3
Temperature: 160 °C
Reaction time: 0.42 h
Yield: 99 %

Procedure:
To a stirred solution of 6-chloro[1,3]dioxolo[4,5-g]quinoline-7-carboxaldehyde (1.14 g, 4.84 mmol) in 1,4-dioxane (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added methylamine (40 wt. %, 4.0 mL, 46.2 mmol) and the reaction mixture was stirred for 25 min at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:2 N aq. HCl=1:1 (10 mL) and stirred for 20 min at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with a 10 N aqueous NaOH solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under vacuum to give 6-(methylamino)-[1,3]dioxolo[4,5-g]quinoline-7-carbaldehyde CCH 34158-1 as a yellow solid (1.10 g, 99% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]([C:34](Cl)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1>N1C=CC=CC=1>[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]([C:34]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][C:9]([C:12]([N:14]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[CH2:18][N:17]5[CH:25]=[CH:26][CH:27]=[C:16]5[CH2:15]4)=[O:13])=[CH:8][CH:7]=3)=[N:2]2)=[O:35])=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccc(-c2ccn(C(=O)c3ccccc3-c3ccccc3)n2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 45.8 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.71 g) in dry pyridine (20 ml) and 2-biphenylcarbonyl chloride (0.65 g), the title compound (0.49 g) was obtained as an amorphous solid, MS, Hz: 534 (M)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16]([OH:21])=[C:17]([OH:20])[CH:18]=[CH:19][C:11]=2[CH2:10]1.C([O-])(=O)C.[Na+]>O>[C:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[C:16]([OH:21])=[C:17]([OH:20])[CH:18]=[CH:19][C:11]=2[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCCc2c(ccc(O)c2O)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NC1CCCc2c(ccc(O)c2O)C1
Reaction time: 4 h

Procedure:
Acetic anhydride is added to a mixture of 6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,2-diol Cannon, J. G., et al., J. Med. Chem., 27, 922(1984)! in water containing sodium acetate. The mixture is chilled and stirred in ice for 4 hours followed by filtration to give N-acetyl-6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,2-diol. Benzyl bromide, powdered potassium carbonate and acetone is added to the isolated N-acetyl-6-amino-6,7,8,9-tetrahydro-5H-benzocycloheptene-1,2-diol and the mixture is stirred for 18 hours. The reaction mixture is poured into water, extracted and concentrated in vacuo to give N-acetyl-6-amino-1,2-dibenzyloxy-6,7,8,9-tetrahydro-5H-benzocycloheptene. Hydrolysis with ethanolic sodium hydroxide gives 6-amino-1,2-dibenzyloxy-6,7,8,9-tetrahydro-5H-benzocycloheptene.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:27])[C:17]=2[N:16]=[C:15]1[CH2:28][CH2:29][CH2:30][CH3:31].O.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH2:27][C:18]1[C:17]2[N:16]=[C:15]([CH2:28][CH2:29][CH2:30][CH3:31])[N:14]([CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[S:9])[C:26]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: S=C=Nc1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=S)Nc1ccccc1
Yield: 65.4 %

Procedure:
Phenyl isothiocyanate (750 mg, 5.55 mmol) was added dropwise with stirring to a chilled (0° C.) solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.36 mmol) in 1-methyl-2-pyrrolidinone (50 mL). The reaction mixture was poured into water (500 mL) and the pH adjusted to 10 with solid potassium carbonate. The resulting precipitate was isolated by filtration and then rinsed with water. This material was slurried with hot methanol and then purified by column chromatography (silica gel eluting with 2% methanol in dichloromethane to 7% methanol in dichloromethane). The purified material was recrystallized from isopropanol to provide 950 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylthiourea as a white solid, m.p. 142.8-144.0° C. Analysis: Calculated for C24H28N6S. C3H8O: %C, 65.82; %H, 7.37; %N, 17.06; Found: %C, 65.77; %H, 7.41; %N, 17.11.
Reaction SMILES: [C:1]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:23][C:24]1[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:26][N:25]=1.Cl>N1C=CC=CC=1>[C:1]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:23][C:24]2[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:26][N:25]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1nnc(N)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(C(=O)OCC)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 65 %

Procedure:
To a solution of 4-decanamidobenzenesulfonyl chloride (220 mg, 0.64 mmol) in pyridine (4 mL) was added ethyl 5-amino-1,3,4-thiadiazole-2-carboxylate (100 mg, 0.58 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×30 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1 to give the product as a solid, mp 101-102° C., in 65% yield (183 mg, 0.38 mmol); 1H NMR (300 MHz, DMSO-d6) δ 0.83 (t, 3H, J=6.6 Hz), 1.22-1.32 (m, 15H), 1.56 (m, 2H), 2.31 (t, 2H, J=6.0 Hz), 4.33 (q, 2H, J=7.6 Hz), 7.71 (m, 4H), 10.19 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.6, 14.6, 22.8, 25.6, 29.3, 29.4, 29.5, 29.6, 31.3, 31.9, 37.1, 62.8, 119.1, 127.6, 136.8, 143.2, 147.7, 159.2, 170.3, 172.5; MS (LCQ, ESI+) Calcd for C21H31N4O5S2 483.2, found 483.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C21H31N4O5S2 483.1736, found 483.1728 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.C1C([N+]([O-])=[O:14])=CC=C(O)C=1.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCOCC1>[CH:26]1([NH:25][C:24]([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:14])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 3 h

Procedure:
The succinylated 2-azetidinone is dissolved in dioxane (10 ml). Anhydrous pyridine (1 ml) and p-nitrophenol (0.2 g) are added followed by dicyclohexylcarbodiimide (0.6 g, 2.5 mmole). Stirring is continued for 3 hours. The dicyclohexyl-urea formed is filtered and the filtrate is added to controlled pore glass (5 g) suspended in dimethylformamide (5 ml). Triethylamine (2 ml) is added and briefly shaken. After leaving it overnight, the CPG is filtered, washed with methanol, ether and air dried.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.CCO.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=O.N#N>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:17]([CH:18]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1)=[O:20])[CH3:23]
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)C=O
Agent: Cl
Agent: N#N
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1NCCc2c1[nH]c1ccccc21
Yield: 66.6 %

Procedure:
2,3,4,9-Tetrahydro-1H-betacarboline-1-carboxylic acid ethyl ester was prepared by the addition of tryptamine-HCl (1.33 g, 6.76 mmol), EtOH (12 mL), and a 50% toluene solution of ethyl glyoxylate (1.66 g, 8.11 mmol) to a 50 mL flask purged with N2. The reaction solution was allowed to reflux 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude material was chromatographed (SiO2, 100% DCM to 4% MeOH) to provide 1.10 g (68% yield) of 2,3,4,9-tetrahydro-1H-betacarboline-1-carboxylic acid ethyl ester; 1H NMR (CDCl3) δ 8.59 (1H, br s), 7.46 (1H, d), 7.39 (1H, d), 7.23 (1H, t), 7.14 (1H, t), 5.40 (1H, s), 4.24 (2H, q), 3.51 (1H, m), 3.07 (1H, m), 2.86 (1H, d), 1.30 (3H, t); 13C NMR (CDCl3) 6166, 137, 126, 123, 122, 120, 119, 112, 108, 64, 60, 53, 41, 14; MS(ESI): 245 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:20]3[C:21]([CH3:27])=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:28][CH3:29])[C:3]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1.[H-].[Na+].[C:43](OC(=O)C)(=[O:45])[CH3:44]>CN(C=O)C>[C:43]([O:13][C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([O:28][CH3:29])[C:3]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=1)=[C:2]2[Cl:1])([C:20]1[C:21]([CH3:27])=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[C:14]1[N:18]([CH3:19])[N:17]=[N:16][CH:15]=1)(=[O:45])[CH3:44]
Reactant: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2ccc(C(OC(C)=O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
To a solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (544 mg, 0.960 mmol, Example 77B) in 20 mL of dry DMF at room temperature was added NaH (75 mg, 1.9 mmol, 60% in mineral oil). After stirring for 20 min, acetic anhydride (0.18 mL, 1.9 mmol) was added. The mixture was stirred for one hour and some suspension formed. After the mixture was quenched with a few drops of water, the suspension was filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated NaHCO3 (aq). The extracts were dried (Na2SO4), filtered, and concentrated to give the title compound as a semi-solid.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21](Cl)=[O:22])=[CH:15][CH:14]=1>[Cl-].[Na+].O>[CH2:19]([O:20][C:21]([N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1)=[O:22])[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: C1=CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CC=CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,2,3,6-Tetrahydro-pyridine (3 g, 36.1 mmol) are treated with 10% aqueous sodium carbonate (2.1 ml) and cooled to 0° C. Within 1 h, benzyl chloroformiate (Z-chloride, 5.1 ml, 36 mmol) is added dropwise within 1 h. After additional stirring for 2 h, the mixture is treated with 30 ml of brine and extracted four times with diethyl ether. The organic layers are dried over sodium sulphate and evaporated. The crude product, 7 g of a colorless oil, is purified by Flash-chromatography (silica gel, cyclohexane/ethyl acetate 9:1).