Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4]>C(OC(C)(C)C)(=O)C.O>[NH2:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([O:8][C:3]([CH3:5])([CH3:4])[CH3:2])=[O:7]
Reactant: CC(C)C(N)C(=O)O
Solvent: CC(=O)OC(C)(C)C
Solvent: O
Product: CC(C)C(N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a stirred solution of DL-valine (25 g, 0.213 mol) in tert-butyl acetate (250 mL) at 00° C., was added HClO4 (64.2 g, 0.320 mol) portionwise. The reaction mixture was stirred for 36 h at RT. It was diluted with water and extracted in ethyl acetate (500 mL). The organic layer was washed with a 10% sodium bicarbonate solution (2×150 mL), dried over Na2SO4 and concentrated, affording of the title compound as brown liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.31 (brs, 2H), 3.62 (d, J=4.4 Hz, 1H), 1.98 (d, J=1.7 Hz, 1H), 1.44 (s, 9H), 0.95 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH:15]=[C:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C@H:18]([OH:26])[CH2:17]5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[N:6]=1.Br>>[NH2:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH:15]=[C:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C:18](=[O:26])[CH2:17]5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[N:6]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3c[nH]c(N)n3)=CC[C@@H]12
Agent: Br
Product: C[C@]12CCC(=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3c[nH]c(N)n3)=CC[C@@H]12

Procedure:
In an analogous manner to example 2 the title compound is prepared from (3β)-17-(2-amino-4-imidazolyl)-androsta-5,16-dien-3-ol.HBr prepared in Example 7.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:20])=[CH:13][CH:14]=2)[C:9]1([CH2:23][CH3:24])[CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(OCC)(=O)C.[F:39][C:40]([F:46])([F:45])[S:41](Cl)(=[O:43])=[O:42]>[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:7][C@@H:8]1[C:9]([CH2:21][CH3:22])([CH2:23][CH3:24])[C:10]2[CH:11]=[C:12]([O:20][S:41]([C:40]([F:46])([F:45])[F:39])(=[O:43])=[O:42])[CH:13]=[CH:14][C:15]=2[CH2:16][C@H:17]1[O:18][CH3:19])=[O:25])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC1(CC)c2cc(O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCC1(CC)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
A mixture of trans-(1,1-diethyl-7-hydroxy-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (195.0 g, 0.558 mol), triethylamine (160 mL, 1.1 mol) and ethyl acetate (2000 mL) was stirred at room temperature for 15 min and cooled to 0° C. followed by slow addition of trifluoro-methanesulfonyl chloride (150 g, 0.89 mol) keeping the internal temperature below 4° C. The resulting slurry was stirred at 0° C. for 1 h. Additional triethylamine (16 mL) followed by additional trifluoromethanesulfonyl chloride (15.0 g) was added slowly maintaining a temperature below 5° C. The reaction mixture was stirred at room temperature for an additional hour. Diluted brine (1.0 L) was added and the reaction mixture was stirred for 10 min at room temperature. The layers were separated; the organic layer was washed with diluted NaHCO3 (1.0 L) and then concentrated to ˜350 mL by rotary evaporation at 28° C. and stirred at room temperature for 30 min. Heptane (700 mL) was added and the resulting slurry was stirred at room temperature for 30 min, cooled to 4° C. and stirred for 1 h. The solids were filtered, washed with heptane, and then dried under vacuum to yield the title compound (193.0 g, >97% purity). The filtrate was concentrated, slurried in an isopropyl acetate and heptane mixture (1:3, 60 mL) over 30 min, filtered and dried to yield additional product (45.0 g, >97% purity).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[Li]C(C)(C)C.CCCCC.[N+:24]([C:27]1[C:32]([CH:33]=[O:34])=[CH:31][C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=1)([O-:26])=[O:25]>C1COCC1>[CH3:38][O:37][C:29]1[C:30]([O:35][CH3:36])=[CH:31][C:32]([CH:33]([C:2]2[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=2)[OH:34])=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: COc1cc(I)cc(OC)c1OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cc(C(O)c2cc(OC)c(OC)c(OC)c2)c([N+](=O)[O-])cc1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A flame-dried round-bottomed flask under N2 atmosphere was charged with 5-iodo-1,2,3-trimethoxybenzene (2.92 g, 9.93 mmol) and THF (31 mL) was added. The solution was cooled down to −78° C. and 1.5 M solution of t-BuLi in pentane (13.6 mL, 20.57 mmol) was added dropwise. The mixture was stirred for 1 h and transferred via canula to a precooled (−78° C.) solution of 6-nitroveratraldehyde (2.02 g, 9.57 mmol) in THF (12 mL) under N2 atmosphere. The resulting mixture was stirred for 2 h and slowly warmed up to 0° C., quenched with saturated aqueous solution of NH4Cl and allowed to warm-up to rt. Solvent was removed in vacuo and the residue was partitioned between water and DCM. Organic layer was collected and washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc/DCM (9:91) affording the title compound 241 (1.46 g, 40% yield) 1H NMR (CDCl3) δ (ppm): 7.61 (s, 1H), 7.16 (s, 1H), 6.58 (s, 2H), 6.45 (s, 1H), 6.09 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.83 (s, 6H). m/z: 402.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20]Br)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[CH:15]=2)[CH:10]=[C:9]1[C:22]1[C:23]2[S:36][C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][C:24]=2[N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCBr)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCCN4CCCCC4)cc3n2C(=O)OC(C)(C)C)c2sc(-c3ccccc3)cc21
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A mixture of 6-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester [300 mg, 0.460 mmol, Intermediate 50)], piperidine (60.2 mg, 0.707 mmol), potassium carbonate (191 mg, 1.38 mmol), potassium iodide (40.0 mg, 0.241 mmol), and anhydrous acetonitrile (5.0 mL) was heated at 70° C. with shaking at 200 rpm. After 20 hours, the reaction was cooled to ambient temperature, filtered, the insolubles washed three times with dichloromethane (5 mL), and the filtrate concentrated under reduced pressure to give a dark residue. The residue was chromatographed on silica, eluting with 10%—1 M ammonia in methanol/90% dichloromethane, to give 2-(1-tert-butoxycarbonyl-5-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-[3-(piperidin-1-yl)-propoxy]-indole-1-carboxylic acid tert-butyl ester (310 mg) as a brittle green foam: LC/MS: 657.3, (M+H), RT=3.92 minutes, 50% UV purity). A mixture of this material (300 mg), 4 M aqueous potassium carbonate (5.0 mL), tetrahydrofuran (5.0 mL) and methanol (5.0 mL) was heated at 60° C. for 2 hours. After cooling to room temperature, the solvent was removed in vacuo to give a solid. The crude solid was suspended in water (25 ml) and the mixture stirred at room temperature for 0.5 hours. The solid was collected by filtration and dried to give a grey solid. Trituration of the solid with 20% methanol/ether provided 2-(5-phenvyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(3-piperidin-1-yl-propoxy)-1H-indole [90.0 mg, 43%, Example 58] as a grey solid. TLC Rƒ0.37 (silica, 14% 1 M ammonia in methanol/86% dichloromethane); LC/MS: 457.3 (M+H), RT=2.93 minutes; 1H NMR [300 Mhz, (CD3)2SO]: δ 13.30 (br s 1H), 11.39 (br s, 1H), 7.78 (D, J=7 Hz, 2H), 7.64 (s, 1H), 7.49-7.35 (m, 4H), 6.92 (s, 1H), 6.65 (d, J=8.5 Hz, 1H), 6.59 (s, 1H), 3.98 (t, J=6 Hz, 2H), 2.43-2.33 (m, 6H), 1.88 (m, 2H), 1.50-1.39 (m, 6H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:4][CH2:3]1.Cl.N1CCC(C2NN=C(C3C=CC(Cl)=CC=3)C=2C2C=CN=CC=2)C[CH2:28]1>>[CH3:28][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:9]=2[C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:6][CH2:7]1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)cc1
Reactant: Clc1cccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncc2)c1
Agent: Cl
Product: CN1CCC(c2[nH]nc(-c3cccc(Cl)c3)c2-c2ccncc2)CC1

Procedure:
By following the method of Example C-75 and substituting 5-(4-piperidyl)-4-(4-pyridyl)-3-(3-chlorophenyl)pyrazole hydrochloride (Example C-88), for 5-(4-piperidyl)-4-(4-pyridyl)-3-(4-chlorophenyl)pyrazole hydrochloride (Example C-74) the title compound was prepared: MS (M+H): 353 (base peak).
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[CH2:8][CH2:7]1.C[O:25][C:26]([C:28]1[C:37]2[C:32](=[CH:33][C:34]([CH2:38][C:39]3[CH:44]=[C:43]([NH:45][C:46](=[O:48])[CH3:47])[N:42]=[CH:41][N:40]=3)=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=O.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O>[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:26]([C:28]3[C:37]4[C:32](=[CH:33][C:34]([CH2:38][C:39]5[CH:44]=[C:43]([NH:45][C:46](=[O:48])[CH3:47])[N:42]=[CH:41][N:40]=5)=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)=[O:25])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])[CH2:8][CH2:7]1
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: COC(=O)c1cccc2cc(Cc3cc(NC(C)=O)ncn3)ccc12
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(Cc2ccc3c(C(=O)Nc4ccc(CN5CCN(C)CC5)c(C(F)(F)F)c4)cccc3c2)ncn1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of 2 ml trimethylaluminium (2 M in toluene, 4 mMol) is added to a stirred solution of 355 mg (1.3 mMol) 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine in 20 ml toluene at 10° C. under an argon atmosphere. After 1 h at r t, a solution of 436 mg (1.3 mMol) 6-(6-acetylaminopyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid methyl ester (Step 9.2) in 5 ml THF is added and the reaction mixture is heated at 90° C. for 45 min. After cooling to 5° C., a solution of sat. aqueous ammonium chloride (50 ml) is added dropwise. The mixture is poured into EtOAc and filtered over hyflo. The separated aq. phase is extracted with EtOAc. The combined organic phases are washed with water and brine, dried (Na2SO4) and concentrated. The crude product is purified by chromatography (SiO2, CH2Cl2/EtOH/NH3 90:9:1) and is recrystallised from hot EtOAc and hexane to afford the title compound as a colourless solid: m.p.: 202-204° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([O:14][CH3:15])[N:5]2[N:16]=[CH:17][CH:18]=[C:4]2[N:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][O:14][C:6]1[N:5]2[N:16]=[CH:17][CH:18]=[C:4]2[N:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1c(-c2ccccc2)c(Cl)nc2ccnn12
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COc1c(-c2ccccc2)c(-c2ccc(C=O)cc2)nc2ccnn12
Temperature: 120 °C

Procedure:
To a solution of 1.00 g 5-chloro-7-methoxy-6-phenylpyrazolo[1,5-a]pyrimidine and 0.69 g 4-formylphenylboronic acid in 20 ml 1,2-dimethoxyethane are added 7.3 ml of a 10% w/w sodium carbonate solution and 0.14 g dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II). The mixture is heated for 45 min under microwave irradiation to 120° C. This mixture is worked up by diluting with water and extraction with dichloromethane. The organic layers are dried over Na2SO4 and concentrated to yield the crude product, which is purified by chromatography on silica gel (methanol/dichloromethane).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.N[C:37]1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.CC1C=CC(N=C=S)=CC=1>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:22]1[CH2:21][C:20]2[C:24](=[CH:25][C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][C:6]([CH3:37])=[CH:7][CH:2]=4)=[S:35])=[CH:12][CH:13]=3)=[CH:18][CH:19]=2)[C:23]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: Cc1ccc(N=C=S)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(C)cc4)cc3)cc2C1=O

Procedure:
The compound of example 53 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 4-methyl phenyl isothiocyanate. The compound of example 53 was used directly without isolation for the preparation of compound of example 54.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.C(OCC)C>CO.C(OCC)(=O)C.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 18 h
Yield: 89.6 %

Procedure:
To a solution of tert-butyl 4-(3-methoxy-4-nitrophenyl)piperazine-1-carboxylate (I1) (1.90 g, 5.63 mmol) in methanol (20 mL) and ethyl acetate (80 mL) was added 10% Pd/C (0.500 g). The mixture was evacuated and backfilled three times with hydrogen gas then stirred under a hydrogen atmosphere for 18 hours. The crude reaction mixture was filtered through a plug of Celite, washing with ethyl acetate and the filtrate evaporated in vacuo then dried under high vacuum to give a dark red viscous oil. The oil was suspended in a 2:1 solution of diethyl ether and petroleum ether (15 mL) and sonicated for 3 minutes. The resulting mixture was evaporated in vacuo and dried under high vacuum to give the title compound (I2) (1.55 g, 89%) as a dark red solid; 1H NMR (300 MHz, d6-DMSO) δ 1.47 (s, 9H), 2.97 (t, 4H, J=4.7 Hz), 3.57 (t, 4H, J=4.7 Hz), 3.83 (s, 3H), 6.40 (dd, 1H, J=8.3, 2.1 Hz), 6.50 (d, 1H, J=2.0 Hz) and 6.64 (d, 1H, J=8.3 Hz). LCMS Method B: rt 5.02 min; m/z 308.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:30])([CH3:29])[CH2:23][CH2:24][N:25]3[CH3:28])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:28][N:25]1[C:26]2[C:21](=[CH:20][CH:19]=[C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=3)[CH:27]=2)[C:22]([CH3:29])([CH3:30])[CH2:23][CH2:24]1
Reactant: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCC(C=Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 6 h
Yield: 46.8 %

Procedure:
A solution of 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic acid methyl ester (0.23 g, 0.5 mmole) in 10 mL of a 1:1 THF/methanol mixture was treated with a solution of 0.09 g of lithium hydroxide monohydrate in 2.5 mL of water and stirred at 40° C. for 6 hours. The mixture was diluted with 10 mL of water and the pH adjusted to 2.0 with 2N HCl solution. The mixture was extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by preparative tlc (SiO2, 25% ethyl acetate in hexanes) to yield 0.095 g of 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic acid as a pale yellow oil. MS (EI): (M+): 405.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:32][N:24]([CH2:23][C:14]1[CH:15]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]([S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[NH:35][N:34]=[N:33][N:2]=3)[CH:4]=2)(=[O:10])=[O:11])[CH:13]=1)[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C#N)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(-c3nnn[nH]3)c2)c1)C(=O)OC(C)(C)C
Yield: 16.4 %

Procedure:
A mixture of tert-butyl ({1-[(3-cyanophenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (0.29 g), sodium azide (70 mg), triethylamine hydrochloride (0.19 g) and toluene (10 ml) was heated under reflux for 7 days. After cooling the reaction mixture, ethyl acetate was added to the mixture, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=10:1) to give the title compound as an oil (yield 0.052 g, 16%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[O:4].[P:14](Cl)([Cl:17])([Cl:16])=O>>[F:1][C:2]([F:12])([F:13])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][P:14]([Cl:17])[Cl:16])=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(NCCCCCO)C(F)(F)F
Product: O=C(NCCCCCOP(Cl)Cl)C(F)(F)F

Procedure:
3',5'-Bis-(5-aminopentylphosphoryl)-thymidine of step 7 may also be prepared by reacting 5-trifluoroacetamido-pentanol with phosphoryl chloride, forming 5-trifluoroacetamidopentylphosphorodichloridite, that can be reacted in pyridine with thymidine followed by hydrolysis in aqueous piperidine.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1>CCCCCC.O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[F:13][CH:14]([C:24]1[N:25]=[C:26]([O:28][CH3:29])[CH:27]=[C:22]([O:21][CH3:20])[N:23]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CF
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)C(F)c1nc(OC)cc(OC)n1
Reaction time: 0.5 h
Yield: 10 %

Procedure:
Butyllithium (21ml of a 1.6M solution in hexane) was added to di-isopropylamine (4.94ml) in dry tetrahydrofuran (100ml) under nitrogen at a temperature of -78° C., and the mixture was stirred for 30 minutes. A solution of ethyl fluoroacetate (2.51g) in dry tetrahydrofuran (20ml) was then added at a temperature of -60° C., and the mixture was stirred for 1 hour. Hexamethylphosphoric triamide (5.12ml) was added, and the mixture was stirred for a further 10 minutes. Then 4,6-dimethoxy-2methylsulfonylpyrimidine (5.0g) was added portionwise, and the temperature of the reaction mixture rose within 2.5 hours to room temperature. The reaction mixture was washed with saturated ammonium chloride and sodium chloride solution, the aqueous phase was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate and evaporated. The product obtained was chromatographed on silica gel using hexane/ethyl acetate (0-20% ethyl acetate), to give the desired compound as a yellow oil (0.56g), refractive index at 20° C. =1.4829.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N+:21]([O-])=O)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1>C(O)(=O)C.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:21])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2cc(S(=O)(=O)c3cccc(F)c3)cnc12
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cccc2cc(S(=O)(=O)c3cccc(F)c3)cnc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
10.13 g of 3-(3-fluorophenylsulfonyl)-8-nitroquinoline (30.5 mmol) were suspended in 150 ml of acetic acid and warmed to 110° C. 8.51 g of iron powder (152 mmol) were added in small portions with stirring. Stirring was continued for 1 h. Then, the reaction mixture was cooled to room temperature, partitioned between water and ethyl acetate. The organic phase was separated and the aqueous layer was extracted three times with ethyl acetate. Water was added to the combined organic layers and the pH was adjusted to alkaline conditions with aqueous ammonia solution under rapid stirring. The organic layer was separated, extracted twice with water, dried over magnesium sulfate, filtered and the solvents were evaporated to yield 9.2 g of the product. MS (ESI+) m/z=303.0 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][O:9][C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1
Reactant: OCc1ccncc1Br
Reactant: Oc1ccc(F)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OCc2ccncc2Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a solution of (3-bromo-pyridin-4-yl)-methanol (650 mg, 3.5 mmol), 4-fluoro-phenol (260 mg, 2.3 mmol) and PPh3 (1.7 g, 6.4 mmol) in THF (50 mL) is added a solution of di-tert-butyl azodicarboxylate (1.2 g, 5 mmol) in THF at 0° C. After addition, the mixture is stirred at room temperature for 16 hrs. The solvent is removed and the residue is purified by flash column chromatography to give 600 mg of 3-bromo-4-(4-fluoro-phenoxymethyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:21]([O:27][CH3:28])=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:21]([O:27][CH3:28])=[N:22][C:23]([NH:26][S:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:24][CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1nc(N)ccc1CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1nc(NS(=O)(=O)c2cccnc2Cl)ccc1CNC(=O)OC(C)(C)C
Yield: 64.4 %

Procedure:
The title compound (1.51 g, 3.53 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.16 g, 5.48 mmol), tert-butyl(6-amino-2-methoxypyridin-3-yl)methylcarbamate (IntC7) (1.53 g, 6.03 mmol) and pyridine (1.33 mL, 16.4 mmol) in DCM (20 mL) at rt using the methods of (IntC1).