Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC([C:4]1[O:5][CH2:6][CH2:7][N:8]=1)O.[B:9]([OH:12])([OH:11])[OH:10]>C1(C)C=CC=CC=1>[B:9]([OH:12])([OH:11])[OH:10].[O:5]1[CH2:6][CH2:7][N:8]=[CH:4]1
Reactant: OC(O)C1=NCCO1
Agent: OB(O)O
Solvent: Cc1ccccc1
Product: C1=NCCO1

Procedure:
Approximately 150 grams of the above dihydroxymethyl oxazoline, 40 grams of boric acid and 100 grams of toluene were heated in a reactor equipped as described above to 160° C. (320° F.) until water evolution during azeotropic distillation ceased. The solvent was vacuum topped at 160° C. (320° F.) to remove solvent and filtered at 100°-110° C. (212°-230° F.) through diatomaceous earth to form an amber-colored oxazoline borate. The product contained approximately 4.9% boron.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:9][C:8](=[O:10])[N:7]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[O:20][CH3:21])=[O:5])C.[OH-].[Na+].O>C(O)C>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:7]1[C:8](=[O:10])[CH2:9][CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1CC(=O)N1Cc1ccc(OC)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CN2C(=O)CC2C(=O)O)c(OC)c1
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 5.80 g (0.020 mole) of ethyl-[1-(2,4-dimethoxy-benzyl)-4-oxo-2-azetidine-carboxylate] in 25 ml of ethanol a solution of 0.88 g (0.022 mole) of sodium hydroxide and 60 ml of water is added. The reaction solution is stirred for 2 hours and extracted three times with 20 ml of ether each. The aqueous layer is acidified to pH 2 with concentrated aqueous hydrochloric acid and extracted three times with 20 ml of dichloromethane each. The united organic solutions are dried over anhydrous magnesium sulfate, filtered and from the filtrate the dichloromethane is distilled off. The residue is treated with ether, the yellowish-white crystalline product is filtered off and recrystallized from benzene. Thus 4.0 g of 1-(2,4-dimethoxy-benzyl)-4-oxo-2-azetidine-carboxylic acid are obtained. Yield: 75.4%. M.p.: 124°-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]23[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]4)[CH2:13]2)[CH2:19]3)=[O:9])[C:5]([Cl:22])=[CH:4][N:3]=1.C(OC([N:30]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=O)(C)(C)C.Cl>CS(C)=O.CO.O1CCOCC1>[ClH:1].[Cl:22][C:5]1[C:6]([C:8]([NH:10][CH2:11][C:12]23[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]4)[CH2:19]2)[CH2:21]3)=[O:9])=[CH:7][C:2]([N:30]2[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ncc1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(N2CCCNCC2)ncc1Cl
Yield: 78.8 %

Procedure:
A solution of 2,5-dichloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-pyridine-4-carboxamide (0.50 g, Example 1a) and 1-t-butoxycarbonylhomopiperazine (0.76 g) in dimethylsulfoxide (5 ml) was heated at 100-120° C. for 24 hours. The solution was cooled and partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane and the organic layer dried over magnesium sulphate. Concentration in vacuo and chromatography on silica gave a colourless solid. This was redissolved in methanol (10 ml) and treated with 4M HCl in dioxan (2 ml). Once deprotection was complete (14 hours) the solution was partially concentrated in vacuo then diluted slowly with diethyl ether with rapid stirring. The resulting white precipitate was filtered, washed with diethyl ether and dried to afford the title compound (0.51 g).
Reaction SMILES: [C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[CH2:40][CH:39]([N:41]([CH3:43])[CH3:42])[CH2:38]4)[CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[CH:19][CH:18]=1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])=[CH:49][CH:48]=1>C(O)C>[F:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:53][C:54]([NH:56][C:57](=[S:58])[NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:32][CH2:33][CH:34]([N:37]5[CH2:38][CH:39]([N:41]([CH3:43])[CH3:42])[CH2:40]5)[CH2:35][CH2:36]4)=[O:30])[CH:23]=3)=[CH:44][CH:45]=2)=[O:55])=[CH:51][CH:52]=1
Reactant: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)C1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.5 %

Procedure:
After adding (1S)-(+)-10-camphorsulfonic acid (90.7 mg) to a solution of 4-[3-(dimethylamino)azetidin-1-yl]piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (91.5 mg) in ethanol (2.0 ml), the mixture was stirred for 10 minutes at room temperature. Then, 2-(4-fluorophenyl)acetyl isothiocyanate (1.28 ml, 0.25 M solution in toluene) was added and stirring was carried out at room temperature for 50 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1 to 10:1). Fractions containing the target compounds were combined and concentrated. The residue was then purified by LC-MS (eluent; acetonitrile-water-trifluoroacetic acid system). Fractions containing the target compound were combined and concentrated, and then saturated aqueous sodium hydrogencarbonate was added to the residue. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. It was then concentrated, and the obtained precipitate was suspended in diethyl ether-hexane and filtered. The filtered solid was washed with diethyl ether. It was then dried by aspiration to provide the title compound (14.2 mg, 10.5%) as white powder.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:11][CH:12]1[C:24]2[N:23]3[CH:25]=[CH:26][N:27]=[C:22]3[C:21](=[O:28])[NH:20][C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.C>[OH-].[Na+].CS(C)=O>[C:1]([NH:11][CH:12]1[C:24]2[N:23]3[CH:25]=[CH:26][N:27]=[C:22]3[C:21](=[O:28])[NH:20][C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
1.7 g of benzoyl chloride are added over 1 minute to a solution of 3.1 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 200 ml of 0.1N sodium hydroxide. The mixture is stirred for 2 hours at a temperature in the region of 20° C. and the insoluble material is separated out by filtration, washed twice with 200 ml in total of distilled water and air-dried. The product obtained (3 g) is dissolved in 100 ml of dimethyl sulphoxide and, after addition of decolorizing charcoal, the solution is filtered. The filter is washed with 20 ml of dimethyl sulphoxide and the filtrate and the washings are then combined and 80 ml of distilled water are added at 20° C. The insoluble material is separated out by filtration, washed twice with 50 ml in total of distilled water and with 25 ml of acetone and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1.75 g of 10-benzamido-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one are thus obtained, decomposing without melting at 300° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): 6.40 (d, J=8.5 Hz, 1H: CH--N); from 7.30 to 7.70 (mt, 8H: --H6, --H7, --H8, --H9, aromatic --H para and meta to the --CO--NH-- and --H of the imidazole); from 7.80 to 8.00 (mt, 3H: aromatic --H ortho to the --CO--NH-- and --H of the imidazole); 9.14 (d, J=8.5 Hz, 1H: --NH--); 12.55 (cplx, 1H: --CO--NH-- of the ring)].
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:34])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[NH:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:9]=1.[NH3:35]>C(O)C>[NH2:35][C:5]1[C:4](=[O:34])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[NH:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:9]=1
Reactant: COc1ccc(C(NCC(C)c2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Reactant: N
Solvent: CCO
Product: COc1ccc(C(NCC(C)c2ccccc2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(2-phenylpropylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione (2.35 g) [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 10.2 ml) were reacted, to give the title compound (1.87 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH2:22])=[C:20]([O:27][CH3:28])[CH:19]=1>>[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[C:20]([O:27][CH3:28])[CH:19]=1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: COc1cc(Cl)c(OC)cc1N
Product: COc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)c(OC)cc1Cl
Yield: 48.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 4-chloro-2,5-di-methoxyaniline (122 mg, 0.65 mmol) to provide 203 (80 mg, 48% yield) as a white solid. LC-MS (M+H=382, obsd.=382).
Reaction SMILES: [O:1]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[C:22]([CH2:23][OH:24])=[C:21]([O:29][CH3:30])[CH:20]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[C:36]([Si:40](Cl)([CH3:42])[CH3:41])([CH3:39])([CH3:38])[CH3:37].O>CN(C)C=O>[O:24]([CH2:23][C:22]1[C:21]([O:29][CH3:30])=[CH:20][C:19]([O:1][Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:26][C:25]=1[O:27][CH3:28])[Si:40]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of the crude 4-t-butyldiphenylsiloxy-2,6-dimethoxybenzyl alcohol (4.01 g) obtained by the above-described procedure in anhydrous dimethylformamide (30 mL) were added imidazole (1.29 g, 18.98 mmol) and t-butylchlorodimethylsilane (1.79 g, 11.86 mmol). After stirring at 50° C. for 4 hours, water was added and the resulting mixture was extracted with ethyl acetate-hexane (1:2). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude 4-(t-butyldimethylsiloxy)methyl-1-t-butyldiphenylsiloxy-3,5-dimethoxybenzene was obtained as a colorless amorphous powder (5.33 g).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[O:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(Oc2cccc(CNC(=O)OC(C)(C)C)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Oc2cccc(CN)c2)cc1
Reaction time: 2 h

Procedure:
The methyl 4-(3-((tert-butoxycarbonylamino)methyl)phenoxy)benzoate (0.040 g) was taken up in 4 M HCl in dioxane (3 ml) at rt and was stirred for 2 h. The reaction was complete, was concentrated under reduced pressure, taken up in acetonitrile and re-concentrated under reduced pressure two times to give crude methyl 4-[3-(aminomethyl)phenoxy]benzoate-HCl (0.045 g) as a semisolid residue. Analytical LCMS (M+H)+: m/z=258.0.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([CH:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19][C:18]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:17]1=2)=O)([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([CH:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19][C:18]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:17]1=2)=[S:41])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc2c(c1)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(C(=S)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Yield: 96.3 %

Procedure:
After 1.09 g of Compound 4 obtained in Example 4 was dissolved in 10 ml of toluene, 1.07 g of Lawesson's reagent was added to the solution. The mixture was heated under reflux for an hour. The reaction mixture was allowed to stand at room temperature, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: hexane-ethyl acetate (2:1)] to obtain 1.46 g of a crude product. The crude product was recrystallized from ethyl acetate-hexane to obtain 1.09 g of Compound 36.
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:6])[CH2:4][CH3:5].FC(F)(F)S(O[C:13]1[C:18]([F:19])=[CH:17][C:16]([CH:20]2[CH2:25][CH2:24][Si:23](CCCCC)([C:26]3C=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)=[CH:15][C:14]=1[F:37])(=O)=O>>[CH2:26]([Si@H:23]1[CH2:24][CH2:25][C@H:20]([C:16]2[CH:17]=[C:18]([F:19])[C:13]([CH2:2][C@@H:3]([CH3:6])[CH2:4][CH3:5])=[C:14]([F:37])[CH:15]=2)[CH2:21][CH2:22]1)[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(c2cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c2)CC1
Reactant: CC[C@H](C)CBr
Product: CCCCC[Si@H]1CC[C@H](c2cc(F)c(C[C@@H](C)CC)c(F)c2)CC1

Procedure:
The general procedure of Example 18 was repeated using (S)-1-bromo-2-methylbutane and (2,6-difluoro-4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)phenyl) trifluoromethanesulfonate, thereby obtaining the intended compound.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC=CC=1OC)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: COc1ccccc1COC(=O)c1cc(Br)ccc1OCc1ccccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1COc1ccc(Br)cc1C(=O)O
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (385 mg, 9.18 mmol) in water (20 ml) was added dropwise to a stirred solution of [2-(methyloxy)phenyl]methyl 5-bromo-2-({[2-(methyloxy)phenyl]methyl}oxy)benzoate (may be prepared as described in Description 31; 420 mg, 0.92 mmol) in THF (20 ml) over 5 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3×20 ml). The organic phase was then evaporated in vacuo to yield the title compound as a light yellow solid. 280 mg.
Reaction SMILES: [BH4-].[Na+].[O:3]=[CH:4][CH2:5][O:6][CH:7]1[CH2:24][CH2:23][C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9][CH2:8]1>CO>[OH:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:24][CH2:23][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(OCC=O)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(OCCO)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
NaBH4 (13.46 mmol, 2.0 eq.) was added portion wise to a stirred solution of tert-butyl 9-(2-oxoethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (6.73 mmol, 1.0 eq.) in MeOH (65 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 16 h. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (300 ml) and washed with water (200 ml) and brine (200 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography eluting with 20% ethyl acetate in hexanes to give the desired product as a yellow sticky solid. Yield: 40%
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[C:25]([C:30]([OH:32])=[O:31])[C:26]=1[N+:27]([O-:29])=[O:28])[O:7][CH2:8][C:9]([N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:10])([OH:3])=[O:2].CN(C)[CH:35]=[O:36].[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Cl)=[CH:42][CH:41]=1>C(N(CC)CC)C>[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][O:31][C:30]([C:25]2[CH:24]=[C:6]([CH:5]=[C:4]([C:1]([O:3][CH2:1][C:4]3[CH:5]=[CH:6][C:24]([O:36][CH3:35])=[CH:25][CH:26]=3)=[O:2])[C:26]=2[N+:27]([O-:29])=[O:28])[O:7][CH2:8][C:9]([N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:10])=[O:32])=[CH:42][CH:41]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(CCl)cc1
Reactant: CCCCCCN(CCCCCC)C(=O)COc1cc(C(=O)O)c([N+](=O)[O-])c(C(=O)O)c1
Solvent: CCN(CC)CC
Product: CCCCCCN(CCCCCC)C(=O)COc1cc(C(=O)OCc2ccc(OC)cc2)c([N+](=O)[O-])c(C(=O)OCc2ccc(OC)cc2)c1
Temperature: 100 °C

Procedure:
To a solution of (3,5-dicarboxy-4-nitrophenoxy)-N,N-dihexylacetamide in dimethylformamide containing two equivalents of triethylamine are added two equivalents of p-methoxybenzylchloride. The mixture is stirred and heated to about 100° C. for 1 hr. After this time, the reaction is cooled to room temperature and poured into ice water. The aqueous mixture is extracted with 2 portions of methylene chloride. The combined extracts are back-extracted with water to remove dimethylformamide, dried over anhydrous calcium sulfate, filtered and concentrated under reduced pressure. The remaining oil which was not induced to crystallize is analyzed by NMR and used directly in the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([NH2:20])=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.I.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](SC)=[NH:28]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][C:27]([C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[NH:28])=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(c1)CCCN2CCCN1CCOCC1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(Nc1ccc2c(c1)CCCN2CCCN1CCOCC1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a stirred solution of 1-(3-morpholinopropyl)-1,2,3,4-tetrahydroquinolin-6-amine (190 mg, 0.690 mmol) in ethanol (10 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (393 mg, 1.380 mmol). The resulting suspension was then stirred overnight at room temperature. The mixture was then diluted with water and sodium carbonate and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in ethyl acetate, followed by 5-10% (2M NH3 in MeOH) in dichloromethane, giving the desired N-(1-(3-morpholinopropyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide 72 (132 mg, 0.343 mmol, 49.8% yield). 1H NMR (DMSO-d6) δ 7.67 (d, J=3 Hz, 1H), 7.56 (d, J=4.8 Hz, 1H), 7.09-7.06 (m, 1H), 6.56 (brs, 2H), 6.49 (s, 1H), 6.33 (brs, 2H), 3.60-3.56 (m, 4H), 3.26-3.17 (m, 4H), 2.66 (t, J=6.3 Hz, 2H), 2.34-2.28 (m, 6H), 1.89-1.81 (m, 2H), 1.69-1.63 (m, 2H). EI-MS (m/z, %) 384 (100, MH+), 270 (52). HPLC purity: 99%.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][CH:35]1[NH:39][CH2:38][CH:37]([NH:40][CH3:41])[CH2:36]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]([CH:37]5[CH2:36][CH:35]([CH2:34][O:33][CH3:32])[NH:39][CH2:38]5)[CH3:41])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC1CNC(COC)C1
Product: COCC1CC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CN1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-methoxymethyl-pyrrolidin-3-yl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and (5-Methoxymethyl-pyrrolidin-3-yl)-methyl-amine following General Procedure C.
Reaction SMILES: [Si]([O:8][C@H:9]([C:48]1[CH:57]=[CH:56][C:55]([OH:58])=[C:54]2[C:49]=1[CH:50]=[CH:51][C:52](=[O:59])[NH:53]2)[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([C@@H:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:33][CH2:34][N:35]([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH:26]=2)=[CH:16][CH:15]=1)(C(C)(C)C)(C)C.CCN(CC)CC.F.F.F.N>O1CCCC1>[NH3:11].[CH:39]([N:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][C@@H:32]([C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:48]3[CH:57]=[CH:56][C:55]([OH:58])=[C:54]4[C:49]=3[CH:50]=[CH:51][C:52](=[O:59])[NH:53]4)[OH:8])=[CH:15][CH:16]=2)[CH:30]=[CH:29][C:28]=1[OH:31])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c4[nH]c(=O)ccc34)cc2)ccc1O)C(C)C
Agent: F
Agent: N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O)c3ccc(O)c4[nH]c(=O)ccc34)cc2)ccc1O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}amino)ethyl]-8-hydroxyquinolin-2(1H)-one (Preparation 32, 305 mg, 0.37 mmol) was dissolved in tetrahydrofuran (5 ml) and triethylaminetrihydrofluoride (0.30 ml, 1.9 mmol) was added, and the mixture stirred overnight at room temperature. Tetrahydrofuran (6 ml) and 880 ammonia (6 ml) were then added, the mixture stirred for 20 minutes, organics were then separated and washed with saturated aqueous sodium hydrogen carbonate (10 ml), then brine (10 ml), then dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98/2/0.2 to 88/12/1.2 by volume) to furnish the title compound as a yellow solid, 99 mg.