Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:38])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]([N:19]3[CH2:24][CH2:23][C:22]4([CH2:36][CH2:35][C:27]5(OCC(C)(C)C[O:28]5)[CH2:26][CH2:25]4)[O:21][C:20]3=[O:37])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)=[O:4]>O>[CH3:38][N:2]([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]([N:19]3[CH2:24][CH2:23][C:22]4([CH2:36][CH2:35][C:27](=[O:28])[CH2:26][CH2:25]4)[O:21][C:20]3=[O:37])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)N(C)C)nc2)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(C(=O)N(C)C)nc2)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Yield: 54 %

Procedure:
The title compound is prepared from 5-{4-[(S)-1-(12,12-dimethyl-2-oxo-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadec-3-yl)-ethyl]-phenyl}-pyridine-2-carboxylic acid dimethylamide following a procedure analogous to that described in Step 10 of Intermediate 2. Yield: 54% of theory; Mass spectrum (ESI+): m/z=436 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.57 (d, J=7.1 Hz, 3H), 1.85-2.05 (m, 5H), 2.09-2.28 (m, 3H), 2.45-2.57 (m, 2H) superimposed by DMSO-d5, 2.83-2.91 (m, 1H), 3.01 (s, 3H), 3.03 (s, 3H), ca. 3.27-3.35 (m, 1H) superimposed by H2O, 5.56 (q, J=7.1 Hz, 1H), 7.47 (dm, J=8.2 Hz, 2H), 7.65 (dm, J=8.2 Hz, 1H), 7.79 (dm, J=8.2 Hz, 2H), 8.20 (dd, J=8.2, 2.3 Hz, 1H), 8.91 (d, J=2.3 Hz, 1H).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][NH:17][C:18](=O)/[C:19](=[N:26]\[O:27][CH2:28][C:29]1[N:34]=[C:33]([NH:35][C:36](=[O:42])[O:37][CH2:38][CH2:39][C:40]#[CH:41])[CH:32]=[CH:31][CH:30]=1)/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1.[N-:50]=[N+:51]=[N-:52].[Na+]>C(#N)C>[CH2:38]([O:37][C:36](=[O:42])[NH:35][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:28][O:27]/[N:26]=[C:19](\[C:18]2[N:17]([CH3:16])[N:52]=[N:51][N:50]=2)/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:34]=1)[CH2:39][C:40]#[CH:41]
Reactant: C#CCCOC(=O)Nc1cccc(CO/N=C(\C(=O)NC)c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: C#CCCOC(=O)Nc1cccc(CO/N=C(/c2ccccc2)c2nnnn2C)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
With ice cooling, 85 μl of trifluoromethanesulphonic anhydride were added to a solution of 100 mg (0.25 mmol) of but-3-yn-1-yl(Z)-{6-[({[2-(methylamino)-2-oxo-1-phenylethylidene]amino}oxy)methyl]pyridin-2-yl}carbamate (only Z diastereoisomer) and pyridine (81 μl, 4 eq.) in acetonitrile (2 ml). The mixture was heated at 50° C. for 2 h and then cooled to room temperature. Then, 49 mg of sodium azide were added and the mixture was stirred again at 50° C. for 2 h. The homogeneous orange solution was then cooled to room temperature and filtered over silica gel, and the silica gel filter layer was washed with 50 ml of EtOAc. The combined organic phases were concentrated by evaporation in vacuo, giving 87 mg (84% purity) of (Z)-but-3-yn-1-yl{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@@H:31]([NH2:36])[CH2:32][C:33]([OH:35])=[O:34])=[CH:22]1.C([BH3-])#N.[Na+]>CO.C1COCC1.C(OCC)(=O)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@@H:31]([NH:36][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:32][C:33]([OH:35])=[O:34])=[CH:22]1
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccccc1
Reactant: N[C@@H](CC(=O)O)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCN[C@@H](CC(=O)O)Cc1c[nH]c2ccccc12)CCc1ccccc1

Procedure:
Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2-phenyl-ethylamine (5.03 g, 19.0 mmol) and (R)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((R)-tryptophan methyl ester hydrochloride salt) (4.9 g, 19.42 mmol) in methanol (50 mL) and stir for 30 minutes. Add sodium cyanoborohydride in solution (15.0 mL, 1M in THF, 15.0 mmol) and stir under an inert atmosphere for 16.5 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel eluting with 50% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [F:1][C:2]([CH3:20])([CH3:19])[CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH2:17][OH:18].C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:28]([O:18][CH2:17][C:5]1[N:4]([CH2:3][C:2]([F:1])([CH3:20])[CH3:19])[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(F)Cn1c(CO)nc2cnc3cccnc3c21
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1nc2cnc3cccnc3c2n1CC(C)(C)F
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A solution of [1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methanol (1.53 g, 5.58 mmol) dissolved in 50 mL of CH2Cl2 was treated with triethylamine (1.55 mL, 11.2 mmol), acetic anhydride (663 μL; 6.70 mmol), and 10 mg of 4-(dimethylamino)pyridine (DMAP). After stirring for 2 hours, the reaction mixture was treated with saturated NaHCO3 solution and the layers were separated. The organic portion was washed successively with 3.5% NaH2PO4 solution, H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 40-60% acetone/hexanes) gave 1.59 g of [1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate as an off-white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1([CH3:25])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]2[CH:22]=[N:23][NH:24][C:10]1=2.[ClH:26]>ClCCl>[ClH:26].[ClH:26].[CH3:8][C:9]1([CH3:25])[CH2:14][NH:13][CH2:12][C:11]2[CH:22]=[N:23][NH:24][C:10]1=2
Reactant: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C(C)(C)C1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCc2cn[nH]c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 mL trifluoroacetic acid were added at 0° C. to 1.6 g (6.1 mmol) tert.butyl 7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate in 15 mL dichloromethane and stirred for 2 h at RT. The reaction mixture was evaporated down. The residue was taken up in ethanol and mixed with 12 mL (15 mmol) 1.25 M ethanolic HCl and then evaporated down. The residue was triturated with ethanol and the solid was separated off by suction filtering and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C1(C)C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([F:19])[CH:13]=1)[O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[CH3:10]
Reactant: Fc1cc(F)cc(F)c1
Reactant: Cc1cc(N)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(N)cc(C)c1Oc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
A mixture of 4-amino-2,6-dimethylphenol (6.92 g), 1,3,5-trifluorobenzene (10.00 g), anhydrous potassium carbonate (13.93 g) and anhydrous cuprous chloride (0.50 g) in dry dimethylsulfoxide (100 ml) was heated under reflux for 4 hours, whereby the inner temperature raised from 120° C. to 150° C. After completion of the reaction, the reaction mixture was cooled to room temperature, and cold water (200 ml) and toluene (100 ml) were added thereto. After continuation of stirring for 30 minutes, the resultant mixture was filtered on celite to remove insoluble materials. The toluene layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of methylene chloride and n-hexane (1:1) as an eluting solvent to give 9.50 g of 4-(3,5-difluorophenoxy)3,5-dimethylaniline as yellowish white crystals. M.P., 67.6° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH:6]([CH3:11])[CH2:5]1)(=[O:3])[CH3:2].Cl.C[C@H]1[C@@H]([NH2:20])CCOC1>>[NH2:20][C@H:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C@H:6]1[CH3:11]
Reactant: CC(=O)N1CCC(=O)C(C)C1
Reactant: C[C@@H]1COCC[C@@H]1N
Agent: Cl
Product: CC(=O)N1CC[C@H](N)[C@H](C)C1

Procedure:
Racemic cis 1-(4-amino-3-methyl-piperidin-1-yl)-ethanone was prepared in the same manner from racemic 1-acetyl-3-methyl-piperidin-4-one. In this instance, 1 atm H2 was used instead of 55 psi, and the HCl treatment was omitted.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[C:18]1([N:24]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Br:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:2]([C:29]4[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=4)[N:24]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:3][C:4]=3[C:5]2([CH3:16])[CH3:17])=[CH:10][CH:9]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: OB(O)c1cccc(N(c2ccccc2)c2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)c2cc(Br)ccc2-c2ccc(-c3cccc(N(c4ccccc4)c4ccccc4)c3)cc21
Reaction time: 12 h
Yield: 41 %

Procedure:
2,7-dibromo-9,9-dimethyl-9H-fluorene (5.0 g, 14.201 mmol), 3-(diphenylamino)phenylboronic acid (2.05 g, 7.10 mmol), Pd(pph3)4 (820 mg, 0.71 mmol), K2CO3 (1.96 g, 14.201 mmol) were put in a 250 mL two-neck flask and dissolved in toluene/H2O. The solution was refluxed and stirred for 12 hours. After completion of the reaction, the solution was distilled under reduced pressure to remove the solvent. The resultant was columned with a solution of hexane and methylenechloride (4:1). The solution was distilled under reduced pressure and was re-crystallized in a solution of methylene chloride and petroleum ether such that the white solid compound was obtained, (1.50 g, yield: 41%).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[O:31][CH:30]=[CH:29][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([C:16]([CH3:28])=[N:17][N:18]4C(OC(C)(C)C)=O)=[CH:14][CH:13]=3)[N:10]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]2[C:6]3[O:31][CH:30]=[CH:29][C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:20]=[C:19]4[C:15]([C:16]([CH3:28])=[N:17][NH:18]4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:2][CH2:3]1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc(Nc3nc(NC4CC4)c4occc4n3)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2cc(Nc3nc(NC4CC4)c4occc4n3)ccc12
Reaction time: 4 h
Yield: 63.1 %

Procedure:
To a flask was added tert-butyl 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-3-methyl-1H-indazole-1-carboxylate (12.5 g, 29.7 mmol), DCM (270 mL) and TFA (45.8 mL, 595 mmol). The mixture was stirred for about 4 h. The mixture was concentrated and the residue was dissolved in MeOH (100 mL). The resulting solution was added into stirred aqueous NaHCO3 (10 wt %, 1000 mL) and the mixture was allowed to stir for about 1 h. The resultant suspension was filtered. To the solid was added hot water (60° C., 1000 mL) and the mixture was stirred for about 45 min and then filtered. The solid was then added to a mixture of DCM (270 mL) and MeOH (30 mL) in a flask, the mixture was heated to reflux then additional MeOH (25 mL) was added portion wise over a period of about 45 min, until a clear solution formed. The solution was filtered while hot. The filtrate was cooled in an ice bath for about 1 h. The mixture was then filtered to provide the desired product (6 g). The filtrate was combined with silica gel (15 g, 200-400 mesh size) and concentrated to a free flowing powder. The material was purified via column chromatography (0-3% MeOH in DCM over 35 min; 120 g silica gel) to give additional product (2.2 g). The two batches of product were combined to give N4-cyclopropyl-N2-(3-methyl-1H-indazol-6-yl)furo[3,2-d]pyrimidine-2,4-diamine (8.2 g, 86%); LC/MS (Table 2, Method c) Rt=1.61 min.; MS m/z: 321 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.04 (s, 1H), 8.44 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 7.83 (s, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.26 (dd, J=8.8, 1.7 Hz, 1H), 6.75 (d, J=2.1 Hz, 1H), 3.00 (td, J=7.1, 3.6 Hz, 1H), 2.41 (s, 3H), 0.90-0.83 (m, 2H), 0.68-0.61 (m, 2H). Syk IC50=A
Reaction SMILES: [Na].C([C:7]1([OH:18])[CH2:16][CH2:15][CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:8]1[CH3:17])(OCC)=O.[CH2:19]([OH:21])C>O>[OH:21][CH2:19][CH2:17][CH:8]1[CH:9]2[CH:14]([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:15][CH2:16][CH:7]1[OH:18]
Reactant: CCOC(=O)C1(O)CCC2CCCCC2C1C
Reactant: CCO
Agent: [Na]
Solvent: O
Product: OCCC1C(O)CCC2CCCCC21

Procedure:
86.25 g Of small pieces of sodium are added to 60 g of 2-carbethoxy-methyl-2-hydroxy-decalin and 900 ml of anhydrous ethyl alcohol. A vigorous reaction sets in which causes the reaction medium to reflux. Reflux is maintained for 1 hour. The mass is cooled, 1000 ml of water added, the alcohol distilled off and the residue is taken up in a little warm water. After cooling the mass is extracted three times with 250 ml of diethyl ether. The ethereal solutions are washed to neutrality and distilled; there are thus obtained 40 g of crude product which are rectified under 0.5 mm. This rectification gives 22 g of 2-hydroxyethyl-2-hydroxy-decalin (b.p.0.5 = 138°-140°C), which represents a conversion of about 42%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[OH:23][C:24]1[C:31]([O:32][CH3:33])=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[O:34][CH3:35].[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:28][C:27]4[CH:26]=[C:25]([O:34][CH3:35])[C:24]([OH:23])=[C:31]([O:32][CH3:33])[CH:30]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc(OC)c1O

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 4-hydroxy-3,5-dimethoxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(4-hydroxy-3,5-dimethoxy-benzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; HPLC: TRet (Grad5-40)=17.0.
Reaction SMILES: [CH2:1]([CH:8]1[CH:17]2[C:18]3[C:23]([CH2:24][CH2:25][NH+:16]2[C:15]([CH3:30])([CH3:29])[C:14]2[C:13]([O:31][CH3:32])=[C:12]([O:33][CH3:34])[CH:11]=[CH:10][C:9]1=2)=[CH:22][C:21]1[O:26][CH2:27][O:28][C:20]=1[CH:19]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[BH4-].[Na+]>CO>[CH2:1]([CH:8]1[CH:17]2[C:18]3[C:23]([CH2:24][CH2:25][N:16]2[C:15]([CH3:30])([CH3:29])[C:14]2[C:13]([O:31][CH3:32])=[C:12]([O:33][CH3:34])[CH:11]=[CH:10][C:9]1=2)=[CH:22][C:21]1[O:26][CH2:27][O:28][C:20]=1[CH:19]=3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1OC)C(C)(C)[NH+]1CCc3cc4c(cc3C1C2Cc1ccccc1)OCO4
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1OC)C(C)(C)N1CCc3cc4c(cc3C1C2Cc1ccccc1)OCO4
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a solution of 13-benzyl-9,10-dimethoxy-8,8-dimethyl-5,6,8,13-tetrahydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; bromide (100 mg, 0.19 mmol) in methanol (10 mL) was added sodium borohydride (14 mg, 0.38 mmol) in small portions at 25° C. After stirring at 25° C. for 10 min, the mixture was concentrated in vacuo. The resulting residue was extracted with diethyl ether (2×50 mL), washed with water (2×25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 13-benzyl-9,10-dimethoxy-8,8-dimethyl-5,8,13,13a-tetrahydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (64 mg, 73%). LC/MS m/e calcd for C29H31NO4 (M+H)+: 458.57, observed: 458.3; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 3 H) 1.64 (s, 3 H) 2.34-2.49 (m, 2 H) 2.53-2.68 (m, 2 H) 2.75-2.85 (m, 1 H) 3.11-3.16 (m, 1 H) 3.26-3.31 (m, 1 H) 3.72 (s, 3 H) 3.80 (s, 3 H) 4.14 (s, 1 H) 5.94-5.99 (m, 3 H) 6.64 (d, J=8.34 Hz, 1 H) 6.69 (s, 1 H) 6.76 (d, J=7.07 Hz, 2 H) 6.94 (s, 1 H) 7.06-7.17 (m, 3 H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[C:20](C1NC=CN=1)(C1NC=CN=1)=[S:21]>C(Cl)Cl>[N:13]([C:12]1[C:7]([O:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3][C:2]([F:1])([F:18])[F:19])=[N:8][CH:9]=[CH:10][CH:11]=1)=[C:20]=[S:21]
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1cccnc1Oc1ccccc1OC(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1ccccc1Oc1ncccc1N=C=S
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 133a (16.21 mg, 0.0600 mmol) in anhydrous DCM (1.0 ml) was added dropwise to a cold solution of thiocarbonyl diimidazole (21.39 mg, 0.1200 mmol) in anhydrous DCM (0.50 ml). The reaction was stirred at 0° C. for 1 h and then warmed to rt with stirring for 2 h. The mixture was concentrated down to afford crude 133b which was taken directly onto the next step without purification.
Reaction SMILES: [CH3:1][SH:2].C(=O)([O-])[O-].[K+].[K+].[N+]([C:12]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])([O-])=O>CC(C)=O>[CH3:1][S:2][C:12]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1cc(C(F)(F)F)ccc1C#N
Temperature: 20 °C
Reaction time: 23 h
Yield: 88.5 %

Procedure:
Methanethiol (278 g, 5.78M) was added during 20 minutes to a stirred mixture of acetone (5 litres) and potassium carbonate (593 g, 4.29M) at −15° C. A solution of 2-nitro-4-trifluoromethylbenzonitrile (618 g, 2.86M) in acetone (500 ml) was added during 10 minutes. The mixture was allowed to warm to 20° C. with stirring for 23 hours and then heated at 55° C. for 2 hours to remove most of the methanethiol and then flushed with nitrogen for 4 hours. The mixture was poured onto ice/water, the solid filtered off, washed and dried to give 2-methylthio-4-trifluoromethylbenzonitrile (550 g). The yield of product was 89%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:70])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[C:28]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]=[CH:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH:27]=1)C(OC(C)(C)C)=O)(C)(C)C.[ClH:72]>C(OCC)(=O)C>[ClH:72].[ClH:72].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:70])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[C:28]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]=[CH:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH:27]=1
Reactant: CCCCCCCCC=CCCCCCCCCOc1ccc(C(=O)NCCCCN(CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1OCCCCCCCCC=CCCCCCCCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCC=CCCCCCCCCOc1ccc(C(=O)NCCCCNCCCCN)cc1OCCCCCCCCC=CCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A concentrated solution the amide 20 (0.22 g, 0.22 mmol) in ethyl acetate was added cooled to 0° C. A total of 5 mL of a freshly prepared saturated solution of HCl in ethyl acetate was added dropwise and the solution stirred for 1 h at room temperature during which time a white precipitate formed. The ethyl acetate was removed in vacuo and the residue co-evaporated with ethyl acetate and chloroform to give the product 27 as a white powder (0.19 g, 98%); 1H NMR (CDCl3) d 8.95 (br s, 2H, R2N+H2), 8.20 (br s, 3H, RN+H3), 7.45 (m, 2H, aryl), 6.78 (m, 1H, aryl), 5.33 (m, 4H, olefinic), 3.95 (m, 4H, OCH2), 3.38 (m, 2H, CH2), 3.11 (m, 2H, CH2), 3.01 (m, 4H, 2×CH2), 2.08-1.89 (m, 14H, 7×CH2), 1.71 (m, 6H, 3×CH2), 1.47-1.18 (m, 44H, 20×CH2), 0.89 (t, 6H, CH3); HRMS (FAB): theory for C51H94N3O3 (M+1), 796.7290; found (M+1), 796.7249; Anal. (C51H95Cl2N3O3.1.6H2O): C, H, N.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:29][CH2:30][CH3:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:29][CH2:30][CH3:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:21]=2)=[O:19])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCC(CCCCCCC(=O)c1c[nH]c2ccccc12)c1ccc(CC(C)C)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1

Procedure:
A mixture of 3-[8-(4-isobutylphenyl)undecanoyl]indole obtained in Pre. Ex. 8 (62 mg), ethyl 4-bromobutyrate (58 mg) and potassium carbonate (62 mg) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 16 hours. After filtration, the solution was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on a silica gel column (hexane-ethyl acetate, 4: 1) to give ethyl 4-[3-[8-(4-isobutylphenyl)-undecanoyl]-1-indolyl]butyrate as an oil. (48 mg)
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19]=[O:20])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].FC1C=C(C(NN)=O)C=CC=1C(OC)=O.[Cl-].[Na+]>C(O)(=O)C.O>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:19]=2[OH:20])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CNN=CC(C)=O
Reactant: CC(C)(C)c1ccc(C(=O)C=O)cc1
Agent: COC(=O)c1ccc(C(=O)NN)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
2-Oxopropanal methylhydrazone (46.375 mmol, 4.64 g) synthesized in Reference Synthetic Example 1 and (4-tert-butylphenyl)(oxo)acetaldehyde synthesized in Reference Synthetic Example 4 (46.375 mmol, 8.82 g) were dissolved is in acetic acid (140 mL) and stirred at 100° C. for 2 hours. The reactor was cooled to room temperature, and after addition of water (100 mL) and saturated aqueous sodium chloride (50 mL), it was extracted with chloroform three times. The resulting organic layer was dried and filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the desired product as a yellow solid (5.79 g, yield 46%).