Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13](O)=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](O)=[O:8].[Cl-:17].[Cl:18]C1N(C)CC[NH+]1C>>[NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:17])=[O:8]
Reactant: [Cl-]
Reactant: CN1CC[NH+](C)C1Cl
Reactant: Nc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Product: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reaction time: 6 h
Yield: 93 %

Procedure:
The same procedures as described in Example 7 were carried out except that the reaction of 5-amino-2,4,6-triiodoisophthalic acid and 2-chloro-1,3-dimethylimidazolinium chloride was carried out at 90°-95° C. for 6 hours. 5-Amino-2,4,6-triiodoisophthaloyl dichloride thus obtained was 5.53 g (93% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[C:12]([CH3:20])[NH:11][C:10]([CH3:21])=[C:9]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])[CH:5]=[CH:6][CH:7]=1.I[C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][CH2:37][CH2:38][C:39]#[N:40])=[O:35])=[CH:32][CH:31]=1.C(N(CC)CC)C.O>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([O:16][CH2:17][CH:18]=[CH:19][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH2:37][CH2:38][C:39]#[N:40])=[O:35])=[CH:41][CH:42]=3)=[O:15])=[C:12]([CH3:20])[NH:11][C:10]([CH3:21])=[C:9]2[C:22]([O:24][CH2:25][CH2:26][C:27]#[N:28])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)C1c1cccc(Cl)c1
Reactant: N#CCCOC(=O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCC=Cc2ccc(C(=O)OCCC#N)cc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
307 mg (0.77 mmol) of 5-(2-propene-1-yl) 3-(2-cyanoethyl) 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, 278 mg (0.92 mmol) of 2-cyanoethyl 4-iodobenzoate, 19 mg(0.08 mmol) of palladium acetate and 0.14 ml (1.0 mmol) of triethylamine were heated at 100° C. under stirring in 5 ml of DMF overnight. Water was added to the reaction mixture. After the extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][CH2:5][NH:6][CH:7]=[O:8].[CH2:10]([N:12]([CH2:19][CH2:20][Cl:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:11]>O>[Cl-:21].[CH3:1][N+:2]([CH3:9])([CH2:20][CH2:19][N:12]([CH2:10][CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH:7]=[O:8]
Reactant: CN(C)CCCNC=O
Reactant: CCN(CCCl)c1ccccc1
Solvent: O
Product: CCN(CC[N+](C)(C)CCCNC=O)c1ccccc1
Product: [Cl-]
Temperature: 80 °C

Procedure:
A stirred mixture of 157 parts of N-(3-dimethylaminopropyl)formamide in 20.0 parts of water was heated to 80° C. and over a period of one and one half hours there was added 171 parts of N-ethyl-N-(2-chloroethyl)aniline. The reaction mixture was heated at 95°-100° C. until a small sample when diluted with water gave a clear solution. After about seven hours of heating at 95°-100° C. there was obtained N,N-dimethyl-N-2-(N'-ethylanilino)ethyl-N-3-formamidopropylammonium chloride in the form of an aqueous solution.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.C1COCC1.CO.[Li+].[OH-]>O>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH2:12]2)[NH:4][CH:3]=1
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 50 °C
Yield: 58.8 %

Procedure:
tert-Butyl 4-(3-methyl-5-phenyl-1-(phenyl sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.9 g, 1.69 mmol) was placed in 1:1 THF:MeOH (10 mL). 3M LiOH (aq., 5.63 mL, 16.9 mmol) was added, and the reaction was heated to 50° C. for 1 hour. The reaction was then cooled, added to water and extracted with DCM. The organics were dried, filtered and concentrated to give the crude product which was purified (500:3 to 500:8 DCM:MeOH) to give tert-butyl 4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.390 g, 58.8% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([C:31]([F:34])([F:33])[F:32])[CH:23]=1.[CH3:35][PH:36](=[O:38])[CH3:37]>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([P:36]([CH3:37])([CH3:35])=[O:38])=[CH:23][C:24]=2[C:31]([F:34])([F:33])[F:32])[CH:3]=1)[CH3:11]
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: OB(O)c1ccc(Br)cc1C(F)(F)F
Reactant: C[PH](C)=O
Product: CC(Oc1cc(-c2ccc(P(C)(C)=O)cc2C(F)(F)F)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromo-2-trifluoromethyl-phenyl boronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 521 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])/[C:12](O)=[O:13])=[CH:7][CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:12](=[O:13])/[C:11](/[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[CH2:16][CH3:17])=[CH:26][CH:27]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC/C(=C(\C(=O)O)c1ccc(OCOC)cc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC/C(=C(\C(=O)Nc1ccc(O)cc1)c1ccc(OCOC)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
To a mixture of 3 (60 mg, 0.192 mmol), 4-aminophenol (23.0 mg, 0.211 mmol), 4-Dimethylaminopyridine (1.2 mg, 0.00982 mmol) and N,N-Diisopropylethylamine (37.2 mg, 0.287 mmol) in CH2Cl2 (2 ml) was added O-Benzotriazoyl-N,N,N′,N′-tetramethyluronium Hexafluorophosphate (76.5 mg, 0.202 mmol) under ice cooling, and the mixture was stirred at 0° C. for 5 min, and at room temperature for 15 h. The reaction was quenched with saturated aqueous NaHCO3 under ice cooling, and the whole was extracted with CHCl3, the organic layer was washed with brine, dried over Na2SO4, and then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 3:1 to 2:1) gave 6a (68%). 6a: colorless powder; 1H-NMR (CDCl3) δ 1.05 (3H, t, J=7.5 Hz), 2.77 (2H, t, J=7.5 Hz), 3.43 (3H, s), 5.09 (2H, s), 6.79 (4H, m), 7.00 (2H, d, J=8.8 Hz), 7.00 (1H, brs), 7.07 (2H, m), 7.15-7.22 (3H, m), 7.37 (2H, d, J=8.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.COC(OC)[N:27]([CH3:29])C.C(O)(=O)C.O.[NH2:37]N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3[CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[S:16][C:12]=3[C:11]3[NH:37][N:27]=[CH:29][C:10]=3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Reactant: COC(OC)N(C)C
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(C2Cc3cn[nH]c3-c3sc(-c4ccncc4)cc32)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
In a 100 mL round bottomed flask was placed 4-(4-chlorophenyl)-2-pyridin-4-yl-5,6-dihydro-1-benzothiophen-7(4H)-one (60 mg, 0.2 mmol) and then suspended in 1,1-dimethoxy-N,N-dimethylmethanamine (3 mL, 20 mmol). The mixture was stirred for 6 h at 120° C. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The residue was dissolved in acetic acid (5 mL, 90 mmol) and then was added hydrazine hydrate (100 uL, 2 mmol) and the mixture was stirred for 16 h at 50° C. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and was washed with saturated aqueous solution of NaHCO3 (50 mL), brine (50 mL), dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (24 g) column chromatography eluted with a 50% to 100% EtOAc/hexane to yield target compound as an yellow solid (72 mg), which include some impurities and further purification has been performed by preparative HPLC to yield title compound (30 mg, 50%) as an yellow solid. LCMS: (FA) ES+ 364, 366; 1H NMR (400 MHz, d6-DMSO) δ ppm 12.74 (br s, 1H), 8.50-8.52 (m, 2H), 7.58-7.59 (m, 2H), 7.55 (s, 1H), 7.40 (d, 2H), 7.25 (d, 2H), 7.18 (s, 1H), 4.40 (t, 1H), 3.13-3.19 (m, 1H), 2.93 (dd, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CS(C)=O>[CH2:12]([N:2]([CH2:9][C:5]1[CH:6]=[CH:10][CH:11]=[CH:3][CH:4]=1)[C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH:8]=[CH:9][C:5]=2[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc2occc2c1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(CN(Cc2ccccc2)c2ccc3occc3c2)cc1

Procedure:
A stirred solution of 5-aminobenzo[b]furan hydrochloride in dry DMSO is treated with excess benzyl bromide followed by solid NaHCO3 to give the title compound.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1.C1N=CN([C:15]([N:17]2C=N[CH:19]=[CH:18]2)=[O:16])C=1.CCN(C(C)C)C(C)C.[F:31][C:32]1[CH:33]=C([CH:37]=[C:38]([F:40])[CH:39]=1)CN>>[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:15]([NH:17][CH2:18][C:19]2[CH:33]=[C:32]([F:31])[CH:39]=[C:38]([F:40])[CH:37]=2)=[O:16])[S:7][CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(CCl)cs1
Reactant: NCc1cc(F)cc(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cc(F)cc(F)c1)Nc1nc(CCl)cs1

Procedure:
A 3-neck 500 ml round bottle flask was charged with 4-Chloromethyl-thiazol-2-ylamine hydrochloride (Intermediate 1, 1 eq.) and CDI (1.05 eq.) and purged with nitrogen. Anhydrous THF was added via cannula. To the resulting stirring granular suspension was added DIPEA (1.05 eq.) dropwise via an addition funnel. After the addition of DIPEA was complete, the 3,5-difluoro-benzyl amine (1.0 eq.) was added dropwise in the same manner. The reaction was quenched with DI water and the THF was removed in vacuo. The resulting orange residue was partitioned with water and DCM. The organic layer was dried with Na2SO4, filtered and solvent was removed in vacuo. The crude was purified by column chromatography (acetone/hexanes) followed by recrystallization from iPrOAc and hexanes. The solid was isolated via filtration and dried under vacuum to give 1-(4-Chloromethyl-thiazol-2-yl)-3-(3,5-difluoro-benzyl)-urea.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:9][CH:10]=1)(=[O:4])=[O:3].[CH:23]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:23]1([CH2:29][C:30]([N:20]2[CH2:21][CH2:22][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][O:11][C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][N:9]=3)[CH2:18][CH2:19]2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)CC1CCCCC1
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)CC3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 23 mg (0.071 mmol) of 5-(methylsulfonyl)-2-{2-[(1S,2R)-2-piperidin-4-ylcyclopropyl]ethoxy}pyridine in 0.6 ml anhydrous N,N-dimethylformamide at ambient temperature was added 0.020 ml (0.14 mmol) cyclohexylacetic acid, followed by 27 mg (0.14 mmol) EDCl, 9.6 mg (0.071 mmol) HOBt, and 0.062 ml (0.35 mmol) diisopropylethylamine. The solution was stirred overnight at ambient temperature. The crude in N,N-dimethylformamide was purified directly by reverse phase HPLC (TMC Pro-Pac C18; 30-100% acetonitrile/0.1% formic acid in water gradient). The pure fractions were lyophilized to yield the title compound as white solid. 1H NMR (DMSO): δ 8.65 (d, J=2.1 Hz, 1H), δ 8.15 (dd, J=8.8 Hz, 2.5 Hz, 1H), δ 7.01 (d, J=8.7 Hz, 1H), δ 4.43 (t, J=6.8 Hz, 2H), δ 4.36 (t, J=12.0 Hz, 1H), δ 3.85 (t, J=13.7 Hz, 1H), δ 3.31 (s, 1H), δ 3.28 (s, 1H), δ 3.24 (s, 3H), δ 2.94 (t, J=12.7 Hz, 1H), δ 2.15 (d, J=6.5 Hz, 2H), δ 2.00-2.04 (m, 1H), δ 1.51-1.75 (m, 9H), δ 1.08-1.23 (m, 6H), δ 0.83-0.94 (m, 3H), δ 0.53-0.59 (m, 2H). LC/MS 589.3 (M+1). GPR119 Human EC50: 11.8 nM
Reaction SMILES: CCC(C1NC(=O)CNC(=O)C2NC(C(C(C(O)CO)C)NC(C3N(C(C(CC(N)=O)NC(=O)C(CS(C4NC5C=C(OC)C=CC=5C=4C2)=O)NC(=O)CNC1=O)=O)CC(O)C3)=O)=O)C.[I:66]N1C(=O)CCC1=O.[Br:74][C:75]1[C:76]([OH:81])=[N:77][CH:78]=[CH:79][CH:80]=1>>[OH:81][C:76]1[C:75]([Br:74])=[CH:80][C:79]([I:66])=[CH:78][N:77]=1
Reactant: Oc1ncccc1Br
Reactant: O=C1CCC(=O)N1I
Agent: CCC(C)C1NC(=O)CNC(=O)C2Cc3c([nH]c4cc(OC)ccc34)S(=O)CC(NC(=O)CNC1=O)C(=O)NC(CC(N)=O)C(=O)N1CC(O)CC1C(=O)NC(C(C)C(O)CO)C(=O)N2
Product: Oc1ncc(I)cc1Br

Procedure:
Following a previously reported method (Meana A, et al, Synlett 2003, 1678-1682) compound I8 was prepared from N-iodosuccinimide (2.48 g, 11.0 mmol) and 3-bromo-2-hydroxypyridine I7 (1.74 g, 10.0 mmol) as a pale brown solid (2.55 g, 85%). 1H NMR (DMSO-d6) δ 12.27 (br s, 1H), 8.08 (d, 1H, J=2.3 Hz), 7.71 (d, 1H, J=2.3 Hz).
Reaction SMILES: [CH2:1]([C@H:8]([NH:30]C(=O)OC)[C@H:9]([OH:29])[CH2:10][N:11]1[C@H:20]([C:21](=[O:28])[NH:22]OC(C)(C)C)[CH2:19][C@H:18]2[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[NH2:30][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([OH:29])[CH2:10][N:11]1[C@H:20]([C:21]([NH:22][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:28])[CH2:19][C@H:18]2[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1
Reactant: COC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NOC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 202.4 %

Procedure:
A suspension of 41.37 g of methyl (1S,2R)-[1-benzyl-3-[(3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinolin-2-yl]-2-hydroxy-propyl]-carbamate and 23.0 g of sodium hydroxide in 90 ml of ethanol and 90 ml of water was heated at reflux for 3.5 hours, diluted with 45 ml of water and cooled to 22°, and the separated solid was filtered off, washed with a 1:4 mixture of ethanol/water and dried, there being obtained 35.35 g (98%) of pure 2-[3 (S)-amino-2(R)-hydroxy-4-phenyl-butyl]-N-tert.butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, m.p. 173°-175° C. IR (KBr): 3435 m, hr. (NH, OH), 1665s (C=O), 1562 m (amide II).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C1(C)C=CC(C=[O:17])=CC=1.O=O.C=C.C1OC1>CC1C=CC(C)=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:17])=[O:7])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1ccc(CO)cc1
Agent: C=C
Agent: O=O
Solvent: Cc1ccc(C)cc1
Solvent: C1CO1
Product: Cc1ccc(C(=O)O)cc1
Temperature: 190 °C

Procedure:
Into a pressure vessel equipped with magnetic agitation is placed a liquid charge of 92% p-xylene and 4.0% each of p-methyl benzyl alcohol and p-tolualdehyde which are obtainable from recycling streams and is then pressurized with 45 p.s.i.a. oxygen and then pressurized with ethylene. The reaction mixture is heated to 190° C. and reacted for 30 min. with agitation at a system pressure of 1420 p.s.i.g. The liquid phase effluent is found to contain 1.52% ethylene oxide, 4.5% p-methyl benzyl alcohol and 4.4% p-tolualdehyde. The amount of p-toluic acid formed was not determined.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:26][CH2:25][C:3]1[C:2]([NH:1][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:15][C:6]2[N:7]([CH3:14])[C:8](=[O:13])[N:9]([CH3:12])[C:10](=[O:11])[C:5]=2[C:4]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: BrCCc1ccccc1
Reactant: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C
Product: COc1ccc(F)cc1-c1c(CN)c(NCCc2ccccc2)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
The synthesis of title compounds started from Compound 70a (Example 64) and 1-(bromoethyl)benzene, according to procedures described in the synthesis of Compound 56. 1H NMR (400 MHz, CHLOROFORM-d) δ MS [m+H] calc'd C25H27FN5O3 464; found 464.
Reaction SMILES: [CH3:1][CH:2]([CH:8]=[O:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>CCOCC>[CH2:10]1[CH2:11][O:12][CH:8]([CH:2]([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[O:9]1
Reactant: COC(=O)CC(C)C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: COC(=O)CC(C)C1OCCO1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-methyl-4-oxo-butanoate (86.3 g), ethylene glycol (61.75 l g, 0.996 m), p-toluenesulfonic acid (1 g) and benzene (700 ml) is refluxed under nitrogen for 16 hr. The resulting mixture is allowed to cool to room temperature and treated with ether (300 ml). The organic phase is washed with 5% sodium bicarbonate solution (100 ml), dried (Na2SO4) and evaporated in vacuo to give methyl 4,4-ethylenedioxy-3-methylbutanoate as a crude product (63.2 g). This material is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[NH:9][C:8](=[O:18])[CH2:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:33][C:34]([F:38])([F:37])[CH2:35]I>CN(C=O)C.C(OCC)(=O)C.O>[F:33][C:34]([F:38])([F:37])[CH2:35][N:9]1[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12](=[O:13])[N:6]([CH2:5][C:4]2[C:19]([O:25][CH3:26])=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:3]=2[O:2][CH3:1])[CH2:7][C:8]1=[O:18]
Reactant: FC(F)(F)CI
Reactant: COc1cc(OC)c(CN2CC(=O)Nc3ccccc3C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(OC)c(CN2CC(=O)N(CC(F)(F)F)c3ccccc3C2=O)c(OC)c1
Temperature: 55 °C
Reaction time: 16 h
Yield: 34.9 %

Procedure:
The product from Step 4B (6 g, 0.017 mol) was dissolved in DMF (40 ml) at room temperature under nitrogen. Caesium carbonate (8.2 g, 0.025 mol) was added followed by trifluoroethyl iodide (8.8 g, 0.025 mol) and the mixture stirred at 55° C. for 16 hr. The reaction mixture was taken up in ethyl acetate/water, the organic layer washed (water, brine), dried (MgSO4) and evaporated in vacuo. Purification by chromatography (SiO2, ethyl acetate/dichloromethane) afforded the product as a white solid (2.6 g, 35%). (1H NMR, CDCl3) δ 3.68–3.83 (11H, m), 4.13–4.17 (1H, m), 4.72 (1H, S d, J=13.6 Hz), 4.84–4.88 (1H, m) 5.04 (1H, d, J=13.6Hz), 6.13 (2H, s), 7.18 (1H, d, J=8.3 Hz), 7.32–7.50 (2H, m), 7.96 (1H, m).
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([N:22]([CH3:24])[CH3:23])[CH2:13][C:12]2=1)=O)(C)(C)C.[F:25][C:26]1[CH:34]=[CH:33][C:29](C(Cl)=O)=[CH:28][CH:27]=1>FC(F)(F)C(O)=O>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]2[CH2:16][CH2:15][CH:14]([N:22]([CH3:23])[CH3:24])[CH2:13][C:12]3=2)=[O:5])=[CH:28][CH:27]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(NC(=O)OC(C)(C)C)cc3c2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
A solution of 0.10 gm (0.30 mMol) 6-(t-butoxycarbonyl)amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole in 1.0 mL trifluoroacetic acid was stirred for 20 minutes at room temperature. The reaction mixture was then concentrated under reduced pressure. The residual oil was then dissolved in 5 mL tetrahydrofuran. To this solution was added 1.5 mL triethylamine followed by 5.0 μL (0.42 mMol) 4-fluorobenzoyl chloride and the solution was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. This solution was washed with aqueous potassium carbonate and was then concentrated under reduced pressure. The residue was dissolved in dilute aqueous tartaric acid and the solution was extracted well with dichloromethane. The remaining aqueous phase was made basic with dilute aqueous sodium hydroxide and was extracted well with dichloromethane. These organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 95:5 chloroform:5% ammonium hydroxide in methanol. Fractions containing the product were combined and concentrated under reduced pressure to give 0.102 gm (95%) of 6-(4-fluorobenzoyl)amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](Cl)=[O:12])=[CH:5][CH:4]=1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C(C)=O.[Na].O>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:12])[CH2:15][C:14]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCC(=O)Cl)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
3-(4-Methoxyphenyl)propionyl chloride (84.6 g, 0.426 mole) was added to a stirred suspension of ethyl acetoacetate, sodium salt (64.7 g, 0.426 mole) in ether (250 ml) over a period of 1.5 hours and the reaction was allowed to sit for 16 hours. The reaction mixture was treated with water (100 ml) and extracted with ether. The ether extract was cooled in an ice bath and ammonia gas was bubbled into the solution for 2.5 hours while the reactants were allowed to warm to room temperature. The reaction was washed with water, filtered and the ether fraction was stirred with 3N hydrochloric acid (100 ml) for 16 hours. The ether layer was washed with water, 5% sodium bicarbonate, brine and dried with sodium sulfate. The solvent was removed and the residue was distilled under high vacuum to give the product as an yellow oil (30.0 g, 28%).
Reaction SMILES: C[O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.B(Br)(Br)Br>ClCCl.O>[OH:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1c(O)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of 5-methoxy-4-nitroindole (110 mg, 0.57 mmol) in dichloromethane (12 ml) was cooled to −30° C. under an atmosphere of nitrogen. Boron tribromide (0.74 ml of a 1M solution in dichloromethane, 0.74 mmol) was added dropwise then the mixture warmed to ambient temperature and stirred for 1 hour. The mixture was cooled to 5° C., diluted with dichloromethane (5 ml), and water (10 ml). After stirring for 5 minutes the insoluble material was filtered off and the dichloromethane layer separated, dried (MgSO4), and evaporated to give a dark oil which was and purified by silica column chromatography eluting with dichloromethane to give 5-hydroxy-4-nitroindole (68 mg, 67%).