Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:38])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[N:13]=[C:12]([C:17]4[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=4)[N:11]([CH:27]([CH3:29])[CH3:28])[C:10]=3[C@H:9]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[CH3:37])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:49](Cl)(=[O:53])[O:50][CH2:51][CH3:52]>C1COCC1>[CH2:51]([O:50][C:49]([C:9]1([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[CH3:37])[C:10]2[N:11]([CH:27]([CH3:28])[CH3:29])[C:12]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)=[N:13][C:14]=2[C:15](=[O:16])[N:8]1[C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH3:38])=[O:53])[CH3:52]
Reactant: COc1ncc(-c2nc3c(n2C(C)C)[C@@H](c2ccc(Cl)cc2C)N(c2cc(Cl)ccc2C)C3=O)c(OC)n1
Reactant: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(Cl)cc2C)c2c(nc(-c3cnc(OC)nc3OC)n2C(C)C)C(=O)N1c1cc(Cl)ccc1C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of the product from example 76 (100 mg, 0.2 mmol) in THF (3 mL) at −78° C. was added NaHMDS (181 μL, 0.2 mmol) and the mixture was stirred at −78° C. for 15 min. Ethyl carbonochloridate (86 μL, 0.9 mmol) was added at −78° C. and the mixture was allowed to warm up to rt and stirred for 1 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution, then was diluted in EtOAc and extracted with brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by preparative HPLC (Column: Sunfire C18, 30×100 mm, 5 μm. Flow: 30 mL/min. Gradient 5-100% B in 20 min; A=0.1% TFA in water, B═CH3CN). tR: 1.39 min (LC-MS 2); ESI-MS: 624.4/626.4 [M+H]+ (LC-MS 2).
Reaction SMILES: [ClH:1].[C:2]1([C:8]2([C:18]([O:20]CC)=O)[CH2:10][CH:9]2[CH2:11][N:12]2CCOCC2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:23]>>[Cl:1][C:5]1[CH:6]=[CH:7][C:2]([C:8]2([C:18]([NH2:23])=[O:20])[CH2:10][CH:9]2[CH2:11][NH2:12])=[CH:3][CH:4]=1
Reactant: CCOC(=O)C1(c2ccccc2)CC1CN1CCOCC1
Reactant: N
Reactant: Cl
Product: NCC1CC1(C(N)=O)c1ccc(Cl)cc1

Procedure:
In a manner similar to that described in Example 1, but hydrolyzing the hydrochloride of 1-p-chlorophenyl 1-ethoxycarbonyl 2-aminomethyl cyclopropane (Z) and then treating the intermediate acid chloride with ammonia and salifying with hydrochloric acid, there is obtained the product of the formula ##STR16##
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:19]=[C:18]([C:20]([N:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:33][CH3:34])[C:28]=4[OH:32])[CH2:23]3)=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.O.[NH4+].[Cl-]>[Fe].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:19]=[C:18]([C:20]([N:22]3[CH2:31][CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:33][CH3:34])[C:28]=4[OH:32])[CH2:23]3)=[O:21])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc([N+](=O)[O-])cc3)nc3ccccc13)C2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(N)cc3)nc3ccccc13)C2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-[[2-(4-nitrophenyl)quinazolin-4-yl]carbonyl]-5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline (9 g, 19.72 mmol, 1.00 equiv), water (300 mL), ethanol (300 mL), Fe (2.5 g, 2.30 equiv) and NH4Cl (2.4 g, 44.87 mmol, 2.30 equiv). The resulting solution was stirred overnight at 90° C. The solids were collected by filtration. The residue was dissolved in 200 mL of DMSO. The solids were filtered out. The resulting solution was diluted with 3 L of H2O. The solids were collected by filtration. The filter cake was washed with 1×1 L of water. This resulted in 2.5 g (30%) of 2-[[2-(4-aminophenyl)quinazolin-4-yl]carbonyl]-6-methoxy-1,2,3,4-tetrahydroisoquinolin-5-ol as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.88 (2t, 2H), 3.45 and 4.01 (2t, 2H), 3.74-3.80 (2s, 3H), 4.36 and 4.89 (2s, 2H), 5.80 (s, 2H), 6.31-6.92 (m, 4H), 7.53-7.63 (m, 1H), 7.73-7.84 (2d, 1H), 7.94-7.99 (m, 2H), 8.18-8.25 (m, 2H), 8.68-8.74 (2s, 1H); MS (ESI) m/z 427 ([M+H]+).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][C@@H:12]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C@@H:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:14].[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46](O)=[O:47])[CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:29][CH:28]([CH3:30])[CH2:27][C@H:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:46](=[O:47])[CH2:45][N:42]1[CH2:43][CH2:44][O:39][CH2:40][CH2:41]1)[CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(O)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Referring to FIG. 45. DIPEA (592 μL, 3.6 mmol, 2.6 eq) was added to a mixture of (S)-benzyl 2-((S)-2-amino-4-phenylbutanamido)-4-methylpentanoate hydrochloride (600 mg, 1.4 mmol), 2-morpholinoacetic acid (312 mg, 2.1 mmol, 1.5 eq) and HATU (816 mg, 2.1 mmol. 1.5 eq) in CH2Cl2 (25 mL) and the mixture was stirred overnight at RT. The reaction mixture was washed with water and the aqueous layer was extracted once with CH2Cl2. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-100% EtOAc in heptanes, followed by 10% MeOH in EtOAc) to yield product (700 mg, 98%) as a yellow oil.
Reaction SMILES: FC1C(F)=C(F)C(F)=C(F)C=1[O:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=3[C:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH:28]=3)[CH2:15][CH2:14][O:13][C:12]=2[CH:40]=1)(=O)=[O:6].[N:49]1[CH:54]=[CH:53][N:52]=[CH:51][C:50]=1[NH2:55].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(O)(C(F)(F)F)=O.C1COCC1>[N:49]1[CH:54]=[CH:53][N:52]=[CH:51][C:50]=1[NH:55][S:5]([C:8]1[CH:9]=[CH:10][C:11]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:19][C:18]=3[C:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH:28]=3)[CH2:15][CH2:14][O:13][C:12]=2[CH:40]=1)(=[O:6])=[O:4]
Reactant: Nc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Oc4c(F)c(F)c(F)c(F)c4F)ccc32)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cnccn1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1C1=CCNCC1
Reaction time: 0.33 h
Yield: 49.1 %

Procedure:
A round-bottom flask was charged with tert-butyl 4-(2-(7-((perfluorophenoxy)sulfonyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE AA, 37.7 mg, 0.053 mmol), pyrazin-2-amine (7.61 mg, 0.080 mmol, TCI America, Portland, Oreg.), and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (112 μL, 0.112 mmol) was added dropwise over 30 s to give a light-yellow solution. After 20 min, the flask was lowered into an ice bath. After another 30 min, TFA (3 drops) was added via syringe, and the mixture was concentrated. The residue was dissolved in DCM (1 mL) and TFA (0.5 mL). After 20 min, the mixture was concentrated, and the residue was dissolved in MeOH and loaded onto a 500 mg SCX-2 ion exchange column. The column was eluted with MeOH then with 2N ammonia in methanol. The basic fraction was concentrated. The residue was further purified by chromatography on silica gel (12 g column, 10% MeOH/DCM, then 20% of a 2N ammonia in methanol solution dissolved in DCM) to give N-(pyrazin-2-yl)-4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (13.49 mg, 0.026 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.08 (s, 1 H), 8.02 (s, 1 H), 7.86 (br. s., 1 H), 7.72 (dd, J=1.7, 8.6 Hz, 2 H), 7.59 (d, J=1.9 Hz, 1 H), 7.54 (d, J=8.1 Hz, 1 H), 6.43 (d, J=8.5 Hz, 1 H), 5.87 (br. s., 1 H), 4.27 (br. s., 2 H), 3.61-3.53 (m, J=6.1 Hz, 5 H), 3.09 (br. s., 2 H), 2.39-2.30 (m, 1 H). m/z (ESI) 518.4 (M+H)+.
Reaction SMILES: [CH2:1]([Si:3](Cl)([CH2:6]C)[CH2:4]C)C.[OH:9][CH2:10][C@@H:11]1[CH:26]=[C:25]2[C@@H:15]([CH2:16][CH:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH2:18]3)[N:13]([CH3:14])[CH2:12]1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:6][Si:3]([CH3:1])([CH3:4])[O:9][CH2:10][C@@H:11]1[CH:26]=[C:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:13]([CH3:14])[CH2:12]1
Reactant: CN1C[C@H](CO)C=C2c3cccc4c3C(CN4)C[C@H]21
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C[C@H](CO[Si](C)(C)C)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Yield: 78.5 %

Procedure:
Triethylsilyl chloride (TES-Cl, 1.30 g) is added into a mixture of dihydrolysergol (1.47 g), triethylamine (1.74 g) and DMAP (0.14 g) in N,N-dimethylformamide (10 mL) and the mixture is stirred at room temperature. After complete reaction, the mixture is cooled and water (15 mL) is added. The resulted suspension is stirred for an additional 2 h and then filtered and washed with water. The product is dried and recrystallized from dichloromethane/heptanes to give 1.47 g of 8β-(trimethylsiloxymethyl)-9,10-didehydro-6-methyl-ergoline in 70% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](Br)=[CH:12][C:13]=2[OH:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]([Cl:30])(=[O:29])[S:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1C=CC=CC=1>[C:23](=[O:29])([O-:14])[S:24][CH2:25][CH2:26][CH2:27][CH3:28].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([Cl:30])=[CH:12][C:13]=2[OH:14])=[CH:4][CH:3]=1
Reactant: Oc1cc(Br)nnc1-c1ccc(Cl)cc1
Reactant: CCCCSC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCSC(=O)[O-]
Product: Oc1cc(Cl)nnc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3-(4'-Chlorophenyl)-4-hydroxy-6-bromopyridazine (14.2 g, 0.0497 mol) was suspended in 100 ml of benzene, triethylamine (5.5 g, 0.0543 mol) was added, and the mixture was stirred for 3.5 hours at room temperature to complete the reaction. S-Butyl thiochlorocarbonate (7.85 g, 0.05162 mol) was then added dropwise to the mixture in the course of 5 minutes, and the reaction mixture was stirred for 3 more hours without heating. The triethylamine hydrochloride which had precipitated was filtered off, and the benzene solution was washed in succession in each case with 150 ml portions of water, highly dilute hydrochloric acid, highly dilute sodium hydroxide solution and then again water, and dried over sodium sulfate. The solvent was then removed completely in vacuo, and finally under an oil-pump vacuum (0.2 Torr, 90° C. bath temperature). The S-butyl thiocarbonate of 3-(4'-chlorophenyl)-4-hydroxy-6-chloropyridazine, which was first obtained as an oil (17.5 g, 0.04356 mol, 87.6% of theory), solidified upon prolonged standing and, when dissolved in and allowed to crystallize from hexane, showed amp. of 68°-71° C.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Na].[CH2:15](Cl)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31].O>CS(C)=O.O1CCCC1>[CH2:31]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCCCCCCCCCCCCCCCl
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a suspension of sodium theobromine (2.02 g, 10.0 mmol) in dimethylsulfoxide/tetrahydrofuran (2:1, 30 ml) was added 16-heptadecenyl chloride and the reaction stirred for 16 hours at 60° C. The mixture was then poured into water (75 ml) and extracted with ethyl acetate (3×75 ml). The organic portions were combined, dried over magnesium sulfate and the solvent evaporated, leaving a cream-colored solid residue. Recrystallization of the residue from hot hexane resulted in 2.31 g of 1-(16-Heptadecenyl)-3,7-dimethylxanthine as a white solid (85% yield).
Reaction SMILES: [CH:1]#[CH:2].[CH:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1.[C:8]12[CH2:14][C:11]([CH2:12][CH2:13]1)=[CH:10][CH:9]=2>>[CH3:1][CH2:2][CH2:9][CH:10]=[CH:11][CH2:14][CH2:8][CH:13]=[CH:12][CH2:3][CH2:7][CH2:6][CH2:5][CH3:4]
Reactant: C1=CCC=C1
Reactant: C1=C2CCC(=C1)C2
Reactant: C#C
Product: CCCC=CCCC=CCCCCC

Procedure:
A reaction was conducted under the same reaction conditions as in Example 1 except that acetylene and cyclopentadiene, which are both raw materials for norbornadiene, were used instead of norbornadiene to try a direct reaction of acetylene and cyclopentadiene. It was however impossible to obtain pentacyclo[5.4.21.7.13.6.010.13.012.14 ]-tetradeca-4,8-diene.
Reaction SMILES: [C:1]([N:3]=[C:4]([O:8][CH3:9])[CH2:5][C:6]#[N:7])#[N:2].CCOCC.[ClH:15].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Cl:15][C:1]1[N:3]=[C:4]([O:8][CH3:9])[CH:5]=[C:6]([NH2:7])[N:2]=1
Reactant: Cl
Reactant: COC(CC#N)=NC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N)nc(Cl)n1
Yield: 83.1 %

Procedure:
After 1.23 g of methyl N-cyanocyanoacetimidate was dissolved in 10 ml of glacial acetic acid, 10.7 g of a 20% ether solution of hydrogen chloride was added dropwise at 15°-25°C to the solution. Then, the solution was made to react for 6 hours at room temperature. After the reaction, the solvent was distilled off to give a residue. The residue was dissolved in 10 ml of water and the solution was neutralized with sodium bicarbonate solution to give precipitates. Then, the precipitates were collected by filtration, washed with water and dried to give 1.47 g of crude crystals. The crystals were recrystallized from diluted hydrochloric acid to give 1.33 g of 2-chloro-4-methoxy-6-aminopyrimidine (yield 83.1%), mp 186°-187°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C(OCC)(=O)C>CC1C=CC=CC=1C>[CH3:1][C:2]1([CH3:21])[O:7][C:6](=[S:31])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC1(C)OC(=S)Nc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 25 °C
Yield: 19.8 %

Procedure:
A mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile (1 g, 3.6 mmol) and Lawesson's reagent (1.8 g, 4.3 mmol) in o-xylene (30 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, poured into ethyl acetate (50 mL) and washed with 1 N HCl (2×20 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified via flash chromatography (silica gel, 20% ethyl acetate/hexane) to give 3-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile (0.21 g, 20%) as a white solid: mp 236-237° C.; 1H-NMR (DMSO-d6) δ 12.3 (s, 1H), 8.24 (s, 1H), 8.05 (d, 1H, J=8.07 Hz), 7.82 (d, 1H, J=7.68 Hz), 7.74-7.64 (m, 3H), 7.14 (d, 1H, J=8.78 Hz), 1.71 (s, 6H); MS (APCI) m/z 295 ([M+H]+, 100%); Anal. Calcd. For C17H14N2OS: C, 69.36; H, 4.79; N, 9.52. Found: C, 68.35; H, 4.91; N, 9.07
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15](O)=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1)=O)(C)(C)C.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=O)[CH3:27].[OH-].[Na+]>O>[Cl:18][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][N:11]=1)[NH:8][C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Cl:19])=[CH:27][C:15]2=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Reactant: CC(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(-c2ccccc2Cl)[nH]c2cnc(Cl)cc12
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 5.5 %

Procedure:
5-(tert-Butoxycarbonylamino)-2-chloroisonicotinic acid (502 mg, 1.84 mmol) was suspended in polyphosphoric acid (9.5 g, 102 mmol) at ambient temperature and stirred for 10 mins causing a bright yellow coloration and visible evolution of gas. 2′-Chloroacetophenone (570 mg, 3.69 mmol) was added and the mixture heated to 150° C. for 2.5 h. The mixture was diluted with cold water (50 mL), and then cooled in ice and treated with solid sodium hydroxide (6.0 g, 150 mmol) to pH˜7. The mixture was filtered and the recovered oily solids washed with water, dissolved in methanol and reconcentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 0.5-20% methanol in DCM) to afford the title compound as a cream solid (29.2 mg, 5.5%). 1H NMR (400 MHz, MeOD) δ 8.87 (s, 1H), 8.12 (s, 1H), 7.64-7.58 (m, 2H), 7.58-7.46 (m, 2H), 6.47 (s, 1H); NH absent. LCMS: M+H+=291 & 293.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:16]([C:14]2[O:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)=[O:18])=[CH:23][CH:22]=1
Reactant: CCc1cc(-c2ccc(C(=O)O)o2)c(C)[nH]c1=O
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: CCc1cc(-c2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3)o2)c(C)[nH]c1=O
Yield: 60 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-furan-2-carboxylic acid and 4-trifluoromethyl-benzylamine to afford the title compound (60% yield). LC/MS: RT 2.95 min; m/e 405 (M+H).
Reaction SMILES: [CH3:1][C:2](=[CH2:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[C:14]1([S:20]([CH2:23][C:24]#[N:25])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1>C(O)C>[C:14]1([S:20]([C:23](=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH2:3][C:2]([CH3:1])=[CH2:13])=[CH:6][CH:7]=2)[C:24]#[N:25])(=[O:21])=[O:22])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#CCS(=O)(=O)c1ccccc1
Reactant: C=C(C)COc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: C=C(C)COc1ccc(C=C(C#N)S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 4-(2-methylallyloxy)-benzaldehyde (7.03 g, 40 mmol) and of (phenylsulfonyl)acetonitrile (7.24 g, 40 mmol) in 70 ml absolute ethanol is heated under reflux in the presence of a catalytic quantity of piperidine (0.5 ml) for 48 hours. The reaction medium is cooled to room temperature and the precipitate formed is filtered and washed with cold ethanol. After drying in a dessicator, 10.45 g (yield 77%) of 2-benzenesulfonyl-3-[4-(2-methylallyloxy)phenyl]acrylonitrile are obtained in the form of a very pale yellow solid which is used as it is in the next step.
Reaction SMILES: [CH2:1]([C:8]12[C:16](=[O:17])[N:15]([CH3:18])[CH2:14][CH:13]1[CH2:12][CH2:11][N:10](CC1C=CC=CC=1)[CH2:9]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Pd].O>[CH2:1]([C:8]12[C:16](=[O:17])[N:15]([CH3:18])[CH2:14][CH:13]1[CH2:12][CH2:11][NH:10][CH2:9]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CC2CCN(Cc3ccccc3)CC2(Cc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: CN1CC2CCNCC2(Cc2ccccc2)C1=O
Yield: 77.8 %

Procedure:
To a solution of the compound of Example 200, Step D (0.034 g, 0.10 mmol) in acetic acid (18 mL) was added a slurry of palladium on carbon (10% by weight, 0.030 g) in H2O (2 mL). The reaction mixture was shaken under 50 psig hydrogen for 24 h, an additional aliquot of palladium on carbon (0.030 g) was introduced and the reaction was continued under 50 psig hydrogen for another 24 h. The reaction mixture was filtered through a bed of Celite® with the aid of MeOH, concentrated under vacuum, and the residue was partitioned between CH2Cl2 and H2O at pH 9. The organic layer was removed and the aqueous layer was washed twice with CH2Cl2, the organic layers were combined and washed with a saturated aqueous brine solution, dried over Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 3% MeOH/0.2% NH4OH/CH2Cl2 as the eluant afforded the compound of Example 200, Step E (0.019 g): +APcI MS (M+1)+ 245; 1H NMR (400 MHz, CDCl3) δ: 7.10-7.24 (arom, series of m, 5H), 3.21 (m, 1H), 2.71 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][NH:27][CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:30])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:31](=O)[CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.C(O)(=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]4[CH2:29][CH2:28][N:27]([CH2:31][CH3:32])[CH2:26][C:21]=4[N:22]3[CH3:25])=[CH:18][CH:17]=2)[C:12](=[O:30])[CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCNC2
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN1CCc2c(n(C)c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.6 %

Procedure:
To a solution of 4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (120 mg, 0.28 mmol) in dichloromethane/acetic acid (1% acetic acid, 10 mL) were sequentially added acetaldehyde (0.50 mL, 13 mmol) and NaBH(OAc)3 (1.0 g, 4.7 mmol). The reaction mixture was stirred at ambient temperature for 1 h. The mixture was concentrated, and the residue was purified by flash chromatography (silica gel silica gel, (1:1 hexanes/EtOAc)/(10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide), 1:0 to 0:1) to provide 4-(benzyloxy)-1-(2-ethyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (120 mg, 72%) as a white solid. The free base was converted to the HCl salt using 1.25 M HCl in methanol, providing the title compound (120 mg, 95%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 7.57 (d, J=7.5 Hz, 1H), 7.54-7.34 (m, 7H), 6.97 (d, J=8.0 Hz, 1H), 6.10 (dd, J=7.5, 2.0 Hz, 1H), 5.97 (s, 1H), 5.16 (s, 2H), 3.67 (s, 3H), 3.45-3.18 (4H, overlapping with solvent peak), 3.26 (br m, 2H), 2.96 (m, 2H), 1.33 (br m, 3H); ESI MS m/z 414 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=14.6 min.
Reaction SMILES: [CH2:1]([C:4]1[S:13][C:7]2[N:8]=[CH:9][N:10]=[C:11](O)[C:6]=2[CH:5]=1)[CH2:2][CH3:3].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:11]1[C:6]2[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[S:13][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1cc2c(O)ncnc2s1
Product: CCCc1cc2c(Cl)ncnc2s1
Reaction time: 16 h

Procedure:
The product of Example 3b was reacted with excess POCl3 at reflux for 3 h then at room temperature for 16 h. The reaction was poured over ice and partitioned between water and ethyl acetate. The organic layer was concentrated to provide the title compound.