Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[S:31](Cl)([C:34]1[C:46]2[CH:45]=[CH:44][CH:43]=[C:39]([N:40]([CH3:42])[CH3:41])[C:38]=2[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32]>>[CH3:41][N:40]([CH3:42])[C:39]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:38]=1[CH:37]=[CH:36][CH:35]=[C:34]2[S:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])(=[O:33])=[O:32]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3ccc(N4CCNCC4)cc3NS(=O)(=O)c3ccccc3)cccc12

Procedure:
5-(Dimethylamino)-N-{4-(1-piperazinyl)-2-[(phenylsulfonyl)amino]phenyl}-1-naphthalenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and dansylchloride (64 mg, 0.239 mmol) according to general method 3 to give 60 mg of a purple solid. MS (posES-FIA) m/z=Found: 566.3; Calcd: 566.18; 1H NMR δ 8.84 (d, 1H), 8.60 (d, 1H), 8.08 (d, 2H), 7.84-7.47 (m, 7H), 6.70 (d, 1H), 6.56-6.53 (m, 1H), 6.41-6.37 (m, 1H), 3.46 (s, 6H), 3.25-3.12 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:36]([O:38][C:39]([C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)=[O:40])[CH3:37].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:45][C:44]3[CH:46]=[CH:47][C:41]([C:39]([O:38][CH2:36][CH3:37])=[O:40])=[CH:42][CH:43]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
To a solution of 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol) and triethylamine (140 μL, 1 mmol) in DMF (5 mL) was added isobutyl chloroformate (130 μL, 0.9 mmol) at -10° C. After being stirred for 15 min, p-ethoxycarbonylaniline (200 mg, 1.2 mmol) was added. The mixture was stirred overnight at room temperature and 0.2N hydrochloric acid was added. The precipitates formed were collected by filtration, washed with water, and dried in vacuo. The crude product was rinsed with methanol-water, and dried in vacuo to give 230 mg of the title compound (46%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 10.35 (s, 1H), 7.92 (d, 2H, J=9 Hz), 7.70 (d, 1H, J=9 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 2H, J=9 Hz), 5.16~5.28 (m, 1H), 4.28 (q, 2H, J=7.2 Hz), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=16.8 Hz), 2.65 (d, 2H, J=7.6 Hz), 2.10 (dm, 1H, J=13.5 Hz), 1.80~1.97 (m, 1H), 1.31 (t, 3H, J=7.2 Hz).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]1([C:10]([C:17]([O:19]CC)=O)=[N:11][N:12]=[C:13](Cl)[CH2:14][CH3:15])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CN(C)C=O>[CH2:14]([C:13]1[N:2]([NH2:3])[C:17](=[O:19])[C:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:11][N:12]=1)[CH3:15]
Reactant: NN
Reactant: CCOC(=O)C(=NN=C(Cl)CC)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nnc(-c2ccccc2)c(=O)n1N
Reaction time: 8 h
Yield: 67.1 %

Procedure:
10.0 g (0.2 mol) of hydrazine hydrate, dissolved in 20 ml of dimethylformamide, were added dropwise to a solution of 26.7 g (0.1 mol) of 1-phenyl-1-ethoxycarbonyl-4-chloro-4-ethyl-2,3-diazabutadiene in 100 ml of dimethylformamide at a temperature of 5°C to 10°C, whilst stirring. After stirring for 3 hours, 250 ml of water were added to the reaction mixture. The whole was left to stand overnight. Thereafter, the solid which had precipitated was filtered off, well rinsed with water and dried. The yellowish-white crude product (17.4 g = 80% of theory) was purified by recrystallization from isopropanol/water. 14.5 g (67.1% of theory) of 3-ethyl-4-amino-6-phenyl-5-H-1,2,4-triazin-5-one of melting point 164°C were obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[C:14]([O:20][CH2:21][CH3:22])[CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([O:20][CH2:21][CH3:22])[CH:13]=1
Reactant: CCOc1cc(Cl)ccc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(Cl)ccc1C=O

Procedure:
Oxalyl chloride (4.87 g, 38.4 mmol) is added to dry dichloromethane (80 ml) cooled to below −60° C. under an atmosphere of nitrogen followed by dropwise addition of a solution of dry dimethyl sulphoxide (6.25 g, 80.10 mmol) in dry dichloromethane (25 ml) with stirring. After stirring for 15 min. at −78° C., a solution of 4-chloro-2-ethoxybenzyl alcohol (5.97 g, 32.0 mmol) in dry dichloromethane (35 ml) is added dropwise to give a white suspension. The suspension is stirred at −78° C. for 0.5 h then added triethylamine (16.18 g, 0.16 mol) rapidly. The mixture is stirred at room temperature for 1.5 h before quenching with aqueous saturated sodium bicarbonate (100 ml). The aqueous phase is separated and extracted with dichloromethane (2×). The combined organic phases is washed with aqueous HCl (1M) and then with brine, dried over magnesium sulphate, filtered and evaporated to a yellow solid. The solid is dissolved in diethyl ether and purified by eluting through a short plug of flash silica. Evaporate to give 4-chloro-2-ethoxybenzaldehyde as a pale yellow solid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:30]3[C:29](=[O:31])[N:28]([CH2:32][CH3:33])[CH2:27][C:26]([CH3:35])([CH3:34])[O:25][C:24]=3[N:23]=[C:22]([N:36]3[CH2:42][CH:41]4[O:43][CH:38]([CH2:39][CH2:40]4)[CH2:37]3)[N:21]=2)=[CH:16][C:15]=1[F:44].C(N(CC)CC)C.[NH2:52][C@H:53]([CH3:56])[CH2:54][OH:55]>C(Cl)Cl.O>[CH2:32]([N:28]1[CH2:27][C:26]([CH3:34])([CH3:35])[O:25][C:24]2[N:23]=[C:22]([N:36]3[CH2:37][CH:38]4[O:43][CH:41]([CH2:40][CH2:39]4)[CH2:42]3)[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:2]([NH:52][C@H:53]([CH3:56])[CH2:54][OH:55])=[O:4])=[C:15]([F:44])[CH:16]=3)[C:30]=2[C:29]1=[O:31])[CH3:33]
Reactant: C[C@@H](N)CO
Reactant: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(-c3ccc(N)c(F)c3)c2C1=O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)N[C@H](C)CO)c(F)c3)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
A mixture of 134.43 mg (0.45 mmol) of triphosgene, 200 mg (0.45 mmol) of 4-(4-amino-3-fluorophenyl)-6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-6H-9-oxa-1,3,6-triazabenzocyclohepten-5-one and 275.04 mg (2.72 mmol) of triethylamine in 50 ml of DCM is stirred at room temperature for 30 minutes. 138.88 mg (1.81 mmol) of (R)-2-aminopropan-1-ol are then added and the mixture is stirred at room temperature for 2 hours. The resulting mixture is hydrolysed with 5 ml of water and the solvent is then evaporated off under reduced pressure. The product is precipitated by addition of ethyl acetate/water. The product is filtered off and solvents are evaporated off under reduced pressure to give 68 mg of 1-{4-[6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]-2-fluorophenyl}-3-((R)-2-hydroxy-1-methylethyl)urea.
Reaction SMILES: [CH2:1]([C:3]1([CH3:17])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12](SC)=[CH:11][CH:10]=2)[O:4]1)[CH3:2].[CH2:18]1COCC1.O.O[O:25][S:26]([O-:28])=O.[K+]>C(O)C>[CH2:1]([C:3]1([CH3:17])[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:26]([CH3:18])(=[O:28])=[O:25])=[CH:11][CH:10]=2)[O:4]1)[CH3:2]
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CCC1(C)OC(c2ccc(SC)cc2)=CC1=O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product 2-ethyl-2-methyl-5-{4-(methylthio)phenyl}-3(2H)-furanone from the previous Step 3 was dissolved in 50 ml ethanol, 50 ml THF and 50 ml water, and 10 g of OXONE was added thereto. The reaction mixture was stirred overnight at room temperature. Then the insoluble materials were removed by filtration and the filtrate was concentrated in vacuo. The resulting aqueous layer was extracted with dichloromethane (100 ml×1 and 50 ml×2). The organic layer was concentrated under reduced pressure and the resulting residue was purified by column chromatography (hexane/ethylacetate=2:1) to yield 4.5 g of 2-ethyl-2-methyl-5-{4-(methylsufonyl)phenyl}-3(2H)-furanone. NMR: δ0.89 (t, J=7.2 Hz, 3H), 1.48 (s, 3H), 1.91 (q, J=7.2 Hz, 2H), 3.11 (s, 3H), 6.13 (s, 1H), 8.07 (m, 4H).
Reaction SMILES: CO[CH2:3][NH2:4].C[Mg]I.[CH3:8][C:9]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([C:25]3[CH:26]=[C:27]([C:31]4[N:32]=[C:33]([C:44](OCC)=[O:45])[S:34][C:35]=4[C:36]4[CH:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][CH:37]=4)[CH:28]=[CH:29][CH:30]=3)[CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([S:11]([CH3:14])(=[O:13])=[O:12])[CH3:10].C1C[O:52][CH2:51]C1>>[CH3:51][O:52][N:4]([CH3:3])[C:44]([C:33]1[S:34][C:35]([C:36]2[CH:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][CH:37]=2)=[C:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:23]3[CH:24]=[C:15]([C:9]([CH3:10])([S:11]([CH3:14])(=[O:12])=[O:13])[CH3:8])[CH:16]=[C:17]4[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]4)[CH:26]=2)[N:32]=1)=[O:45]
Reactant: COCN
Reactant: CCOC(=O)c1nc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c(-c2ccc(SC)cc2)s1
Reactant: C1CCOC1
Agent: C[Mg]I
Product: CON(C)C(=O)c1nc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c(-c2ccc(SC)cc2)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of methoxymethylamine in THF (0.08M) at −78° C. was added methylmagnesium iodide (3M, ether, 1 eq) dropwise over 1 h. The reaction mixture was stirred at −78° C. for 10 min, a solution of ester from step 1 was added and the reaction mixture was stirred at −78° C. for 2 h. The mixture was quenched with AcOH, diluted with NH4Cl solution and EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (toluene:acetone, 80:20) to afforded the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])SCCCS1.O.C(=O)(O)[O-:17].[Na+]>CC(C)=O>[O:17]=[C:2]([CH3:1])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)C1(C)SCCCS1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
tert-Butyl 2-methyl-1,3-dithiane-2-carboxylate (2 g, 8.547 mmol) was dissolved in acetone (85.5 mL), and water (0.5 mL) was added. The flask was then cooled in a cold bath at −20° C. Small aliquots of N-bromosuceinimide (15.4 g, 85.47 mmol) were added over 20 minutes. The reaction mixture was stirred at the same temperature for further 30 minutes, and then quenched by adding an aqueous solution of sodium bicarbonate (7.18 g, 85.47 mmol in 90 mL of water). Insoluble material was removed by filtration. The filtrate was diluted in water (200 mL) and extracted with tert-butyl methyl ether (150 mL). The separated organic layer was washed with water and a saturated brine in order, then dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the target compound as pale yellow oil at a yield of 40%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:19]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([NH2:19])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methylpropionic acid (1 g) in N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole (0.63 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.21 g), triethylamine (1.76 mL) and 28% aqueous ammonia solution (2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 mol/L hydrochloric acid, water, 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-benzyloxycarbonylamino-2-methylpropionamide (0.26 g). This material was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (30 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.11 g).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
7 g (30.56 mmol) of ethyl 4-bromobenzoate are dissolved in 60 ml of 1,2-dimethoxyethane and, under argon, 6.96 g (36.67 mmol) of 4-trifluoromethylphenylboronic acid, 271 mg of bis(triphenylphosphine)palladium(II) chloride and 40.7 ml of a 2 M sodium carbonate solution in water are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is subsequently cooled, filtered through 1 g of Extrelute, washed with dichloromethane and concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/dichloromethane 2:1). 6.31 g (21.4 mmol, 70% of theory) of a colorless solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([CH2:15][OH:16])[CH:14]=[C:10]3[C:9](=[O:17])[NH:8][CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.C1COCC1>O=[Mn]=O.C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([CH:15]=[O:16])[CH:14]=[C:10]3[C:9](=[O:17])[NH:8][CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: O=C1NC(c2ccccc2)c2cc(Cl)ccc2-n2nc(CO)cc21
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)NC2=O

Procedure:
A solution of 5.85 g. (17 mmol) of the end product of Example 14 in 600 ml. dry THF was mixed with 24 g. of activated MnO2 and heated to reflux for 17 hours. The mixture was cooled, filtered and the collected solids washed thoroughly with THF. The combined filtrate and washings were concentrated in vacuo. Recrystallization of this crude product from THF/hexane yielded the desired end product. An analytical sample was prepared by an additional recrystallization from THF/hexane and was obtained as colorless plates: mp 276°-278°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([C:31]([C:33]4[S:34][CH:35]=[CH:36][N:37]=4)=[O:32])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>C(#N)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([C:31]([C:33]5[S:34][CH:35]=[CH:36][N:37]=5)=[O:32])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:29][CH:28]=1
Reactant: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Reactant: C1CCNC1
Solvent: CC#N
Product: O=C(c1nccs1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)nc1)C2
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of (R)-(6-((6-chloropyridin-3-yl)sulfonyl)-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (100 mg, 0.180 mmol) and pyrrolidine (37.5 μL, 0.450 mmol) in acetonitrile (2 mL) was stirred at 40° C. for 0.5 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow oil. The crude product was purified by column chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to give a white solid. This was further purified by preparative HPLC (Gilson, Acidic (0.1% Formic acid), Agilent Prep C-18, 5 μm, 21.2×50 mm column, 30-95% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-((6-(pyrrolidin-1-yl)pyridin-3-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone as a white solid (51 mg). LCMS (Method F, ES-API): RT 2.43 min, m+H=590.9; 1H NMR (400 MHz, CDCl3): δ 8.45 (1H, dd, J=2.0, 0.5 Hz), 8.01 (1H, d, J=3.1 Hz), 7.63-7.59 (2H, m), 7.46-7.41 (2H, m), 7.29 (1H, s), 7.19-7.13 (2H, m), 6.51 (1H, d, J=2.1 Hz), 6.27 (1H, d, J=9.1 Hz), 5.47 (1H, dd, J=12.2, 2.1 Hz), 4.20 (1H, d, J=16.8 Hz), 3.87-3.83 (1H, m), 2.91-2.82 (2H, m), 2.71 (1H, d, J=12.3 Hz), 2.53-2.46 (2H, m), 2.06-2.04 (4H, m), 1.33-1.24 (2H, m), 1.17-1.07 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[CH:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH:22]=O.Cl>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:9]2[C:10]3=[C:14]([N+:15]([O-:17])=[O:16])[CH:22]4[O:24][CH:18]([N:11]3[CH2:12][CH2:13]2)[CH2:19][CH2:20][CH2:21]4)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Reactant: O=CCCCC=O
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])C1=C2N(Cc3ccc(Cl)nc3)CCN2C2CCCC1O2
Temperature: 25 °C
Yield: 86 %

Procedure:
To a 50 ml round bottom flask was added 1.27 g (0.005 mol) 2-chloro-5-((2-(nitromethylene)imidazolidin-1-yl)methyl)pyridine, 30 ml acetonitrile, 3 ml 25% glutaraldehyde aqueous solution and catalytic concentrated HCl. The reaction was stirred at r.t. and monitored by TLC. After completion, the mixture was evaporated to remove solvent and purified by column chromatography to afford final product as faint yellow powder with 86% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH2:20][OH:21])=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1([C:27]2[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=2)[CH:26]=[N:25][N:24]=[N:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH2:20][O:21][C:30]3[CH:31]=[CH:32][C:27]([N:22]4[CH:26]=[N:25][N:24]=[N:23]4)=[CH:28][CH:29]=3)=[C:17]([CH3:19])[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccc(-n2cnnn2)cc1
Reactant: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)sc1COc1ccc(-n2cnnn2)cc1
Reaction time: 4 h

Procedure:
To a solution of 4-(5-Hydroxymethyl-4-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g, 3.2 mmol) in THF (6.4 mL) was added, 4-tetrazol-1-yl-phenol (0.52 g, 3.2 mmol), polymer bound triphenylphosphine (3 mmol/g, 1.6 g). To this solution was added ditertierybutylazodicarboxylate (1.1 g, 4.8 mmol), stirred for 4 hours and filtered through a pad of celite. The filtrate was concentrated and purified by silica gel chromatography to provide the desired product. 1H NMR (CDCl3): δ 9.01 (1H, s), 7.66 (2H, d), 7.15 (2H, d), 5.21 (2H, s), 4.19 (2H, m), 3.10 (1H, m), 2.86 (2H, m), 2.45 (3H, s), 2.08 (2H, m), 1.72 (2H, m), 1.47 (9H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([O:39]CC)=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:42])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:37]([OH:39])=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(N3CCOCC3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(N4CCOCC4)ccc3c12
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of ethyl 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-morpholino-9H-pyrido[3,4-b]indole-1-carboxylate (0.3539 g, 0.627 mmol) in THF (17.4 mL) and MeOH (5.8 mL) was added a solution of lithium hydroxide hydrate (0.105 g, 2.507 mmol) in water (3 mL). After 1 hr, the reaction was concentrated in vacuo. Water (12 mL) was added, and the solution was acidified with aqueous 1N HCl to pH 5-6 by litmus paper. The precipitate was filtered, washed with water, dried over Drierite to give the desired product (0.286 g, 0.533 mmol, 85% yield) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][CH:22]([C:25]([F:28])([F:27])[F:26])[NH:21][CH2:20]2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.CCOC(C)=O>O1CCOCC1>[CH:10]1([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][CH:22]([C:25]([F:28])([F:26])[F:27])[N:21]([C:6]3[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=3)[CH2:20]2)=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: O=C(NC1CCCCC1)C1CCC(C(F)(F)F)NC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)C1CCC(C(F)(F)F)N(c2cc(Cl)nc(Cl)n2)C1
Temperature: 80 °C
Reaction time: 72 h
Yield: 35.4 %

Procedure:
To a mixture of 2,4,6-trichloropyrimidine (0.18 mL, 1.59 mmol) and N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (0.5 g, 1.588 mmol) in 1,4-dioxane (15 mL) was added Hunig's base (0.56 mL, 3.18 mmol), and the reaction mixture was stirred over the weekend (3 days) at 80° C. into a sealed tube. Approximately 35% starting material was remaining. The temperature was increased to 140° C., and the reaction mixture was stirred at this temperature for 3 hours. The reaction was then heated for 1 hour at 160° C. Since there was still remaining starting material, the reaction was stirred overnight at 140° C. The reaction mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 50% EtOAc in Hexanes) afforded the title compound (239 mg) as a white solid, and the corresponding regioisomer (196 mg) as a white solid. LC-MS (ES) m/z=425, 427 [M+H]+.