Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>ClCCl>[Cl:3][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCCO
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCCCl
Yield: 88.3 %

Procedure:
A solution of thionyl chloride (6.74 g, 56.6 mmol) in dichloromethane (50 mL) was slowly added to a solution of N-(6-hydroxyhexyl)3-nitroquinolin-4-amine (14.9 g, 51.5 mmol) in dichloromethane (200 mL). After the addition was complete the reaction mixture was stirred for about an hour and then it was concentrated under reduced pressure. The residue was suspended in water, slurried for about an hour, isolated by filtration, washed with water and then dried to provide 14.0 g of N-(6chlorohexyl)-3-nitroquinolin-4-amine as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CCCC=O
Product: CCCCNCCc1ccc(Cl)c(Cl)c1
Yield: 23.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, 2-(3,4-dichlorophenyl)ethanamine (1.27 g, 6.68 mmol) and butyraldehyde (600 μL, 6.68 mmol) were converted to the title compound (390 mg, 24%). 1H NMR (CDCl3) δ 7.37 (d, J=8.1 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.06 (dd, J=2.1, 8.3 Hz, 1H), 2.97-2.90 (m, 2H), 2.88-2.81 (m, 2H), 2.75-2.66 (m, 2H), 1.53 (quin, J=7.5 Hz, 2H), 1.34 (qd, J=7.4, 15.0 Hz, 2H), 0.92 (t, J=7.3 Hz, 3H); MS(ESI+) m/z 246.1 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH2:29][CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.C(N(CC)CC)C.Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C(OCC)(=O)C>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(c1nc2c(s1)CNCC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (50 ml) was dissolved 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (240 mg), followed by the addition of triethylamine (0.28 ml) and then tert-butyl bromoacetate (0.14 ml). The resulting mixture was stirred overnight at room temperature. After concentration of the reaction mixture under reduced pressure, ethyl acetate was added to the residue. The resulting mixture was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (Φ3.0×12.0 cm, hexane:ethyl acetate 3:2), whereby the title compound (207 mg) was obtained as a colorless foam.
Reaction SMILES: [CH2:1]([C:3]1[C:4](N)=[N:5][C:6]([O:22][CH3:23])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[O:20][CH3:21])[N:8]=1)[CH3:2].N([O-])=O.[Na+].[BrH:29]>O.[Cu](Br)Br>[Br:29][C:4]1[N:5]=[C:6]([O:22][CH3:23])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[O:20][CH3:21])=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: Br
Reactant: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1N
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1Br
Temperature: 70 °C

Procedure:
To a stirred solution of 3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy) phenyl]pyrazin-2-ylamine (86 mg, 0.25 mmol) in 48% hydrogen bromide (0.3 mL) at 0° C. is added a solution of sodium nitrite (21 mg, 0.3 mmol) in water (1 mL). After 1.5 h copper bromide (43 mg, 0.3 mmol) is added and the mixture heated to 70° C. for 1 h. The mixture is cooled to room temperature and extracted with ether. The extracts are dried (sodium sulfate), filtered and concentrated to give [4-(5-bromo-6-ethyl-3-methoxypyrazin-2-yl)-3-methoxyphenoxy]trifluoromethane (76 mg).
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][C:12]1(C(OCC)=O)[C@H:16](/[CH:17]=[CH:18]/[C:19]([OH:26])([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][C@H:14](C(OCC)=O)[C:13]1=[O:32])([O:3]CC)=[O:2].[OH-].[Na+].Cl>O.CO.[Cl-].[Na+]>[OH:26][C:19]([CH3:25])([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:18]=[CH:17][C@H:16]1[CH2:15][CH2:14][C:13](=[O:32])[C@H:12]1[CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][C:1]([OH:3])=[O:2]
Reactant: CCCCCC(C)(O)/C=C/[C@@H]1C[C@H](C(=O)OCC)C(=O)C1(CC=CCCCC(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCC(C)(O)C=C[C@H]1CCC(=O)[C@H]1CC=CCCCC(=O)O

Procedure:
The cyclopentanonetriester of formula 6, diethyl cis,-trans-3-(6-carboethoxy-2-hexenyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate (11.2 g), described in Example 45, is heated to reflux for 1 hr. in a solution of sodium hydroxide (13.4 g) in 80 ml of water and 110 ml of methanol. The mixture is cooled, adjusted to pH 5 with 2N HCl, diluted with saturated sodium chloride solution and extracted with ether. The ether extract is dried (Na2SO4) and concentrated. Chromatography on silica gel yields the title compound νmax CHCl 3 3580, 1740, 1720 cm-1, nmr (CDCl3) δ 0.88 (t, J = 5, 3H), 1.28 (s, 3H), 5.3 - 5.75 (m, 4H), 6.3 (2xs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.OC1C=CC=CC=1C=NO.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: COc1cn(-c2cc(I)ccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: c1cn[nH]c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: COc1cn(-c2cc(-n3cccn3)ccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 3.9 %

Procedure:
A mixture of 1-(2-fluoro-5-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), pyrazole (34.0 mg, 0.5 mmol), 2-hydroxybenzaldehyde oxime (27.4 mg, 0.2 mmol), Cu2O (7.2 mg, 0.05 mmol) and Cs2CO3 (326 mg, 1.0 mmol) in acetonitrile (1 mL) was heated to reflux for 14 h under Ar. The mixture was diluted with saturated NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and on silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (8.3 mg, 4% yield) as a white solid: mp 186-187° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.78 (3H, s), 6.59-6.66 (1H, m), 6.95 (1H, d, J=1.9 Hz), 7.17-7.27 (1H, m), 7.30-7.42 (4H, m); 7.56-7.67 (1H, m), 7.76-7.90 (3H, m), 7.93-8.02 (1H, m), 8.47 (1H, d, J=2.6 Hz), 8.59 (1H, d, J=1.9 Hz). Anal. Calcd for C23H17FN6O2: C, 64.48; H, 4.00; N, 19.62. Found: C, 64.21; H, 4.08; N, 19.42.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:7][N:8]([CH:15]([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][OH:6].[N:18]#[C:19]Br>>[CH:15]([N:8]([CH2:7][C@H:4]1[CH2:5][O:6][C:19]([NH2:18])=[N:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:17])[CH3:16]
Reactant: CC(C)N(C[C@H](N)CO)c1ccccc1
Reactant: N#CBr
Agent: Cl
Product: CC(C)N(C[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1.d (S)-2-amino-3-(isopropyl-phenyl-amino)-propan-1-ol dihydrochloride was reacted with cyanogen bromide to give (S)-4-[(isopropyl-phenyl-amino)-methyl]-4,5-dihydro-oxazol-2-ylamine as light yellow amorphous solid. MS (ISP): 234.3 ([M+H]+)
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][C:18]([OH:19])=[C:15]([O:16][CH3:17])[CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:12]([C:13]1[CH:21]=[CH:20][C:18]([O:19][C:2]2[N:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=2)=[C:15]([O:16][CH3:17])[CH:14]=1)=[O:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: NC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Yield: 97.7 %

Procedure:
Dissolve 5-chloropyrazine-2-carboxamide (Example 387, Part A) (0.374 g, 2.34 mmol) and vanillin (0.361 g, 2.34 mmol) in DMF (23.7 mL). Add K2CO3 (0.821 g, 8.94 mmol) and heat at 100° C. for 1.5 hours. Concentrate the reaction mixture. Take the solid up in water (50 mL) and extract with dichloromethane (3×100 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.625 g, 96.4%): TOF MS ES+ 274.1 (M+H)+, HRMS calcd for C13H12N3O4 274.0828 (M+H)+, found 274.0829, time 0.55 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95 over 19 min], tR=10.2 min, 98.1% purity.
Reaction SMILES: C(O[K])(C)(C)C.[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.CC1C=CC(S([CH2:30][N+:31]#[C-])(=O)=O)=CC=1>COCCOC.CCO>[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:30]#[N:31])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCN(c2ccncc2)CC1
Agent: CC(C)(C)O[K]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
tBuOK (2.29 g, 20.45 mmol, 2.5 eq) was added in portions at −5° C. to a solution of 1-(pyridin-4-yl)piperidin-4-one (1.44 g, 8.18 mmol, 1 eq) and TOSMIC (1.91 g, 9.81 mmol, 1.2 eq) in DME (20 ml) and EtOH (0.5 ml), and then stirring was carried out for 2 h at RT. The reaction mixture was hydrolyzed with ice-water (50 ml), extracted with dichloromethane (2×100 ml). The combined organic phases were washed with water and sat. NaCl solution (in each case 100 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 4% MeOH in dichloromethane), the desired product was obtained in the form of a brown solid. Yield: 34% (530 mg, 2.83 mmol).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4](N)[CH2:3][CH2:2]1.[ClH:12].[NH:13]1[CH2:19][CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[ClH:12].[CH2:3]1[N:4]2[C:5]3[C:10]([C:17]4[CH2:18][CH2:19][NH:13][CH2:14][CH2:15][C:16]=42)=[CH:9][CH:8]=[CH:7][C:6]=3[S:1][CH2:2]1
Reactant: O=C1CCCNCC1
Reactant: NN1CCSc2ccccc21
Agent: Cl
Product: c1cc2c3c(c1)c1c(n3CCS2)CCNCC1

Procedure:
1,2,8,9,10,11-Hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole hydrochloride was prepared from 2,3-dihydro-4H-1,4-benzothiazin-4-amine and hexahydro-4H-azepin-4-one hydrochloride following the procedure of example 471, step A to give the 1,2,8,9,10,11-hexahydro-7H-azepino[4,5-b][1,4]thiazino[2,3,4-hi]indole hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OCC3C=CC=CC=3)=O)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[CH2:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36](=[O:52])[C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH:30]=1)[CH3:28]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][NH:13]3)=[N:9][C:10]=2[C:40]2[CH:41]=[CH:42][C:37]([C:36]([NH:35][C:31]3[CH:30]=[C:29]([CH2:27][CH3:28])[CH:34]=[CH:33][N:32]=3)=[O:52])=[CH:38][CH:39]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Product: CCc1ccnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCN4)n4ccnc(N)c34)cc2)c1
Yield: 89 %

Procedure:
This intermediate was prepared, in an analogous manner as described for intermediate 2, from (S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Intermediate 1e) and N-(4-ethylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (intermediate 12) to afford the title compound (133.8 mg, 89%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:19]([Si:16]([CH3:18])([CH3:17])[O:15][CH2:14][CH2:13][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.426 g, 10.7 mmol) in DMF (30 mL) at room temperature was added 3-hydroxybenzaldehyde (1.00 g, 8.20 mmol). The resulting suspension was stirred at room temperature for 1 hour and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (4.4 mL, 20.5 mmol), was then added. The resulting mixture was stirred at 60° C. under nitrogen for 14 hours, cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (250 mL), and concentrated. The crude product was purified by column chromatography (SiO2, hexane/ethyl acetate=4:1) to afford 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde. It was re-dissolved in THF (50 mL), mixed with 1 N tetra-n-butylammonium fluoride in THF (15 mL), and stirred at room temperature for 8 h. The reaction mixture was then concentrated and the residue was purified by column chromatography (SiO2, hexane/ethyl acetate=4:1) to afford 3-(2-hydroxy-ethoxy)-benzaldehyde as a colorless oil. Yield: 0.68 g (50% for two steps).
Reaction SMILES: [OH:1][CH:2]([C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1)[CH:3]([CH3:5])[CH3:4].[NH2:14][C@@H:15]([CH3:31])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[CH:23]=2)=[N:18]1.C(Cl)Cl.CN(C=O)C>O>[Cl:30][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:11]([C:8]3[CH:7]=[C:6]([CH:2]([OH:1])[CH:3]([CH3:4])[CH3:5])[O:10][N:9]=3)=[O:13])[CH3:31])[N:18]=2)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(C)C(O)c1cc(C(=O)O)no1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Yield: 5.2 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 5-(1-hydroxy-2-methyl-propyl)isoxazole-3-carboxylic acid (1.566 mmol, 290 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.044 mmol, 272 mg) using a mixture of DCM (5 ml) and DMF (1 ml) as the solvent. DCM and water were added, the phases were separated and the water phase was extracted with DCM. The combined organics were washed twice with water. The DCM phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 23.4 mg of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 0.94 (d, 3H), 0.98 (d, 3H), 1.23 (d, 3H), 2.06-2.21 (m, 1H), 4.21-4.30 (m, 1H), 4.37-4.46 (m, 1H), 4.51-4.67 (m, 2H), 6.57-6.65 (m, 2H), 7.50 (d, 1H), 7.68 (d, 1H), 7.78-7.86 (m, 1H), 7.97 (d, 1H), 8.04 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[N:14]=[CH:15][N:16]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)([OH:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:37]([NH:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)(=[O:39])[CH3:38]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:12][C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:44]2[CH:45]=[CH:46][C:41]([NH:40][C:37](=[O:39])[CH3:38])=[CH:42][CH:43]=2)=[CH:3][CH:4]=1)([C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: CC(C)C(O)(c1ccc(Br)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)Nc1ccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)cc1
Yield: 31.8 %

Procedure:
By the reaction in the same manner as in Example 4-(ii) using 1-(4-bromophenyl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.00 g), 4-(acetylamino)phenylboronic acid (510 mg) and tetrakis(triphenylphosphine)palladium(0) (200 mg), the title compound (350 mg) was obtained as a colorless powder crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.C=O.[CH:31](O)=O.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][N:23]([CH3:31])[CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C)CC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Yield: 61.3 %

Procedure:
The solution of (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) in formaldehyde (37 wt % aqueous solution, 97 mg, 1.16 mmol) and formic acid (54 mg, 1.16 mmol) was heated at 80° C. for 2h. The reaction mixture was diluted with H2O then basified with 1N NaOH to pH 12 and extract with CHCl3. The combined organic solution was dried over MgSO4, concentrated in vacuo, and the residue was chromatographed (silica gel; CHCl3:MeOH 99:1-95:5) to give the title compound as a pale yellow oil (19 mg, 61%). MS (CI, NH3): 403.1 (base, M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]3[CH:15]=[CH:14][NH:13][C:12](=[O:25])[C:11]=3[N:10]=2)=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.C(#N)C.[O-2].[O-2].[Mn+4]>[O:25]=[C:12]1[C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=3)[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][C:16]=2[CH:15]=[CH:14][NH:13]1
Reactant: O=c1[nH]ccc2cc(-c3ccccc3)c(-c3ccc(CO)cc3)nc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(-c2nc3c(=O)[nH]ccc3cc2-c2ccccc2)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-[4-(hydroxymethyl)phenyl]-3-phenyl-1,7-naphthyridin-8(7H)-one (46 mg, 0.14 mmol) in chloroform (4 mL) and acetonitrile (4 mL) was added activated manganese dioxide (200 mg, 2.2 mmol). This suspension was warmed at 60° C. for three hours. The warm suspension was filtered, rinsed with chloroform and the solvents removed in vacuo to give the title compound. 1H-NMR (500 MHz, CDCl3): δ 12.68 (1H, s), 10.00 (1H, br s), 7.99 (1H, s), 7.82 (2H, d, J=8.3 Hz), 7.77 (2H, d, J=8.3 Hz), 7.40 (1H, d, J=6.9 Hz), 7.31-7.37 (3H, m), 7.20-7.24 (2H, m), 6.61 (1H, d, J=7.1 Hz). m/e (m+1): 327.2.
Reaction SMILES: C1(NC=CP(=O)(OCC)OCC)CCCCC1.[H-].[Na+].[CH:20]([C:23]1[C:28]([CH:29]=O)=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:26]([CH:38]=[N:39][O:40][CH3:41])=[C:25]([CH:42]([CH3:44])[CH3:43])[N:24]=1)([CH3:22])[CH3:21].O.O.[C:47]([OH:52])(=O)[C:48](O)=O>O1CCCC1.O>[CH:20]([C:23]1[C:28](/[CH:29]=[CH:48]/[CH:47]=[O:52])=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:26]([CH:38]=[N:39][O:40][CH3:41])=[C:25]([CH:42]([CH3:44])[CH3:43])[N:24]=1)([CH3:21])[CH3:22]
Reactant: CON=Cc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: O=C(O)C(=O)O
Agent: CCOP(=O)(C=CNC1CCCCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=Cc1c(C(C)C)nc(C(C)C)c(/C=C/C=O)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
750 mg (2.9 mmol) of diethyl 2-(cyclohexylamino)vinylphosphonate, dissolved in 30 ml of dried tetrahydrofuran, are added dropwise at -5° C. under nitrogen to a suspension of 110 mg (3.6 mmol) of 80% pure sodium hydride in 15 ml of dry tetrahydrofuran. After 30 minutes, 810 mg (2.4 mmol) of the compound from Example 3 in 40 ml of dry tetrahydrofuran are added dropwise at the same temperature and the mixture is heated to reflux for 30 minutes. After cooling to room temperature, the mixture is added to 200 ml of ice-cold water and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulphate. After concentrating in vacuo, the residue is taken up in 70 ml of toluene, a solution of 4.5 g (3.5 mmol) of oxalic acid dihydrate in 30 ml of water is added and the mixture is heated to reflux for 30 minutes.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]([OH:23])=O)[C:18]([CH3:24])=[C:17]3[C:13]=2[C:14]2[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][NH:34][C:21]([C:19]1[C:18]([CH3:24])=[C:17]2[C:13]([C:14]3[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=3[NH:16]2)=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)[CH:20]=1)=[O:23]
Reactant: CN(C)CCN
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)O)c(C)c3[nH]c4ncc(C)cc4c23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1cccc(-c2cc(C(=O)NCCN(C)C)c(C)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(3-(ethylsulfonyl)phenyl)-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylic acid (3.0 g, 73 mmol), N,N-Dimethylethylene diamine (g, mmol), HATU (g, mmol), triethylamine (g, mmol) and DMF (mL) was stirred at room temperature for two days. The reaction mixture was poured over ice affording a precipitate, The resulting suspension was filtered, rinsed with H2O and dried in vacuo to g (%). 1H NMR (400 MHz, DMSO-d6): δ 12.04 (s, 1H), 8.28-8.31 (m, 2H), 8.12 (s, 1H), 8.01-8.05 (m, 2H), 7.89 (t, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 3.43 (q, 2H), 2.63 (s, 3H), 2.27 (s, 3H), 2.20 (s, 6H), 1.17 (t, 3H). MS (ES) [m+H] calc'd for C26H30N4O3S, 479; found 479.4.