Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S([N:7]=[C:8]([C:28]1[O:29][C:30]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:31]=2[N:32]=1)[C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH3:20])=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2C(OC(C)(C)C)=O)=O)(C)(C)C.[F-].C[N+](C)(C)C.[Si]([C:52]([F:55])([F:54])[F:53])(CC)(CC)CC.Cl.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.[NH4+].[Cl-].[Cl-].[Na+].O>[NH2:7][C:8]([C:28]1[O:29][C:30]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][C:31]=2[N:32]=1)([C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH3:20])=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:52]([F:55])([F:54])[F:53]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(=NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2o1
Reactant: CC[Si](CC)(CC)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C)c2[nH]ccc2c1C(N)(c1nc2cc(C#N)ccc2o1)C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a suspension of (±)-tert-butyl 4-((tert-butylsulfinylimino)(5-cyanobenzo[d]oxazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (56 mg, 0.105 mmol) and tetramethylammonium fluoride (29.3 mg, 0.314 mmol) in THF (1 mL), TESCF3 (38.6 mg, 0.209 mmol) was added at 0° C. Then, the reaction mixture was allowed to reach rt. After stirring for 2 h, additional tetramethylammonium fluoride (9.76 mg, 0.105 mmol) and TESCF3(38.6 mg, 0.209 mmol) were added. After stirring for 0.5 h at rt, the reaction was diluted with aq. NH4Cl and brine. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was dissolved in HCl (1.25 M in MeOH) (0.840 mL, 1.050 mmol) and stirred at rt for 15 min. At this point the reaction was warmed to 50° C. and heated at this temperature for 45 minutes. The mixture was concentrated and the resulting residue was dissolved in MeOH (1 mL). Cs2CO3 (137 mg, 0.420 mmol) was added and the mixture was stirred at 60° C. for 1.5 h. At this point an additional aliquot of Cs2CO3 (137 mg, 0.420 mmol) was added. After stirring for 50 min, the reaction mixture was cooled to rt, concentrated, and then diluted with aq. NH4Cl, brine and EtOAc. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography on silica gel (heptane/EtOAc=100:0 to 35:65). 1H NMR (400 MHz, CD2Cl2) δ ppm 8.15-8.17 (br. m, 1H), 8.02 (d, J=1.26 Hz, 1H), 7.57 (m, 1H), 7.48 (m, 1H), 7.18 (dd, J=3.03, 2.78 Hz, 1H), 6.95 (br. s, 1H), 6.62 (s, 1H), 3.28 (s, 3H), 2.43 (s, 3H). HRMS calcd. for C20H15F3N4O2 (M+H)+ 401.1220. found 401.1221.
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][S:11][C:5]2=[N:4][C:3]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=1[O:22][CH2:23][CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+].[CH2:33](O)[CH3:34].O>C1(C)C=CC=CC=1>[CH3:3][N:4]([CH3:5])[C:34]1[CH:33]=[CH:15][C:14]([C:2]2[C:7](=[O:8])[N:6]3[CH:9]=[CH:10][S:11][C:5]3=[N:4][C:3]=2/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=2[O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:13][CH:12]=1
Reactant: CCO
Reactant: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(N(C)C)cc2)c1OCC(C)C

Procedure:
The title compound was prepared from Intermediate 7 (100 mg, 0.207 mmol), 4-N,N-dimethylaminophenylboronic acid (47 mg, 0.290 mmol), Pd[(C6H5)3P]4 (10 mg, 0.009 mmol) and sodium carbonate (131 mg, 1.244 mmol) in a mixture of toluene, ethanol and water according to the procedure outlined in Example 1 to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 75 mg of the product; 1H NMR (300 MHz, DMSO-d6) δ 0.98 (d, J=6.9 Hz, 6H), 1.85-1.89 (m, 1H), 2.95 (s, 6H), 3.62 (d, J=6.3 Hz, 2H), 3.77 (s, 3H), 6.77 (d, J=9.0 Hz, 2H), 6.82-6.92 (m, 1H), 6.98-7.04 (m, 3H), 7.15 (d, J=9.0 Hz, 1H), 7.45 (d, J=4.8 Hz, 1H), 7.95 (d, J=4.8 Hz, 1H), 8.08 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 476.46 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:20]2[C:19](=[O:21])[C:18]([C:22]([O:24]CC)=[O:23])=[CH:17][N:7]3[C@H:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:3]=1[F:37].[OH-].[Na+].Cl.O>CCO>[F:1][C:2]1[C:20]2[C:19](=[O:21])[C:18]([C:22]([OH:24])=[O:23])=[CH:17][N:7]3[C@H:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:3]=1[F:37]
Reactant: CCOC(=O)c1cn2c3c(c(NCCNc4ccccn4)c(F)c(F)c3c1=O)OC[C@H]2c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c3c(c(NCCNc4ccccn4)c(F)c(F)c3c1=O)OC[C@H]2c1ccccc1
Temperature: 50 °C
Yield: 76.2 %

Procedure:
To a mixture of ethyl (R)-8,9-difluoro-2,3-dihydro-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (627 mg, 1.24 mmol) in EtOH (8 mL) was added 2M aq. NaOH (6.20 mL, 12.4 mmol) at room temperature and the mixture was heated at 50° C. for 3 h. The reaction mixture was added 2N HCl (11.4 mL) and water. A precipitate formed and was collected by filtration, washed successively with water and then dried to give (R)-8,9-difluoro-2,3-dihydro-7-oxo-3-phenyl-10-[2-(2-pyridylamino)ethylamino]-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (452 mg, 75%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH:9]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH:9]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(CO)CCN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1CC(C=O)CCN1C(=O)OC(C)(C)C

Procedure:
A solution of 7.9 g of ethyl 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)-piperidine-2-carboxylate and 9.9 g of pyridinium chlorochromate in 175 ml of methylene chloride is stirred at room temperature for 3 hours. The mixture is filtered and purified by flash chromatography using ethyl acetate/hexane (25:75) to yield 1-(tert-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-carboxaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[ClH:15]>S(Cl)(Cl)=O.O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1Br
Reactant: Cl
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Br

Procedure:
10 g of 4-bromo-3-sulfamoylbenzoic acid were heated under reflux in a mixture of 80 ml of thionyl chloride and 50 ml of dioxane until HCl had completely developped. Then, the reaction mixture was concentrated under reduced pressure to 40 ml, 200 ml of petroleum ether were added and the crystals were filtered off. Melting point: 138° C. (decomposition).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=[CH:8]2)=O.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>O1CCCC1>[C:17]([O:16][C:14]([N:10]1[C:11]2[C:7](=[CH:6][C:5]([CH2:3][OH:2])=[CH:13][CH:12]=2)[CH:8]=[CH:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2cc(CO)ccc21
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of N-tert-butoxycarbonylindole-5-carboxylic acid methyl ester (23.6 g, 85.7 mmol) in dry tetrahydrofuran (225 mL) at −78° C. was added 1.5 M DIBALH in toluene (171 mL, 257 mmol). After 2 h, the reaction mixture was quenched by the slow addition of methanol (45 mL), water (60 mL), and saturated aqueous NH4Cl (30 mL). The cold bath was removed and after stirring for an additional 1 h, the reaction mixture was filtered over Celite. The Celite cake was washed with tetrahydrofuran and the filtrate was concentrated to remove the more volatile tetrahydrofuran. The biphasic mixture was extracted with ethyl acetate. The combined organic layers were washed with water and the aqueous layer back extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to afford N-tert-butoxycarbonylindol-5-yl methanol (21.2 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][C:21]2([S:25][CH2:24][CH2:23][S:22]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].[C:31]1([C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N+]=[N-])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C>[CH2:1]([O:3][P:4]([CH2:16][C:17]([N:19]1[C@H:27]([C:28]([O:30][CH:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:29])[CH2:26][C:21]2([S:22][CH2:23][CH2:24][S:25]2)[CH2:20]1)=[O:18])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:5])[CH3:2]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2
Reaction time: 3.5 h
Yield: 140.9 %

Procedure:
(S)-7-[[Ethoxy(4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid (3.2 g) in ethyl acetate is treated with 2.0 g of diphenyldiazomethane in ethyl acetate. After 3.5 hours, the reaction mixture is partitioned between ethyl acetate and water. The layers are separated and the organic portion is washed with saturated sodium bicarbonate, 5% potassium bisulfate, brine and dried (MgSO4). The solvent is stripped leaving 6.1 g of residue which is chromatographed on 180 g of silica, eluting with ethyl acetate to yield 3.4 g of the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([F:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[F:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:2]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])=[CH:17][CH:16]=1
Reactant: C1COCCN1
Reactant: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(N2CCOCC2)nc1

Procedure:
N-[7-Fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-6-morpholin-4-yl-nicotinamide was prepared starting from 6-chloro-N-[7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-yl-methyl]-nicotinamide (Example I-105) and morpholine. 1H MS calcd. for C26H22F2N4O3 [(M+H)+] 477.2, obsd. 477.0.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[C:9](=[O:17])[N:10]([CH3:16])[C:11](=[O:15])[N:12]([CH3:14])[N:13]=1.C(N(CC)CC)C.ClCCl>C1(C)C=CC=CC=1>[CH3:14][N:12]1[C:11](=[O:15])[N:10]([CH3:16])[C:9](=[O:17])[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:13]1
Reactant: C1CNCCN1
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1nc(N2CCNCC2)c(=O)n(C)c1=O
Temperature: 110 °C
Yield: 79.6 %

Procedure:
4.75 g (55.15 mmol) of piperazine are placed in the presence of 4.05 g (18.4 mmol) of intermediate 1b in toluene at room temperature for 30 min. 2.8 mL (20.1 mmol) of triethylamine are added and the mixture is heated for 18 h at 110° C. After concentration of the reaction medium, the obtained residue is taken up with dichloromethane and washed with water. After drying on MgSO4, the organic phase is dry concentrated. The obtained residue is purified by flash chromatography (CH2Cl2-MeOH: 60-40). 3.3 g of intermediate 12a is obtained as a white powder (yield: 79%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[O:49][CH2:50][CH:51]([OH:66])[CH2:52][N:53]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)[CH2:54]1>CN1C(=O)CCC1.N1C=CC=CC=1>[Cl:65][C:62]1[CH:61]=[CH:60][C:59]([O:58][CH:55]2[CH2:56][CH2:57][N:53]([CH2:52][CH:51]([OH:66])[CH2:50][O:49][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[NH:42][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:54]2)=[CH:64][CH:63]=1
Reactant: Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1
Reactant: O=C(O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 80 uL 0.2M 2-thiophenecarboxylic acid in NMP were HBTU (80 uL, 0.2M/NMP), HoBT (80 uL, 0.2M/NMP), DIEA (30 uL, 0.5M/NMP) and pyridine (30 uL, 0.5M/NMP) added and stirred for 30 minutes before 1-[(2-aminophenyl)oxy]-3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-propanol (75 uL, 0.2M/NMP) was added. The mixture was stirred overnight at room temperature before it was concentrated under reduced pressure to dryness. The product was diluted with 1000 uL dichloromethane and washed with with sat.NaHCO3/aq (800 uL), 1.81% HCl/aq(800 uL) and sat. NaCl/aq. The organic layer was concentrated under reduced pressure to dryness and used without further purification. Yield 3.6mg, 51%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:29][C:30]([F:51])([F:50])[S:31]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[C:3]([C:39]2[CH:40]=[C:35]([NH:34][S:31]([C:30]([F:29])([F:50])[F:51])(=[O:33])=[O:32])[CH:36]=[CH:37][CH:38]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cccc(NS(=O)(=O)C(F)(F)F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cccc(NS(=O)(=O)C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Yield: 42.8 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.14 mmol) was treated with 1,1,1-trifluoro-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (124 mg, 0.22 mmol, prepared according to WO 2012013727 A1 20120202), sodium carbonate (2M, 215 μl, 0.43 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8.3 mg, 0.01 mmol) according to the method described in Example 3 to give 35 mg (42% yield) of the title compound. Purity 99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[CH3:16][C:15]([NH:12][CH2:11][CH2:10][C:9]1[C:13]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[NH:7][CH:8]=1)=[O:17]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc2[nH]cc(CCNC(C)=O)c2c1

Procedure:
reacting said essentially pure 5-methoxy-tryptamine from step c) with acetic anhydride to obtain crude melatonin and purifying said crude melatonin by chromatography on silica gel and first eluting with methylene chloride followed by eluting with methylene chloride and acetone to obtain a solution, concentrating said methylene chloride and acetone solution to obtain a solid and recrystallizing said solid whereby purified melatonin
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([NH:15][CH:16]([CH3:18])[CH3:17])[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=1)=[O:4].[OH-].[K+].Cl>O1CCOCC1>[CH:16]([NH:15][C:7]1[C:8]2[N:9]([C:11](=[O:14])[NH:12][N:13]=2)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1)([CH3:18])[CH3:17]
Reactant: COC(=O)c1cn2c(=O)[nH]nc2c(NC(C)C)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Nc1nc(C(=O)O)cn2c(=O)[nH]nc12
Temperature: 25 °C

Procedure:
A solution of 720 mg of the product of Step F in dioxane (10 mL) was treated with 6N KOH (2.0 mL) and the mixture was stirred at ambient temperature. After six h, the pH of the reaction was adjusted to 4.0 with concentrated HCl and the mixture was extracted with 3:1 chloroform/IPA (3×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to provide 8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-6-carboxylic acid as a tan solid. MS (M+H+)=236.0.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]([O:19]C)=[O:18])[CH:9]=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.Cl>[N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]([OH:19])=[O:18])[CH:9]=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ncoc1-c1cccc(N2CCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ncoc1-c1cccc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 5-(3-(pyrrolidin-1-yl)phenyl)oxazole-4-carboxylate (625 mg, 2.3 mmol) in THF (223 mL) was added 1N aq. NaOH-solution (11 mL) and the resulting mixture was stirred at rt overnight. The reaction mixture was poured in 1N aq. HCl-solution and extracted with EtOAc (75 mL). The organic layer was dried (MgSO4), filtered and concentrated to dryness to afford the title compound as a white solid. LC-MS conditions A: tR=0.78 min, [M+H]+=259.00
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10](Br)[CH2:11]2.[CH:23]1([Mg]Br)[CH2:25][CH2:24]1.O1CCCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1(C)C=CC=CC=1>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([CH:23]1[CH2:25][CH2:24]1)[CH2:11]2
Reactant: BrC1=Cc2c(cccc2-c2ccccc2-c2ccccc2)C1
Reactant: Br[Mg]C1CC1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C1=C(C2CC2)Cc2cccc(-c3ccccc3-c3ccccc3)c21
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
A solution of compound 9 (10 g, 28.8 mmol, 1 equiv) and anhydrous toluene (100 mL) was treated with bis(triphenylphosphine)-palladium(II)dichloride (2.35 g, 2.9 mmol, 0.1 equiv). After stirring for 10 minutes, 0.5 M cyclopropylmagnesium bromide in tetrahydrofuran (300 mL, 149.7 mmol, 5.2 equiv) was added dropwise. The reaction was heated at 60° C. overnight. Additional bis(triphenylphosphine)-palladium(II)dichloride (2.35 g, 2.9 mmol, 0.1 equiv) was added and the reaction heated at 60° C. for an additional 24 hours. The reaction was concentrated under reduced pressure and the residue partitioned between water (1 L) and ethyl acetate (1 L). The layers were separated and the aqueous layer washed with ethyl acetate (1 L). The combined organic layers were washed with saturated brine (1 L), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified over silica gel (200 g) eluting with heptanes to give compound 10 (3.3 g, 37% yield) as a light yellow oil.
Reaction SMILES: B1C2CCCC1CCC2.[C:10]([O:14][C:15](=[O:46])[NH:16][C:17]1([CH2:43][CH:44]=[CH2:45])[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][C:33]=2[Cl:34])[C:30]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:29][CH:28]=[CH:27]3)[CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11].[OH-:47].[Na+].OO>C1COCC1>[C:10]([O:14][C:15](=[O:46])[NH:16][C:17]1([CH2:43][CH2:44][CH2:45][OH:47])[CH2:22][CH2:21][CH:20]([O:23][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][C:33]=2[Cl:34])[C:30]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[N:29][CH:28]=[CH:27]3)[CH2:19][CH2:18]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: [OH-]
Reactant: C=CCC1(NC(=O)OC(C)(C)C)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CCCO)CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.87 mL (1.43 mmol) of a 0.5M solution of 9-BBN in THF were added to a solution of 250 mg (0.48 mmol) of [1-allyl-4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (52) in 5 mL THF at 0° C. The reaction mixture was allowed to warm to room temperature over night, before being cooled to 0° C. Then, 5 mL of 3M aqueous sodium hydroxide and 5 mL of 30% aqueous hydrogen peroxide were added slowly, and the mixture was stirred for 5 h. The mixture was extracted twice with ethyl acetate, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. 196 mg of the title compound 53 could be isolated as mixture of diastereoisomers in a purity sufficient for further conversion. Rt=2.05 min (Method C). Detected mass: 541.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:14]([CH:15]=O)[CH:13]2[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(=O)NC(=O)C=C1.ClC1C=C(C=CC=1Cl)N.N1C=CC=CC=1.Cl.[CH3:47][O:48][NH2:49]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH:14]([CH:15]=[N:49][O:48][CH3:47])[CH:13]2[CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON
Reactant: CC(C)(C)OC(=O)N1CC2C(C=O)C2(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Agent: Nc1ccc(Cl)c(Cl)c1
Agent: O=C1C=CC(=O)N1
Solvent: CCO
Solvent: c1ccncc1
Product: CON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)c(Cl)c1
Yield: 90 %

Procedure:
To a solution of tert-butyl 1-(3,4-dichlorophenyl)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.50 g, 7.02 mmol, prepared from maleimide and 3,4-dichloroaniline according to the methods described in WO 2009141412 and WO 2008074716), in ethanol (40 mL) under nitrogen atmosphere, were added pyridine (2.82 mL, 35.04 mmol) and O-methylhydroxylamine hydrochloride (1.17 g, 14.01 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (20 mL). The organic layer was separated, washed with 5% HCl (5 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1:9 EtOAc:Pet Ether) to afford pure tert-butyl 1-(3,4-dichlorophenyl)-6-((methoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.45 g, 90%) as a viscous oil as a mixture of isomers.
Reaction SMILES: [OH:1][C:2]1[C:7]([NH:8][C:9]2[C:10](=O)[C:11](=[O:15])[C:12]=2[O:13]C)=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[O:22][C:21]([CH:23]([NH2:29])[C:24]2([CH3:28])[CH2:27][O:26][CH2:25]2)=[CH:20][CH:19]=1>CO>[OH:1][C:2]1[C:7]([NH:8][C:9]2[C:12](=[O:13])[C:11](=[O:15])[C:10]=2[NH:29][CH:23]([C:21]2[O:22][C:18]([CH3:17])=[CH:19][CH:20]=2)[C:24]2([CH3:28])[CH2:25][O:26][CH2:27]2)=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: COc1c(Nc2cncnc2O)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cncnc3O)c(=O)c2=O)C2(C)COC2)o1
Temperature: 50 °C
Yield: 71.5 %

Procedure:
A mixture of 300 mg (1.36 mmol, 1 eq) of 3-(4-hydroxypyrimidin-5-ylamino)-4-methoxycyclobut-3-ene-1,2-dione and 504 mg (2.78 mmol, 2 eq) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 25 ml of methanol was heated at 50° C. for 22 hours. The reaction medium was filtered and the insoluble material was washed with methanol and with diethyl ether. 0.36 g of product was obtained in the form of a white solid. Yield=72%, HPLC purity=97.81%, Mp=281° C. (degradation).