Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:57][O:58][C:59](=[O:78])[CH2:60][C@@H:61]([NH:69][C:70](=[O:77])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:62]1[CH:67]=[CH:66][C:65]([NH2:68])=[CH:64][CH:63]=1>CN(C)C=O>[CH3:57][O:58][C:59](=[O:78])[CH2:60][C@@H:61]([NH:69][C:70](=[O:77])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:62]1[CH:63]=[CH:64][C:65]([NH:68][C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:66][CH:67]=1
Reactant: COC(=O)C[C@@H](NC(=O)c1ccccc1)c1ccc(N)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](NC(=O)c1ccccc1)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88 %

Procedure:
A solution of 3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetic acid (1.52 g, prepared as described in Reference Example 31) in anhydrous dimethylformamide (40 ml), under an atmosphere of argon, was treated sequentially with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.84 g), diisopropylethylamine (3.4 ml) and a solution of (R)-3-benzoylamino-3-(4-aminophenyl)-propanoic acid methyl ester [2.0 g, Reference Example 13(a)] in dimethylformamide (10 ml). After stirring for 45 minutes at ambient temperature the reaction mixture was evaporated. The residue was treated with water (150 ml) and hydrochloric acid (10 ml, 1M) was added to the aqueous slurry. The mixture was filtered and the insoluble material was washed three times with water (50 ml) then dried in vacuo to give the title compound as white solid (2.53 g).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[O:10]1[CH:16]2[CH:11]1[CH:12]=[CH:13][CH2:14][CH2:15]2.CO>[Pd].O1CCCC1>[OH:10][CH:11]1[CH2:16][CH2:15][C:14]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])=[CH:13][CH2:12]1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C1=CC2OC2CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cn(C2=CCC(O)CC2)c(=O)[nH]c1=O
Reaction time: 4 h
Yield: 16.2 %

Procedure:
6.3 g (50 mmol) of thymine are treated with 2 mol % of the palladium(0) catalyst prepared in situ as described above and with one equivalent of 3,4-epoxycyclohexene in tetrahydrofuran first at 0° C. and then for 4 hours at the reflux temperature. Methanol is added to the reaction mixture, the suspension is filtered, the filtrate is concentrated and the residue is chromatographed over silica gel using methylene chloride/methanol 20/1. 1.8 g (16.2% of theory) of 1-[(4RS)-4-hydroxy-cyclohex-1-en-1-yl]thymine of melting point 223° C. are obtained. 1H NMR (270 MHz, d6 -DMSO); δ[ppm]: 11.23 (s, 1H), 7.69 (s, 1H), 4.59 (m, 1H), 2.84 (t, 1H), 2.42-1.81 (m, 6H), 1.79 (s, 3H), 1.61 (m, 1H).
Reaction SMILES: NC(CS)C(O)=O.C(O)(C(F)(F)F)=O.[CH2:15]([C:19]1[CH:46]=[CH:45][C:22]([CH2:23][O:24][C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH2:35][CH:36]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:29]4=[CH:28][C:27]=3[CH:26]=2)=[CH:21][C:20]=1[C:47]([F:50])([F:49])[F:48])[CH:16]([CH3:18])[CH3:17]>O>[CH2:15]([C:19]1[CH:46]=[CH:45][C:22]([CH2:23][O:24][C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH2:35][CH:36]([CH2:37][C:38]([OH:40])=[O:39])[C:29]4=[CH:28][C:27]=3[CH:26]=2)=[CH:21][C:20]=1[C:47]([F:50])([F:48])[F:49])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Cc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)Cc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A solution of 2-amino-3-mercaptopropanoic acid (0.042 g, 0.347 mmol) in TFA (600 pt, 7.79 mmol) was added to neat tert-butyl 2-(7-(4-isobutyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.058 g, 0.116 mmol). The reaction mixture was stirred for 1 h at room temperature and then diluted with ice and water causing a tan solid to precipitate. The aqueous mixture was decanted off of the tan solid and the solid was rinsed with water. The solid was dried under vacuum to give the title compound (37 mg). LCMS m/z=446.7 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.89 (d, J=6.6 Hz, 6H), 1.87-1.98 (m, 1H), 2.16-2.26 (m, 1H), 2.53-2.82 (m, 5H), 3.53-3.62 (m, 1H), 3.92-4.00 (m, 1H), 4.06-4.14 (m, 1H), 5.13 (s, 2H), 6.01 (s, 1H), 6.77 (dd, J=8.7, 2.4 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.75 (d, J=1.1 Hz, 1H).
Reaction SMILES: [C:1]1(=O)O[CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].[NH2:9][CH2:10][C:11]([CH2:15][NH2:16])([CH2:13][NH2:14])[CH3:12]>O>[NH2:9][CH2:10][C:11]1([CH3:12])[CH2:15][N:16]2[CH2:4][CH2:3][CH2:2][C:1]2=[N:14][CH2:13]1
Reactant: CC(CN)(CN)CN
Reactant: O=C1CCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC1(CN)CN=C2CCCN2C1
Temperature: 250 °C
Reaction time: 1.5 h

Procedure:
A mixture of 21.03 g (0.24 mol) of γ-butyrolactone and 1.31 g (24 mmol) of ammonium chloride in 114.5 g (0.98 mol) of 1,1,1-tris(aminomethyl)ethane was heated at 250° C. in an autoclave. After 1.5 h, the mixture was cooled and the excess amine and the water formed were removed by distillation. The residue was distilled at 200°-240° C./18 mbar. The yield was 22.0 g (54%) of yellowish oil. The boiling point was 117°-120° C./1 mbar. Other data concerning the product was:
Reaction SMILES: C([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[CH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12](C(C)(C)C)=CC=3)[CH:6]=1)(C)(C)C.[C:23]1(=[O:30])[CH:28]=[CH:27][C:26](=[O:29])[CH:25]=[CH:24]1>>[C:23]1(=[O:30])[C:28]2[C:9]3[CH:8]=[C:7]4[C:16]([CH:17]=[CH:18][CH:5]=[CH:6]4)=[CH:15][C:14]=3[CH:13]=[CH:12][C:27]=2[C:26](=[O:29])[CH:25]=[CH:24]1
Reactant: O=C1C=CC(=O)C=C1
Reactant: CC(C)(C)c1ccc2cc3cc(C(C)(C)C)ccc3cc2c1
Product: O=C1C=CC(=O)c2c1ccc1cc3ccccc3cc21

Procedure:
6,14-di-tert-butyl-9,10-dihydro-9,10[1′,2′]benzenoanthracene-1,4-diol 45 is illustrated in FIG. 9F. 2,6-di-tert-butyl-anthracene (19.0 g, 0.0654 mol) and 1,4-benzoquinone (7.78 g, 0.072 mol) in xylenes (150 ml) was heated to reflux for 2 h. Solvent was removed in vacuo and the crude product was purified by flash chromatography (2:3, hexane:dichloromethane) to give benzenoanthracene-1,4-dione, which was dissolved in acetic acid (150 ml) and heated to reflux and a drop of aqueous HBr (48%). After 10 min, the reaction was cooled and water was added. Precipitates were collected and dried to give compound 45 as an off-white solid (12.73 g, 0.0319 mol, 49%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[C:5](Br)=[CH:4][CH:3]=1.[CH3:13][Sn](C)(C)C.[Li+].[Cl-]>CN(C=O)C.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>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([CH3:13])=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(N)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(N)nc1C(=O)O
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To methyl 6-amino-3-bromopicolinate (500 mg, 2.2 mmol), tetramethylstannane (900 μL, 6.5 mmol) and LiCl (354 mg, 8.7 mmol) in DMF (6 mL) was added Pd(PPh3)4 (76 mg, 10 mol %). The reaction mixture was heated at 110° C. for 3 h. Additional tetramethylstannane, LiCl and Pd(PPh3)4 were added and heating continued for 6 h. Purification via silica gel chromatography (0-20% MeOH in DCM) gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>CN(C)C=O.C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([O:7][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])=[O:6]
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(C(=O)ON2C(=O)CCC2=O)cc(C)c1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3,5-dimethyl-4-hydroxybenzoic acid (5.0 g, 30.0 mmol) in N,N-dimethylformamide (150 ml) was cooled to 0° C. and treated with N-hydroxysuccinimide (3.45 g, 30.0 mmol) and 1,3-dicyclohexylcarbodiimide (6.81 g, 33.0 mmol). The solution was stirred under nitrogen at 0° C. for 2 hours and then at 25° C. for 16 hours. The resulting mixture was stirred with 0.5 ml of acetic acid for 15 minutes, and then filtered to remove the insoluble urea. The filtrate was evaporated under reduced pressure to dryness. The dried material was washed with diethyl ether (100 ml) and suspended in boiling ethyl acetate (200 ml). The suspension, when hot, was filtered to remove insoluble impurities. The filtrate was concentrated and suspended in hot ethyl acetate/methylene chloride (1:1, 200 ml) and cooled to give an off-white powder in 2.91 g (37%). Rf 0.6 (silica gel, diethyl ether).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[N:16](C(OC(C)(C)C)=O)[CH:10]([CH2:11][C:12]([C:39]3[O:43][N:42]=[C:41]([CH2:44][CH2:45][CH2:46][O:47][C:48]4[CH:53]=[C:52]([CH3:54])[C:51]([Cl:55])=[C:50]([CH3:56])[CH:49]=4)[CH:40]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=O)(C)(C)C.ClC(Cl)(Cl)C(NC(=O)[O-])(C)C>C1COCC1.CC(O)=O.[Zn]>[CH:35]1([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[C:24]([C:13]2[CH:14]3[NH:16][CH:10]([CH2:11][C:12]=2[C:39]2[O:43][N:42]=[C:41]([CH2:44][CH2:45][CH2:46][O:47][C:48]4[CH:53]=[C:52]([CH3:54])[C:51]([Cl:55])=[C:50]([CH3:56])[CH:49]=4)[CH:40]=2)[CH2:9][NH:8][CH2:15]3)=[O:38])[CH2:37][CH2:36]1
Reactant: Cc1cc(OCCCc2cc(C3=C(C(=O)N(Cc4cccc(Cl)c4Cl)C4CC4)C4CN(C(=O)OC(C)(C)C)CC(C3)N4C(=O)OC(C)(C)C)on2)cc(C)c1Cl
Agent: CC(C)(NC(=O)[O-])C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(OCCCc2cc(C3=C(C(=O)N(Cc4cccc(Cl)c4Cl)C4CC4)C4CNCC(C3)N4)on2)cc(C)c1Cl

Procedure:
This compound is prepared from compound F15, according to the above-described procedure B. After cleaving the Boc-group the trichloro-tert-butylcarbamate was cleaved using Zn-powder in THF/AcOH 3:1. LC-MS: tR=0.93 min; ES+: 629.33.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.OS([O-])(=O)=O.[K+]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCCc1ccccc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCCCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a stirring solution consisting of (S)-4-benzyloxazolidin-2-one (0.9 g, 5.08 mmol) in THF (20 mL) at −78° C. was slowly added n-butyllithium solution (3.5 mL, 5.6 mmol, 1.6 M solution in hexane). The reaction mixture was stirred at −78° C. for two hours, after which time 5-phenylpentanoyl chloride (1 g, 5 mmol, prepared by treatment of 5-phenylpentanoic acid with oxalyl chloride and catalytic DMF) was slowly added. The reaction mixture was stirred at −78° C. for two hours and was then allowed to rise to room temperature overnight. The reaction mixture was acidified with 5% KHSO4 and extracted twice with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (25:75 v/v) afforded the title compound (1.4 g, 82%) as a clear oil; TLC Rf 0.40 (solvent system: 25:75 v/v ethyl acetate-heptane); MS (ESI+) m/z 337.4 (M+H)+, 360.2 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:21][S:22]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][N:26]=1)(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:7]([CH2:9][N:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]([S:22]([CH3:21])(=[O:23])=[O:24])=[N:26]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Reactant: COc1ccc(-n2c(CCl)nc3cc(Cl)ccc32)cn1
Product: COc1ccc(-n2c(Cn3nc(S(C)(=O)=O)c4ccccc43)nc3cc(Cl)ccc32)cn1

Procedure:
The title compound was prepared in analogy to Example 3-1 by using 5-chloro-2-chloromethyl-1-(6-methoxy-pyridin-3-yl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-(4,4,4-tri fluoro-butyl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O.Cl.[CH2:21]([S:23]([C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:28][CH:27]=1)(=[O:25])=[O:24])[CH3:22]>>[CH3:18][C:2]([CH3:1])([CH3:19])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:34]1[CH2:35][CH2:36][N:31]([C:29]2[S:30][C:26]([S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:27][N:28]=2)[CH2:32][CH2:33]1)=[O:9]
Reactant: CC(C)(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CCS(=O)(=O)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CCS(=O)(=O)c1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OCC(C)(C)C)CC2)s1
Yield: 63 %

Procedure:
Prepared in analogy to example 1 (b) from 2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoic acid (Example A11) and 1-(5-ethanesulfonyl-thiazol-2-yl)-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 63%). MS (m/e): 530.2 (M+H+, 64%), 547.2 (M+NH4+, 100%).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:21](=[O:28])[CH2:22][C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:29][CH2:30][O:31]C)[CH:4]=[CH:5]2.O.[C:34](O)(=O)C>>[C:30]([O:29][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][C:21](=[O:28])[CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH:11]=[CH:10][C@@H:9]35)(=[O:31])[CH3:34]
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)Cc4cccs4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@@H](OC(=O)Cc4cccs4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 100 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
A solution of 4,5α-epoxy-3-methoxymethoxy-17-methyl-6α-((2-thienyl)-acetyloxy)-morphinan-7-ene (1.00 g, 2.20 mmol) in glacial acetic acid (30 ml) is mixed with (30 ml) of water and stirred for 5 hours at 100° C. under N2. The solution is evaporated down using a Rotavapor. The residue obtained is purified by flash chromatography (silica gel; mobile phase: CH2Cl2 :MeOH=9:1) and lyophilised in order to obtain 4,5α-epoxy-17-methyl-6α-((2-thienyl)-acetyloxy)-morphinan-7-en-3-ol acetate (0.444 g, 89.9%) as a colourless foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[CH:13]=[C:14]([NH:18][CH:19]([CH:28]([CH3:30])[CH3:29])[C:20]([NH:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[O:21])[CH:15]=[N:16][CH:17]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH:40]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][CH2:42][CH2:41]1>CS(C)=O>[CH3:29][CH:28]([CH3:30])[CH:19]([NH:18][C:14]1[CH:13]=[C:12]([C:11]2[C:5]3[C:6](=[N:7][CH:8]=[C:3]([CH2:2][NH:1][C:45]([CH:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:46])[CH:4]=3)[NH:9][CH:10]=2)[CH:17]=[N:16][CH:15]=1)[C:20](=[O:21])[NH:22][CH2:23][C:24]([F:25])([F:26])[F:27]
Reactant: CC(C)C(Nc1cncc(-c2c[nH]c3ncc(CN)cc23)c1)C(=O)NCC(F)(F)F
Reactant: O=C(Cl)C1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(Nc1cncc(-c2c[nH]c3ncc(CNC(=O)C4CCCC4)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(5-(5-(aminomethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide 10-1c (30 mg, 0.071 mmol) was added to DMSO (0.5 ml) followed by the addition of diisopropylethylamine (0.031 ml, 0.178 mmol). Cyclopentanecarbonyl chloride (9.4 mg, 0.086 mmol) was added and the reaction stirred at room temperature for 3 hrs. The reaction was quenched by addition of methanol. The mixture was diluted with DMSO, filtered and purified by RP-HPLC (water:acetonitrile w/0.1% TFA, C-18, 15-50%). The pure fractions concentrated to remove acetonitrile and mixture neutralized with saturated sodium bicarbonate. The product was extracted with ethyl acetate (3×10 mL). The combined organics were then washed with brine, dried with sodium sulfate, filtered and concentrated to afford the product 10-1. LRMS (ESI) m/z 517.2 [(M+H)+; calcd for C26H31F3N6O2: 517.3
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.OS(O)(=O)=O.[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:19]([O-:21])=[O:20])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])O
Reactant: CN1CCC(c2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 1-methyl-4-phenylpiperidine (2.663 g, 15.19 mmol) was added carefully H2SO4 (15.2 mL). The reaction was cooled in an ice bath and a solution of H2SO4 (1.66 mL) and fuming HNO3 (0.67 mL, 15.95 mmol) was added dropwise over 45 min. The mix was stirred at 0° C. for 3 h then at RT for 1.5 h before being poured over about 90 g ice and basified with 24 g solid NaOH. The mix was extracted with CH2Cl2. The organic layer was washed with H2O, dried over Na2SO4, and concentrated in vacuo. The crude was eluted on a silica gel column with a MeOH/CH2Cl2 gradient to yield 1-methyl-4-(4-nitrophenyl)piperidine which was hydrogenated under H2 to furnish the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]1[CH3:17].[C:18](OC(=O)C)(=[O:20])[CH3:19].I>>[C:18]([C:13]1[CH:14]=[C:15]([CH3:16])[N:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[C:12]=1[CH3:17])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-n2c(C)ccc2C)c(OC)c1
Agent: I
Product: COc1ccc(-n2c(C)cc(C(C)=O)c2C)c(OC)c1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 1, 1-(2,4-dimethoxyphenyl)-2,5-dimethylpyrrole (2.31 g, 10 mmol), acetic anhydride (5 mL), and hydriodic acid (0.13 mL, 1.7 mmol) reacted to give 3-acetyl-1-(2,4dimethoxyphenyl)-2,5-dimethylpyrrole as a tan solid: 1H NMR (CDCl3, 500 MHz) δ 7.02 (dd, 1H), 6.59 (d, 1H), 6.55 (dd, 1H), 6.32 (s, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 2.42 (s, 3H), 2.25 (s, 3H), 1.93 (s, 3H); MS (ESI) 274 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH2:18][O:19][CH:20]([CH3:22])[CH3:21])([C:14]([F:17])([F:16])[CH3:15])[C:4]=2[CH:3]=1.CCOC(C)=O.CCCCCC.[CH3:37][N:38]1C(=O)CCC1>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Zn]>[C:37]([C:2]1[CH:24]=[CH:23][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH2:18][O:19][CH:20]([CH3:22])[CH3:21])([C:14]([F:17])([F:16])[CH3:15])[C:4]=2[CH:3]=1)#[N:38]
Reactant: CC(C)OCC1(C(C)(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reactant: CN1CCCC1=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)OCC1(C(C)(F)F)c2cc(C#N)ccc2Nc2ncccc21
Temperature: 170 °C
Yield: 90 %

Procedure:
A degassed mix of 7-chloro-5-isopropoxymethyl-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b][1,8]naphthyridine (21)(2.501 g, 7.089 mmol), Zn(CN)2 (849 mg, 7.089 mmol), Pd[P(t-Bu)3]2 (1.479 g, 2.836 mmol) and Zinc powder (556 mg, 8.507 mmol) in anhydrous NMP (20 mL) was heated at 170° C. for 22 h 30 min. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through a pad of Celite and washed with EtOAc. The filtrate was washed with 2 N NH4OH (120 mL) and brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (30%-50% EtOAc-Hexane) provided 22 (2.184 g, 90% yield) as a yellow solid: m.p. 134-135° C.; low resolution mass spectrum (ESI) m/z 344.3 [(M+H)+ calcd for C19H20F2N3O: 344.16].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:14](=O)[CH3:15])[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.[H-].[Na+].[Br:19][CH2:20][C:21](Cl)=[O:22]>O1CCCC1>[C:11]([C:10]1[C:14]([CH3:15])=[C:20]([Br:19])[C:21](=[O:22])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)C(=NNc1ccc(Cl)cc1)C(C)=O
Reactant: O=C(Cl)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)c1nn(-c2ccc(Cl)cc2)c(=O)c(Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pentan-2,3,4-trione 3-(4-chlorophenylhydrazone) (23.90 g) was added to a suspension of 66% sodium hydride (7.64 g) in anhydrous tetrahydrofuran (300 ml) under ice cooling, followed by stirring at room temperature for 30 minutes. Then, a solution of bromacetyl chloride (9.1 ml) in anhydrous tetrahydrofuran (100 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. After washing with water and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, the resulting residue was purified by silica gel column chromatography (acetone:hexane=1:9), and crystallized from hexane to obtain 6-acetyl-4-bromo-2-(4-chlorophenyl)-5-methyl-3(2H)-pyridazinone (11.96 g).
Reaction SMILES: CC1(C)[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH2:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][C:4]=2[O:3]1>O1CCOCC1.Cl>[O:17]=[C:15]([CH3:16])[CH2:14][O:13][C:10]1[CH:9]=[C:5]([C:6]([NH2:7])=[O:8])[C:4]([OH:3])=[CH:12][CH:11]=1
Reactant: CC(=O)COc1ccc2c(c1)C(=O)NC(C)(C)O2
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)COc1ccc(O)c(C(N)=O)c1

Procedure:
74 g of the resulting 2,3-dihydro-2,2-dimethyl-6-(2-oxopropoxy)-4H-1,3-benzoxazin-4-one in a mixture of 150 ml of dioxane and 450 ml of 2N hydrochloric acid are heated for 45 minutes on a water bath. The solvent is evaporated off, and the crystalline residue is triturated with water and then filtered off with suction. Recrystallisation from isopropanol yields 5-(2-oxo-propoxy)-salicylamide, which has a melting point of 152°-154°.