Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]([CH3:18])[C:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])(=O)C.Cl.OC(C)C(C1C2C(=CC=CC=2)C=CC=1)=O.[N:35]#[C:36][NH2:37].[OH-].[Na+]>[Cl-].[Na+].O.O1CCCC1.O>[NH2:37][C:36]1[O:7][C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)=[C:5]([CH3:18])[N:35]=1
Reactant: CC(=O)OC(C)C(=O)c1cccc2ccccc12
Reactant: N#CN
Agent: CC(O)C(=O)c1cccc2ccccc12
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N)oc1-c1cccc2ccccc12
Temperature: 40 °C
Reaction time: 16 h
Yield: 22.2 %

Procedure:
A mixture of 2-acetoxy-1-(naphth-1-yl)-1-propanone (2.6 g), IMS (30 ml) and hydrochloric acid (1M; 22 ml) was boiled under reflux for 4 hours. The mixture was cooled, added to brine and extracted twice with dichloromethane. The combined organic extracts were dried with sodium sulphate, filtered and evaporated in vacuo to afford a mixture of crude 2-hydroxy-1-naphthalen-1-yl-propan-1-one and 1-hydroxy-1-naphthalen-1-yl-propan-1-one (B) as an oil (2.2 g). A portion of this material (0.5 g) was dissolved in tetrahydrofuran (2 ml) to which was added cyanamide (0.11 g), water (2 ml) and sodium hydroxide solution (2M; 0.25 ml). The mixture was stirred vigorously for 16 hours then tetrahydrofuran was added (10 ml). The mixture was heated to 40° C. for 30 minutes, cooled and left for a further 6 hours. Brine was added and the mixture was extracted twice with dichloromethane. The combined organic extracts were dried with sodium sulphate, filtered and evaporated in vacuo. The title compound (3) (0.13 g; m.p. 187-189° C.) was obtained following silica gel column chromatography of the residue in 50% ethyl acetate in petroleum ether.
Reaction SMILES: CS(O[CH:6]([CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=O)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O>[N:15]([CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:13][CH3:14])=[N+:16]=[N-:17]
Reactant: CCCCCCC(CC)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCC(CC)N=[N+]=[N-]
Temperature: 50 °C
Reaction time: 16 h

Procedure:
15.0 g (67.46 mmol) of 1-ethyl-heptyl methanesulphonate are dissolved in 300 ml of DMSO and, after addition of 17.54 g (269.8 mmol) of sodium azide, the mixture is stirred at 50° C. for 16 hours. The reaction mixture is poured into ice-water and extracted three times with ether. The extract is dried over sodium sulphate giving 11.4 g (96%) of a yellow liquid.
Reaction SMILES: OP([O-])(O)=O.[K+].[Br:7][C:8]1[CH:9]=[N:10][S:11][C:12]=1[N:13](C(OCC(Cl)(Cl)Cl)=O)[C@H:14]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17]>C1COCC1.C(OCC)(=O)C.[Zn]>[Br:7][C:8]1[CH:9]=[N:10][S:11][C:12]=1[NH:13][C@H:14]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1sncc1Br
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)Nc1sncc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 164.6 %

Procedure:
A 1.0 M aqueous solution of KH2PO4 (1.8 mL) was added dropwise over several minutes to zinc dust (1.13 g, 17.8 mmol) and methyl N-(4-bromoisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate (172 mg, 0.356 mmol) in THF (3.2 mL) with rapid stirring at rt for 30 min. The slurry was diluted with ethyl acetate and filtered (Celite), and the filtrate was washed with water, then saturated sodium chloride solution and dried (Na2SO4). Solvent removal in vacuo afforded 180 mg of methyl N-(4-bromoisothiazol-5-yl)leucinate as a yellow oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][NH2:20])[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][NH:20][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:15]=[CH:16][CH:17]=1
Reactant: NCCc1cccc(Br)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NCCc1cccc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
Benzenesulfonyl chloride (1.54 mL, 12.00 mmol) was added to [2-(3-bromophenyl)ethyl]amine (2.00 g, 10.00 mmol) and N,N-di-iso-propylethylamine (5.22 mL, 29.99 mmol) in dichloromethane (33 mL) at 0° C. under argon and the reaction was allowed to warm to room temperature and stirred for 16 hours. The dichloromethane was concentrated under vacuum; diethyl ether was then added, followed by 10% citric acid. The solution was extracted with diethyl ether and the organic layer was washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:4 ethyl acetate:hexanes to give 3.22 g (95%) of N-[2-(3-bromophenyl)ethyl]benzenesulfonamide as a solid. 1H NMR (400 MHz, d6-DMSO): δ 7.77-7.73 (m, 2H), 7.70 (t, J=6 Hz, 1H), 7.62 (d, J=7 Hz, 1H), 7.57 (t, J=8 Hz, 2H), 7.40-7.34 (m, 2H), 7.22 (t, J=8 Hz, 1H), 7.15 (d, J=8 Hz, 1H), 2.96 (q, J=7 Hz, 2H), 2.67 (t, J=7 Hz, 2H). ESI-LCMS m/z 340 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:25][C:24]([CH2:26]O)=[CH:23][C:13]=3[N:14]([CH2:16][C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:44])(=O)=O.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:25][C:24]([CH2:26][Cl:44])=[CH:23][C:13]=3[N:14]([CH2:16][C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])[CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: CON(C)C(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)cc21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
To a mixture of N-(4-chlorobenzyl)-2-(hydroxymethyl)-4-{2-[methoxy(methyl)amino]-2-oxoethyl}-7-oxo-4,7-dihydrothieno [3,2-b]pyridine-6-carboxamide (80 mg, 0.18 mmol), collidine (59 μL, 0.44 mmol) and DMAP (3.2 mg) in DMF (2.6 mL) was added methanesulfonyl chloride (35 μL, 0.44 mmol). The reaction was stirred at room temperature for 24 hrs, then cooled to 0° C. before the addition of water (5 mL). The resulting ppt was collected by filtration and washed with water and dried in vacuo, leaving the title compound as an off-white solid (80 mg). The title compound is also a compound of formula I.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].[CH:46]1[C:58]2[CH:57]([CH2:59][O:60][C:61]([NH:63][CH2:64][C:65]([CH3:70])([CH3:69])[C:66](O)=[O:67])=[O:62])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:50]=2[CH:49]=[CH:48][CH:47]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:55]1[C:56]2[CH:57]([CH2:59][O:60][C:61]([NH:63][CH2:64][C:65]([CH3:70])([CH3:69])[C:66]([NH:37][C@H:36]([C:35]([N:34]([CH3:42])[C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:6])=[O:45])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:67])=[O:62])[C:58]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]=2[CH:52]=[CH:53][CH:54]=1
Reactant: CC(C)(CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
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: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.9 %

Procedure:
To a stirring solution of #114 (200 mg, 0.316 mmol, 1.00 eq.) in 2 mL of dichloromethane, #124 (107 mg, 0.316 mmol, 1.00 eq.) was added followed by Hunig's base (0.167 mL, 0.948 mmol, 3.00 eq.) and HATU (149 mg, 0.379 mmol, 1.20 eq.). The reaction was allowed to stir at room temperature for ˜12 hours. The reaction was concentrated to a smaller volume, taken up in 10 mL of ethyl acetate, and washed two times with 5 mL of 1M HCl, and once with 5 mL of brine. The organic layer was dried over sodium sulfate and decanted. Organics where concentrated in vacuo and the crude material was taken up in dichloromethane. The precipitate was filtered. The organic layer was concentrated in vacuo and the residue was purified by silica chromatography (Gradient: 0%-50% acetone in heptane) producing #125 (235 mg, 78%) as a white solid. LC-MS (Protocol Q): m/z 954.2 [M+H+] retention time=2.28 minutes.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:15]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][N:9]=2)[S:5][CH:6]=1.[BH4-].[Na+].[NH4+].[Cl-]>CCO>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:14][C:15]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2ncc(C=O)cc2Oc2ccccc2)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1csc(Nc2ncc(CO)cc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a mixture of mL 6-(4-methylthiazol-2-ylamino)-5-phenoxynicotinaldehyde (Example 44, Step A; 150 mg, 0.48 mmol) and EtOH (5 mL) was added sodium borohydride (27.3 mg, 0.72 mmol) and stirred at ambient temperature for 30 minutes. Poured into saturated aqueous NH4Cl and extracted with CH2Cl2. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica gel (1:1 EtOAc:hexanes) to afford the title compound (132 mg, 87.4% yield) as a white solid. 1H NMR (CDCl3) δ 8.66 (bs, 1H), 8.06 (d, 1H), 7.38 (m, 2H), 7.19 (m, 1H), 7.12 (d, 1H), 7.03 (m, 2H), 6.42 (q, 1H), 4.58 (s, 2H), 2.33 (d, 3H), 1.77 (bs, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(N(CC)CC)C.[CH3:19][C:20]1[N:21]=[CH:22][N:23]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][C:26]=2[C:32]([F:35])([F:34])[F:33])[CH:24]=1>O=S(Cl)Cl.CN(C1C=CN=CC=1)C.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([N:23]2[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]2)=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:27]=1)=[O:7]
Reactant: Cc1cn(-c2ccc(N)cc2C(F)(F)F)cn1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccc(NC(=O)c3ccc(C)c(I)c3)cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 40 h
Yield: 72.1 %

Procedure:
A solution of 3-iodo-4-methylbenzoic acid (0.26 g, 1 mmol) in SOCl2 (5 mL) was refluxed for 3 hrs, then evaporated in vacuo to remove residual SOCl2. The residue was dissolved in 5 mL anhydrous THF and added to a solution of triethylamine (0.12 g, 1 mmol), 4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)aniline (0.24 g, 1 mmol) and DMAP (12 mg) in 5 mL anhydrous THF in dropwise. The result mixture was stirred at rt for 40 hrs, and evaporated in vacuo. To the residue water was added and extracted with EtOAc (20 mL×3), the organic layer was washed with brine, dried with Na2SO4, after filtration, the filtrate was purified by chromatography on silica gel (CH2Cl2/CH3OH 97:3) to give 0.4 g crude product. The crude product was triturated with PE/EtOAc to give the title compound 0.35 g as pale yellow solid (72.2%). 1H NMR (300 MHz, CDCl3) δ: 8.91 (1 H, s), 8.37 (1 H, s), 8.08-8.12 (2 H, m), 7.86-7.83 (1 H, d, J=8.4 Hz), 7.54 (1 H, s), 7.34-7.36 (2 H, m), 6.84 (1 H, s), 2.50 (3 H, s), 2.29 (3 H, s). LCMS: m/z [M+H]+ 486.0493.
Reaction SMILES: O[C:2]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:7][C:6]2[C:8]([CH2:16][CH2:17][CH3:18])=[C:9]3[C:14](=[CH:15][C:5]=2[C:4](=[O:19])[CH2:3]1)[CH2:13][CH2:12][CH2:11][CH2:10]3.Cl>C(O)C>[O:19]=[C:4]1[CH:3]=[C:2]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:7][C:6]2[C:8]([CH2:16][CH2:17][CH3:18])=[C:9]3[C:14](=[CH:15][C:5]1=2)[CH2:13][CH2:12][CH2:11][CH2:10]3
Reactant: CCCc1c2c(cc3c1OC(O)(C(=O)OCC)CC3=O)CCCC2
Agent: Cl
Solvent: CCO
Product: CCCc1c2c(cc3c(=O)cc(C(=O)OCC)oc13)CCCC2

Procedure:
The product of step (a) (1 g) in ethanol (50 ml) containing concentrated HCl (1 ml) was heated under reflux for 4 hours. Evaporation of the resulting solution to a volume of 20 mls caused the chromone ester, identical to that of Example 1(d) to crystallise.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([C:13]([CH3:25])([CH3:24])[CH2:14][C:15]([C:20]([F:23])([F:22])[F:21])([OH:19])[CH2:16][C:17]#[CH:18])[CH:10]=[CH:11][CH:12]=1.[C:26]([O:30][C:31](=[O:40])[NH:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1I)([CH3:29])([CH3:28])[CH3:27]>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.C(N(CC)CC)C.CN(C=O)C.C(OCC)C.[Cu]I>[C:26]([O:30][C:31](=[O:40])[NH:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][C:38]=1[C:18]#[C:17][CH2:16][C:15]([OH:19])([C:20]([F:21])([F:22])[F:23])[CH2:14][C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:2]2[O:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:8]=1)([CH3:25])[CH3:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: C#CCC(O)(CC(C)(C)c1cccc(C2OCCCO2)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cnccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cnccc1C#CCC(O)(CC(C)(C)c1cccc(C2OCCCO2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.3 %

Procedure:
A mixture of 6-(3-[1,3]dioxan-2-ylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (300 mg, 0.84 mmol), (4-iodopyridin-3-yl)carbamic acid tert-butyl ester (270 mg, 0.84 mmol), bis(triphenylphosphine)palladium(II) chloride catalyst (29.6 mg, 0.04 mmol) and copper (I) iodide (16 mg, 0.08 mmol) in 4 mL of anhydrous triethylamine and 1 mL of anhydrous DMF was stirred at room temperature for 12 hours. The reaction mixture was then diluted with 30 nL of diethyl ether and washed with 20 mL of aqueous saturated ammonium chloride solution and 20 mL of brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Column chromatography over silica gel with hexanes-ethyl acetate (5:1 to 1:1) provided 250 mg of the title compound as a foam (54% yield).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>C(#N)C>[Br:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]([N:25]=[N+:26]=[N-:27])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Br)o1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)C=Cc1ccc(Br)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a solution of 3-(5-bromo-2-furyl)acrylic acid (41.5 g) in acetonitrile (200 mL) were added triethylamine (23.0 g) and ethyl chloroformate (26.1 g). The mixture was stirred at room temperature for 30 min. To the obtained mixture was added a saturated aqueous solution of sodium azide (18.7 g) at 0° C. and the mixture was stirred at room temperature for 5 hr. The reaction mixture was filtered, and the obtained solid was washed with water. The solid was recrystallized from dichloromethane to give the title compound (20.7 g) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:15][CH2:14]2)=[CH:6][C:5]=1[C:26]([F:29])([F:28])[F:27]>C(O)C.O1CCCC1.[Pd]>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:15][CH2:14]2)=[CH:6][C:5]=1[C:26]([F:28])([F:29])[F:27]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(c3ccccc3C)CC2)cc1C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(N)c(N2CCN(c3ccccc3C)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of 5-nitro-4-(4-o-tolyl-piperazin-1-yl)-2-trifluoromethyl-benzoic acid methyl ester 9a (212.9 mg, 0.50 mmol, 100 mol %) in ethanol (5.0 ml) and tetrahydrofuran (2.0 ml) was added palladium on carbon (5 wt %) (107.0 mg, 0.05 mmol, 10 mol %) and the reaction was stirred at room temperature for 16 h and then filtered through a pad of Celite. The filtrate was then concentrated to a residue that was purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to afford 5-amino-4-(4-o-tolyl-piperazin-1-yl)-2-trifluoromethyl-benzoic acid methyl ester 9b (139.5 mg, 0.36 mmol) as an off-white solid. LCMS (ESI) 394 (M+H).
Reaction SMILES: [C:1]12([C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8]1)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.C(O)C.[BH4-].[Na+]>O>[OH:12][CH:11]1[C:1]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]1=2
Reactant: O=C1c2ccccc2OC12CCCCCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1c2ccccc2OC12CCCCCC2
Temperature: 25 °C
Reaction time: 23 h
Yield: 89.4 %

Procedure:
A mixture of 7.48 g of spiro[benzofuran-2(3H),1'-cycloheptan]-3-one, 175 ml of denatured ethanol and 1.31 g of sodium borohydride was stirred for 23 hours at room temperature under nitrogen. After addition of 250 ml of distilled water and 10-15 minutes of stirring, the mixture was partitioned between 250 ml of distilled water and 250 ml of ether. The phases were separated and the aqueous phase extracted with additional ether (2×250 ml). The combined organic extracts were washed with distilled water (250 ml) and saturated sodium chloride solution (250 ml) and thereafter dried over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded a solid which was triturated, filtered and washed with hexane. The filtrate was concentrated in vacuo to afford a second crop. Trituration and washing with hexane were repeated to afford in two crops 6.75 g of a crystalline solid, m.p. 104°-107° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([N:8]([CH3:26])[C:9]1[C:14]2[N:15]=[C:16]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 8-(N-benzyl-methylamino)-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 121°-123° C.) and piperazine.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]([C@@H:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)=O)=[CH:3][CH:2]=1.S(=O)(=O)(O)O>O1CCCC1>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:6]=1
Reactant: O=C1CC[C@H](C(=O)c2ccc(-c3ccccc3)cc2)N1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1CC[C@H](Cc2ccc(-c3ccccc3)cc2)N1
Temperature: 30 °C
Reaction time: 20 h

Procedure:
14 g of (R)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one are suspended in 80 ml tetrahydrofuran. Subsequently 331 mg of concentrated sulphuric acid are added and the reaction vessel is purged with argon. 1.4 g of palladium on carbon 10% m/m (W. C. Heraeus GmbH, Type K-0218) is added and the mixture is stirred under an atmosphere of hydrogen (3 bar) at 30° C. for 20 h. The black suspension is filtered and the filter cake is washed with tetrahydrofuran. After the addition of 50 ml water, the pH of the emulsion is adjusted to pH 5.5 using sodium hydroxide solution (2M). Under reduced pressure, the organic solvent is removed and 100 ml of isopropyl acetate are added. The aqueous layer is then separated and the remaining organic layer is concentrated to approx. half of its original volume. The suspension is cooled to −5° C. and filtered. The filter cake is washed with cooled isopropyl acetate and is dried under reduced pressure to give (R)-5-biphenyl-4-ylmethylpyrrolidin-2-one as colourless crystals. 1H-NMR (CDCl3): 1.93 (1H); 2.37 (3H); 2.80 (1H, dd, J=8.5, 13.5); 2.92 (1H, dd, J=5.4, 13.5); 3.95 (1H); 5.70 (1H); 7.29 (1H, d, J=7.5); 7.38 (1H); 7.47 (2H); 7.59 (4H). MS (ESI, m/e) 252 [M+H]+; 503 [2M+H]+. IR (solution in CH2Cl2, ν/cm−1): 3191; 3055; 2930; 1692; 1489; 1272; 762; 692.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N1C=CC=CC=1.[CH:13]([O:16][C:17]([N:19]1[C:28]2[C:23](=[N:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C@H:22]([NH:31][CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[CH2:21][C@@H:20]1[CH3:47])=[O:18])([CH3:15])[CH3:14]>ClCCl>[CH:13]([O:16][C:17]([N:19]1[C:28]2[C:23](=[N:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C@H:22]([N:31]([CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:21][C@@H:20]1[CH3:47])=[O:18])([CH3:15])[CH3:14]
Reactant: COc1ccc2c(n1)[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(OC)nc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
Add ethyl chloroformate (0.118 mL, 1.240 mmol), followed by pyridine (0.205 mL, 2.52 mmol), to a solution of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzylamino)-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.210 g, 0.415 mmol) in dichloromeihane (3 mL). After stirring at room temperature for 12 h remove the solvent in vacuo. Purify using silica gel chromatography, eluting with ethyl acetate/hexane (gradient eluent, 0-30% ethyl acetate in hexane) to afford the title compound (0.218 g, 92%): MS (ES+): 578 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH2:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:19])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(N)=O)nn1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C#N)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The phenol from the previous step (1.73 g, 4.9 mmol) in THF (30 ml) was treated with pyridine (0.82 ml, 0.82 g, 10.2 mmol) followed by trifluoroacetic anhydride (1.61 ml, 2.42 g, 11.5 mmol). The mixture turned dark green and was left overnight at ambient temperature. The mixture was then evaporated to a gum, treated with an excess of an aqueous solution of sodium bicarbonate and stirred at ambient temperature for approximately 30 minutes. The resultant red solid was filtered, washed with water and sucked dry (1.8 g) and purified by MPLC to give 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-3-cyanopyridazine (as a white solid (0.87 g, 53%).