Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[O:23][CH2:24][CH3:25])=[O:12])[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28]>O1CCCC1.C(=O)([O-])[O-].[K+].[K+].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>[CH2:24]([O:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]=1[C:11]([N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([C:33]2[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=2)=[CH:3]1)=[O:12])[CH3:25]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCOc1ccc2ccccc2c1C(=O)n1cc(Br)c2cccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc2ccccc2c1C(=O)n1cc(-c2ccc(S(C)(=O)=O)cc2)c2cccnc21
Temperature: 60 °C

Procedure:
(3-Bromo-pyrrolo[2,3-b]pyridin-1-yl)-(2-ethoxy-naphthalen-1-yl)-methanone 85 (35 mg, 0.0088 mmol), 4-Methanesulfonyl-phenylboronic acid (35 mg, 0.18 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg) were stirred in tetrahydrofuran (16 mL) and potassium carbonate solution (8.0 mL, 1 M aqueous). The reaction mixture was stirred over night at 60° C. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and brine. The organic portion was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by flash chromatography (ethyl acetate:hexanes 20%-100%). The desired product, 84 was obtained as a pale yellow powder (10 mg, 20%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:16](=[O:18])[CH3:17])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.[N:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:16]([C:5]1[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])[CH:7]=[C:3]([CH2:2][O:1][C:25]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:26])[N:4]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1nc(CO)cn1COCC[Si](C)(C)C
Reactant: O=C(Cl)N1CCCCC1
Product: CC(=O)c1nc(COC(=O)N2CCCCC2)cn1COCC[Si](C)(C)C

Procedure:
In analogy to Step (4) of Example 48, but using 1-(4-hydroxymethyl-1-(2-trimethylsilylethoxymethyl)-1H-imidazol-2-yl)ethanone (1.50 g) and piperidine-1-ylcarbonyl chloride (0.763 mL), the title compound (1.93 g) was afforded.
Reaction SMILES: S([C:5]1C=[CH:10][C:8](C)=[CH:7][CH:6]=1)(O)(=O)=O.[CH3:12][N:13]([CH3:30])[C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:25][C:26]([NH2:28])=[NH:27])=[CH:20][C:19]=2[Br:29])=[O:15].CC(C)([O-])C.[K+]>CN(C)C=O>[CH3:12][N:13]([CH3:30])[C:14]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([NH:25][C:26]1[N:28]=[C:7]([C:8]3[N:27]=[CH:26][N:25]([CH3:21])[CH:10]=3)[CH:6]=[CH:5][N:27]=1)=[CH:20][C:19]=2[Br:29])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)C(=O)c1cc2cc(NC(=N)N)cc(Br)c2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cc(Nc3nccc(-c4cn(C)cn4)n3)cc(Br)c2[nH]1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1.6 g 4.6, 2.2 g 7.12 and 2.5 g potassium tert-butoxide in 30 ml N,N-dimethylformamide was stirred at 150° C. for 1.5 h under microwave irradiation. The reaction mixture was concentrated in vacuo and the resulting residue was purified by flash chromatography (dichloromethane/methanol 100:0→90:10) to give intermediate 10.1/Example 15.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH3:16])[CH3:15]>>[CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccccc1Br
Reactant: C1CNCCN1
Product: CC(C)c1ccccc1N1CCNCC1

Procedure:
The title compound was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 1-bromo-2-isopropyl-benzene. LRMS (ESI+): 205.4 (M+1)
Reaction SMILES: [Br:1][CH:2]1[CH2:23][CH2:22][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([CH:18]([OH:21])[CH2:19][Br:20])=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:24].C(=O)(O)[O-].[Na+].[Br-].[Na+].O>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1.C(O)(C)C>[Br:1][CH:2]1[CH2:23][CH2:22][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][Br:20])=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:24]
Reactant: O=C1c2cc3c(cc2CCC1Br)-c1ccc(C(O)CBr)cc1CO3
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCC(Br)C3=O
Temperature: 2.5 °C
Yield: 76 %

Procedure:
To 9-bromo-3-(2-bromo-1-hydroxyethyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (approx. 54.4 mmol) in DCM (365 mL) was added sodium bicarbonate (5.45 g), sodium bromide (6.14 g), TEMPO (16.55 mg) and water (60 mL). The solution was cooled between 0-5° C. and 6% bleach (91.5 mL) was added. After 1 h isopropyl alcohol (20 mL) was added and the reaction mixture was warmed to room temperature. Agitation was stopped, the layers separated and the lower organic layer was collected and concentrated removing approximately 345 g of solvent. The slurry was filtered and the cake washed with 50 mL water and then 50 mL DCM (pre-cooled to 5° C.). The solids were collected and dried under vacuum to obtain 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (18.6 g, 76% yield). 400 MHz 1H NMR (CDCl3) δ 8.03-8.01 (m, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H), 4.74 (dd, J=4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92 (m, 1H), 2.59-2.46 (m, 2H); 100 MHz 13C NMR (CDCl3) δ 190.4, 189.6, 154.2, 136.6, 134.1, 133.9, 132.9, 131.8, 129.3, 127.2, 125.6, 124.2, 123.3, 117.0, 68.1, 49.9, 31.8, 30.4, 25.5.
Reaction SMILES: C[O:2][C:3](=[O:59])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([C:43]5[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[CH:44]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[C:50]([C:52]1[N:53]=[C:54]([CH3:58])[O:55][C:56]=1[CH3:57])=[O:51])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.CO.[Li+].[OH-]>C1COCC1>[Cl:49][C:45]1[CH:44]=[C:43]([C:40]2[CH:41]=[CH:42][C:37]([C@H:35]3[CH2:34][O:33][C:29]4=[CH:30][C:31]5[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]6[CH:7]=[CH:8][C:9]([C:12]7[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=7[CH3:19])=[CH:10][CH:11]=6)[C:3]([OH:59])=[O:2])=[O:22])[N:24]([C:50]([C:52]6[N:53]=[C:54]([CH3:58])[O:55][C:56]=6[CH3:57])=[O:51])[CH2:25][C:26]=5[CH:27]=[C:28]4[O:36]3)=[CH:38][CH:39]=2)[CH:48]=[CH:47][CH:46]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1ccc(-c2cccc(Cl)c2)cc1)CO3
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(-c3cccc(Cl)c3)cc2)O4)c(C)o1
Reaction time: 0.5 h

Procedure:
(S)-2-{[(3S,8S)-3-(3′-Chloro-biphenyl-4-yl)-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (0.0139 g) was dissolved in THF (0.3 mL) and MeOH (0.3 mL) and 0.3 mL of 2.0 N LiOH was added at 0° C. and stirred at that temperature for 30 min. pH was adjusted to 6-7, extracted with EtOAc, dried (Na2SO4), evaporated the solvents and dried under vacco to get the title compound. LCMS (m/z): 798.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.CN(C)CCN(C)C.CN(C)[CH:40]=[O:41]>CCOCC.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH:40]=[O:41])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cccc2ccc(OCc3ccccc3)cc12
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: O=Cc1cccc2ccc(OCc3ccccc3)cc12
Temperature: 5 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of 7-benzyloxy-1-iodo-naphthalene (4.60 g, 12.77 mmol) in ether (120 mL) is added 1.7 M tert-butyl-lithium in pentane (8.26 mL, 14.0 mmol) at −78° C. under nitrogen atmosphere and the resulting mixture is stirred for one hour while being warmed up to 5° C. The mixture is cooled to −78° C. again before tetramethylethylene-diamine (1.93 mL, 1.49 g, 12.79 mmol) is added. The mixture is stirred for 10 minutes before N, N-dimethylformamide (0.99 mL, 0.93 g, 12.78 mmol) is added. The mixture is gradually warmed up to room temperature and stirred over night. Ethyl acetate is added to reaction mixture, washed with saturated ammonium chloride, dried over sodium sulfate, filtered and concentrated. The crude product is purified by silica gel chromatography (Hexanes/EtOAc=20/1) to give 7-benzyloxy-naphthalene-1-carbaldehyde (1.95 g, 58.3% yield); 1H NMR 400 Hz (CDCl3) δ 5.27 (s, 2H), 7.33 (m, 2H), 7.42 (m, 2H), 7.52 (m, 3H), 7.83 (d, J=8.98 Hz, 1H), 7.95 (d, J=7.11 Hz, 1H), 8.03 (d, J=8.10 Hz, 1H), 10.32 (s, 1H); MS m/z (M+H+) 263.05.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[C:23]([C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]([CH:20]([CH3:21])[CH3:22])[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]2[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]3=2)[CH:28]=[CH:27][CH:26]=1)#[N:24]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3cccc(C#N)c3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3-cyanophenylboronic acid in step 1.F.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.B>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:13])[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CC(CC(=O)O)c1ccc(Br)cc1
Agent: B
Solvent: C1CCOC1
Product: CC(CCO)c1ccc(Br)cc1
Yield: 84.2 %

Procedure:
To the solution of 3-(4-bromophenyl)butanoic acid (1 g, 4.1 mmol) in tetrahydrofuran (100 mL) was added borane in tetrahydrofuran (8 mL, 1 mol/L), the solution was stirred at reflux for 2 hours, then the solution was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give 3-(4-bromophenyl)butan-1-ol (791 mg, 84.6%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1)=[O:7].C[S-].[Na+]>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2cccs2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(O)cc1)c1cccs1
Yield: 93.3 %

Procedure:
4-Methoxyphenyl 2-thienyl ketone (804 mg) obtained in Example 38 was dissolved in N,N-dimethylformamide (30 ml), sodium thiomethoxide (645 mg) was added, and the admixture was refluxed under argon for 5 hours. The reaction mixture was partitioned in the same manner as described in Example 33. The ethyl acetate layer was dried with anhydrous magnesium sulfate, the solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform to obtain 702 mg of the title compound (yield: 93%).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+].I[CH2:33][CH:34]([OH:37])[CH2:35][OH:36].CN(C)P(N(C)C)(N(C)C)=O>O.CCOCC>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[O:26])=[CH:28][CH:29]=1)([O:3][CH3:4])=[O:2]
Reactant: OCC(O)CI
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 7.34 g. of 4-(15-carbomethoxypentadecylamino)benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml. of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml. of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 4-(15-carbomethoxypentadecylamino)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:15][C:16]1[O:17][CH2:18][C@@:19]2([N:41]=1)[C:32]1[CH:31]=[C:30]([C:33]3[CH2:34][CH2:35][O:36][CH2:37][CH:38]=3)[CH:29]=[C:28]([F:39])[C:27]=1[O:26][C:25]1[C:20]2=[CH:21][C:22]([OH:40])=[CH:23][CH:24]=1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:40][C:22]2[CH:21]=[C:20]3[C:25]([O:26][C:27]4[C:28]([F:39])=[CH:29][C:30]([C:33]5[CH2:34][CH2:35][O:36][CH2:37][CH:38]=5)=[CH:31][C:32]=4[C@@:19]43[CH2:18][O:17][C:16]([NH2:15])=[N:41]4)=[CH:24][CH:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Reactant: Fc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(Oc3cccc(Cl)n3)ccc1Oc1c(F)cc(C3=CCOCC3)cc12
Temperature: 100 °C
Yield: 34.1 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-6-fluoropyridine (88 mg, 0.67 mmol), cesium carbonate (0.027 mL, 0.33 mmol) and (S)-2-amino-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (82 mg, 0.22 mmol, prepared as described in Method BB40 and Example 2 but using 4-bromo-2-fluorophenol and 2-bromo-5-methoxybenzoic acid) in DMF (0.8 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor at 100° C. for 35 min. Then it was heated at 120° C. for 5 min. The crude material was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 35% to 65% to provide (S)-7′-(6-chloropyridin-2-yloxy)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2-amine (36 mg, 0.075 mmol, 33.7% yield) as a off-white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C@@:8]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])([CH2:11][N+:12]([O-])=O)[CH2:7]2)[CH:2]=[CH2:3].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH2:1]([C:4]1[CH2:5][C@@H:6]2[C@H:9]([CH:10]=1)[C@@:8]([CH2:15][C:16]([OH:18])=[O:17])([CH2:11][NH2:12])[CH2:7]2)[CH:2]=[CH2:3]
Reactant: C=CCC1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C=CCC1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Reaction time: 2 h
Yield: 28.4 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-3-allyl-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (335.2 mg, 1.09 mmol) was dissolved in ethanol (10 mL) and water (5 mL). To the solution, iron powder (611.0 mg, 10.9 mmol) and ammonium chloride (57.8 mg, 1.09 mmol) were added, and the mixture was stirred for 2 hours under heating to reflux. The mixture was allowed to cool, then diluted with saturated saline, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate, and filtered through Celite to remove insoluble matter. The filtrate was separated into organic and aqueous layers. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. To the residue, a 4 N hydrochloric acid-ethyl acetate solution (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended in dichloromethane. To the suspension, triethylamine was added dropwise, and the resulting powder was collected by filtration, then washed with dichloromethane, and then dried to obtain the compound of interest as a white powder (68.5 mg, 28%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>O1CCCC1.O.CN(C)P(=O)(N(C)C)N(C)C.CCCCCC>[CH2:28]([CH:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1ccc(OC)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
9.11 g of diisopropylamine are dissolved in 120 ml of dry tetrahydrofuran, and 54 ml of n-hexane containing n-butyl lithium (10 w/v %) are added dropwise thereto for 15 minutes at -10°-0° C. After the mixture is stirred for 10 minutes, 60 ml of tetrahydrofuran containing 12.5 g of ethyl 3-(4-methoxyphenyl)propionate are added dropwise thereto for 45 minutes at the same temperature. The mixture is stirred for 20 minutes, and 50 ml of tetrahydrofuran containing 16.4 g of benzyl bromide and 9.24 g of hexamethylphosphoric triamide are added dropwise for 10 minutes at -60° C. The mixture is stirred at the same temperature for 2 hours, warmed up to room temperature for one hour under stirring, and stirred at room temperature for an additional one hour. Then, water and 10% hydrochloric acid are added thereto under cooling. The solution is extracted with ethyl acetate, washed, dried, filtered and evaporated to remove the solvent. The residue is purified by flash column chromatography (solvent; n-hexane: ethyl acetate=30:1) to give 9.5 g of ethyl 2-benzyl-3-(4-methoxyphenyl)propionate as colorless oil.
Reaction SMILES: F[C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:12][C:13]([F:19])([CH:16]([F:18])[F:17])[CH2:14][OH:15]>>[CH3:11][C:10]1[C:2]([O:15][CH2:14][C:13]([F:19])([F:12])[CH:16]([F:18])[F:17])=[N:3][CH:4]=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: OCC(F)(F)C(F)F
Reactant: Cc1cc(C(=O)O)cnc1F
Product: Cc1cc(C(=O)O)cnc1OCC(F)(F)C(F)F
Yield: 99 %

Procedure:
The title compound is prepared in >99% yield (3.7 g, a white solid) from 6-fluoro-5-methylnicotinic acid (2.0 g, 12.9 mmol) and 2,2,3,3-tetrafluoropropan-1-ol (3.4 g, 25.8 mmol) instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[C:6]([CH3:20])[CH:5]=1)([O-])=O.CO.Cl>CCOCC>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:19])[C:15]([F:16])([F:17])[F:18])=[C:6]([CH3:20])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCNC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1cc(N)ccc1NCCNC(=O)C(F)(F)F
Yield: 108.2 %

Procedure:
1.7 g of nitro derivative (1) prepared above and about 80 ml of methanol were introduced into a 200 ml autoclave (hydrogenator) equipped with a magnetic stirrer. The solution obtained was degassed with nitrogen. 0.2 g of palladium-on-charcoal (5% humidity, comprising 50% water) was added thereto. The reaction mixture was stirred, while flushing once with hydrogen, and hydrogen was then introduced therein at a pressure of about 5 bar. After reaction for 4 hours, the reactor was purged with nitrogen. The reaction mixture was filtered quickly through Celite under a gentle pressure of nitrogen. The filtrate: was recovered in a pre-cooled solution of methanol comprising about 3 equivalents of hydrogen chloride gas. The resulting mixture was rinsed several times with methanol under a stream of nitrogen. The concentrated solution thus obtained was then treated with ether. The product obtained, in the form of a pale pink paste, was stirred and then rinsed several times with acetonitrile and ether under nitrogen. 1.65 g of expected product (2) were isolated in the form of a slightly pink white powder. The proton and 13C NMR spectra and the microanalyses were in accordance with the expected structure of the product.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:25]([CH:22]([CH2:23][CH3:24])[CH2:21][N:11]1[C:12]2[C:7](=[C:6]([OH:34])[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][C:13]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:10]1=[O:27])[CH3:26]
Reactant: NCCC(=O)O
Reactant: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)OC)nc(-c3ccncc3)c21
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(CC)Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)nc(-c3ccncc3)c21
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A mixture of 1-(2-ethyl-butyl)-5-hydroxy-2-oxo-3-phenyl-8-pyridin-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.066 mmol), β-alanine (585 mg, 6.6 mmol) and NaOMe solution (10 mL, 4.9 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound as an off-white solid. MS: (+) m/z 515.36 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:29]3[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cnc(N)nc3)n2)n1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (example E.26) (0.150 g, 0.38 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.092 g, 0.42 mmol) according to the general procedure VI. Obtained as a white solid (0.080 g, 57%). MS (ISP) 407.3 [(M+H)+]; mp 219-222° C.