Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[O:9][CH:8]([C:15]([F:18])([F:17])[F:16])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]2)[CH3:2].B(Br)(Br)Br>C(Cl)Cl.C(=O)=O.CC(C)=O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[O:9][CH:8]([C:15]([F:16])([F:17])[F:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]2)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(CC)c(OC)cc2OC1C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2cc(CC)c(O)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6.8 g (20.6 mmol) of ethyl 6-ethyl-7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 30 mL of anhydrous DCM at −78° C. in dry ice/acetone bath was added dropwise a solution of 206 ml (1.0 M in DCM, 206 mmol) of boron tribromide. After finishing addition, the dry ice/acetone bath was removed. The reaction was stirred at room temperature overnight. The reaction was cooled back to −78° C. in dry ice/acetone bath and treated dropwise with 250 mL of methanol. The reaction was allowed to warm to room temperature and subsequently concd in vacuo. The residue was purified by silica chromatography with EtOAc/hexane (2:8). The collected fractions were concd and used directly in step 3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][C:2]1=[O:7].C([N-]C(C)C)(C)C.[Li+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>O1CCCC1>[CH2:20]([O:19][C:17]([CH:3]1[S:4][CH2:5][CH2:6][NH:1][C:2]1=[O:7])=[O:18])[CH3:21]
Reactant: O=C1CSCCN1
Reactant: CCOC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1SCCNC1=O
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of thiomorpholin-3-one (1 equivalent), tetrahydrofuran (5-40 parts), and lithium diisopropylamide (1-2 equivalents) is stirred at -10° to 50° C. for 1 to 3 hours. To this mixture is added ethyl chloroformate (1 to 2 equivalents). After 1 to 3 hours' stirring, the mixture is acidified with hydrochloric acid, concentrated, diluted with ethyl acetate, washed with water, dried, and concentrated to give 3-oxothiomorpholine-2-carboxylic acid ethyl ester in 80 to 90% yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:29][C:27]1[NH:26][N:25]=[C:24]([NH:23][C:13]2[N:12]=[C:11]([O:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[C:20]3[C:15]([CH:14]=2)=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH:28]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: N#Cc1ccc(O)cc1
Product: COc1ccc2c(Oc3ccc(C#N)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-hydroxy-benzonitrile and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give 4-[3-(5-Methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 372(MH+).
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].N.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([N+:33]([O-])=O)=[CH:28][N:27]=2)[CH2:22][CH2:21]1)=[O:19]>C1COCC1.O>[NH2:33][C:29]1[CH:30]=[C:31]([CH3:32])[C:26]([N:23]2[CH2:22][CH2:21][N:20]([C:18]([C:12]3[C:13]([F:17])=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])=[O:19])[CH2:25][CH2:24]2)=[N:27][CH:28]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCN(C(=O)c2c(F)cccc2F)CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(N)cnc1N1CCN(C(=O)c2c(F)cccc2F)CC1
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
Add Na2S2O4 (10 equiv.) and aqueous ammonia (3 mL/mmol, 32%) to a solution of (2,6-difluoro-phenyl)-[4-(3-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone (3 g, 8.29 mmol) in THF/H2O (166 mL, 1:1). Stir for 30 min., then separate layers. Extract the aqueous layer with DCM, EtOAc and isopropyl alcohol/EtOAc. Combine organic layers and dry over Na2SO4, filter and remove solvent under reduced pressure. Subject crude to a Varian™ SCX column and wash the column with MeOH and then flush off the product with 2 M NH3 in MeOH to obtain 1.2 g of [4-(5-amino-3-methyl-pyridin-2-yl)-piperazin-1-yl]-(2,6-difluoro-phenyl)-methanone (44% yield). ES+(m/z): 333 [M+1]
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([N:19]1[CH2:20][CH2:21][C:16]2([O:15][C:14]3[C:24]4[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=3[S:23][CH2:22]2)=[CH:9][CH:8]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH:25]=4)[CH2:17][CH2:18]1)=[O:33]
Reactant: O=C1C(=O)c2ccc(-c3ccncc3)cc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C1C(=O)c2ccc(-c3ccncc3)cc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2
Yield: 99 %

Procedure:
Compound 66 was synthesized using 9-pyridin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. Yield: 99%. Mp.: 265-267° C.; 400 MHz 1H NMR (DMSO-d6) δ 8.75 (m, 2H), 8.08 (d, J=1.6 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.98 (dd, J=1.6, 8.0 Hz, 1H), 7.83 (m, 2H), 7.56-7.47 (m, 3H), 7.41 (dt, J=1.2, 7.6 Hz, 1H), 4.32 (br, 1H), 3.50 (br, 2H), 3.38-3.30 (m, 1H), 3.14 (s, 2H), 2.15 (m, 1H), 2.02 (m, 1H), 1.91 (m, 2H); LCMS: 517 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH:3]([CH3:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH:14]=[N:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CO>[CH3:25][N:2]([CH3:1])[CH:3]([CH3:24])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH2:14][NH:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(OCC(C)N(C)C)c(C=NCCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(OCC(C)N(C)C)c(CNCCc2ccccc2)c1
Yield: 74.7 %

Procedure:
N-[[2-[2-(Dimethylamino)propoxyl]-5-methoxyphenyl]methylene]benzeneethanamine (39.5 g) is reduced with 13.0 g of sodium borohydride in 200 ml. of methanol following the procedure described in Example 1C yielding 29.7 g of the title compound, boiling point 205°-210° C. at 0.4-0.5 mm of Hg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(O)c1ccnc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a chilled (ice water bath) solution of 1-(2-bromo-pyridin-4-yl)-ethanol (27.5 g, 132 mmol) in dichloromethane (200 mL) was added Dess-Martin periodinane (56.0 g, 132 mmol). The cold bath was then removed and the mixture was stirred at room temperature. After 2 hours, the mixture was diluted with saturated sodium carbonate (100 mL) and partially concentrated to remove the dichloromethane. The crude material was filtered through diatomaceous earth and washed with EtOAc (200 mL). The aqueous layer was separated and extracted with EtOAc (100 mL). The combined organic layers were washed with saturated aqueous sodium carbonate (100 mL), brine (100 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 5-30% EtOAc in hexanes to afford 1-(2-bromo-pyridin-4-yl)-ethanone as white needles.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].B([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(O)O.C(N(CC)CC)C>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:7][O:6][C:4]([C:3]1[CH:8]=[C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:10]=[CH:11][C:2]=1[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:5]
Reactant: COC(=O)c1cc(N2CCCC2=O)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)O)cc1
Temperature: 100 °C

Procedure:
A stirred solution of methyl 2-bromo-5-(2-oxopyrrolidin-1-yl)benzoate (D52, 1.7 g; 5.73 mmol) in DMF (13 ml) was treated with 4-boronobenzoic acid (0.95 g,5.73 mmol) under argon, followed by tetrakis(triphenylphosphine)palladium (O) (104 mg) and triethylamine (2.34 ml, 0.02 mol). After heating for 18 h at 100° C., the reaction mixture was concentrated under reduced pressure and the residue partitioned between 10% aqueous Na2CO3 solution and ethyl acetate. The basic aqueous layer was acidified with 5M HCl acid, precipitating the crude product as a white solid, which was recrystallised from ethanol (137 mg, 7%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:29][OH:30])=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(CC(=O)c2ccncc2)c2ccc(N(C)C)cc2)cc1C
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(C(CC(=NO)c2ccncc2)c2ccc(N(C)C)cc2)cc1C

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-(3,4-dimethyl-phenyl)-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.3:1) as a yellow foam, MS (ESI+): m/z=374.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]>CC#N.CCOC(C)=O.O>[C:17]([O:21][C:22](=[O:47])[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][C:31]([N:33]([CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=3[Cl:1])[S:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:44][CH2:45][CH3:46])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: ClCc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc2cc(N(Cc3cccc(Cl)c3Cl)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2,3-Dichlorobenzyl chloride (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C@H:49]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:48][C@H:49]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[C:50]2[CH:51]=[CH:52][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:54][CH:55]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: CCOP(C)(=O)c1ccc([C@H](N)c2ccccc2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (2.5 g, 12.11 mmol) and Et3N (4.3 mg, 43 mmol) in MeCN (50 ml) was added HATU (4.83 mg, 12.72 mmol). The mixture was stirred for 5 min at room temperature and then ethyl 4-((R)-amino(phenyl)methyl)phenyl(methyl)phosphinate hydrochloride, 23-c, (3.5 g, 12.1 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (petroleum ether:ethyl acetate=2/1) to provide the product, 23-d, (4 g, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Br.Br[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCN(CC)CCBr
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCNCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Chlorobenzylamine (1.0 mL, 8.2 mmol) was added to a solution of 2-bromo-N,N-diethylethylamine hydrobromide (2.4 g, 9.0 mmol) and triethylamine (3.4 mL, 25 mmol) in dichloromethane (16 mL). The mixture was stirred at room temperature for 5 hours. The mixture was then concentrated to give N1-(4-chlorobenzyl)-N2,N2-diethylethane-1,2-diamine as an oil which was used immediately without purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH-:19].[Na+]>>[OH:19][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: [Na+]
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CO
Yield: 71.4 %

Procedure:
Reaction of chloride 2 (500 mg, 1.88 mmol) and aqueous NaOH (2 M, 10 mL, 20 mmol) gave acid 55 (313 mg, 72%) as a cream solid: mp (EtOAc/MeOH) 240-242° C.; 1H NMR δ □ 13.18 (br s, 1H, CO2H), 8.00-8.06 (m, 4H, H-2, H-3, H-5, H-6), 5.11 (br s, 1H, OH), 2.41 (s, 3H, CH3); MS m/z 234.5 (MH+, 100%); HRMS calcd for C12H12NO4: 234.0761. Found: 234.0760.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[N+:24]([O-])=O)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CO>[Pt].C1(C)C=CC=CC=1>[NH2:24][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:13][CH2:12][C:2]([CH3:27])([CH3:1])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(CNC(=O)OC(C)(C)C)CNc1c(N)cnc2ccccc12

Procedure:
A pressure bottle was charged with platinum on carbon (5%, 0.70 g) followed by tert-butyl 2,2-dimethyl-3-[(3-nitroquinolin-4-yl)amino]propylcarbamate dissolved in 250 mL of toluene. The reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). The next day, the reaction mixture was carefully charged with 25 mL of MeOH and filtered through a pad of CELITE filter agent. The pad was rinsed with 1:1 CH2Cl2/methanol. The solvent was removed under reduced pressure to give tert-butyl 3-[(3-aminoquinolin-4-yl)amino]-2,2-dimethylpropylcarbamate as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:14])=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][C:6](=[O:12])[C:5]2=O.Cl.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][N:24]=[C:5]2[C:4]3[C:8](=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[C:3]=3[CH3:14])[NH:7][C:6]2=[O:12])=[CH:19][CH:18]=1
Reactant: Cc1ccc(NN)cc1
Reactant: Cc1cc2c(c(C)c1O)C(=O)C(=O)N2
Agent: Cl
Product: Cc1ccc(NN=C2C(=O)Nc3cc(C)c(O)c(C)c32)cc1
Yield: 41 %

Procedure:
1H NMR (DMSO-d6): δ 2.17 (s, 3H), 2.30 (s, 3H), 6.45 (s, 1H), 8.29 (s, 1H), 10.65 (s, 1H); ESI-MS m/z 190 (M−H)−. The isatin was combined with 4-methylphenylhydrazine hydrochloride according to Procedure H to provide the title compound in 41% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.O.[CH2:12]1[CH2:16]OC[CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:16][CH:12]=[CH2:13])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: C1CCOC1
Reactant: Fc1cc(F)cc(CBr)c1
Solvent: O
Product: C=CCCc1cc(F)cc(F)c1
Reaction time: 1 h

Procedure:
A 176 g portion of 3,5-difluorobenzyl bromide was dissolved in 300 ml of THF to which was subsequently added dropwise 450 ml of allyl magnesium chloride THF solution (2 mol/l) at room temperature. This was stirred for 1 hour and then mixed with 300 ml of water. This was extracted with 800 ml of hexane, washed twice with saturated brine and then dried with anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was distilled (79-82° C./20 mmHg) to obtain 104 g of 3,5-difluoro-1-(3-butenyl)benzene.
Reaction SMILES: [Li][CH2:2][CH2:3]CC.[CH:6]([C:8]1[CH:28]=[C:27]([C:29]2[C:38]3[C:33](=[CH:34][C:35]([O:39][CH3:40])=[CH:36][CH:37]=3)[O:32][C:31](=[O:41])[CH:30]=2)[CH:26]=[CH:25][C:9]=1[O:10][C:11]1[CH:12]=[C:13]([C@@:17]2([CH3:24])[O:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH:14]=[CH:15][CH:16]=1)=O>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH3:40][O:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([C:27]3[CH:26]=[CH:25][C:9]([O:10][C:11]4[CH:12]=[C:13]([C@@:17]5([CH3:24])[O:21][C:20](=[O:22])[NH:19][C:18]5=[O:23])[CH:14]=[CH:15][CH:16]=4)=[C:8]([CH2:6][CH2:2][CH3:3])[CH:28]=3)=[CH:30][C:31](=[O:41])[O:32]2)=[CH:37][CH:36]=1
Reactant: COc1ccc2c(-c3ccc(Oc4cccc([C@@]5(C)OC(=O)NC5=O)c4)c(C=O)c3)cc(=O)oc2c1
Reactant: [Li]CCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1cc(-c2cc(=O)oc3cc(OC)ccc23)ccc1Oc1cccc([C@@]2(C)OC(=O)NC2=O)c1
Temperature: -75 °C
Reaction time: 18 h

Procedure:
To a suspension of ethyltriphenylphophonium bromide (0.56 g, 1.5 mmol) in THF (8 mL) cooled at −75° C. was added n-BuLi (1.6 M in hexane, 1.0 mL). To the resulting orange solution was added the product from step 2 (0.24 g, 0.50 mol) in THF (1.0 mL). The reaction mixture was gradually warmed to 25° C. and quenched with acetic acid (0.1 mL). The solvent was removed and the residue was taken up in diethyl ether and filtered through a short column of silica gel. The filtrated was concentrated and the residue was dissolved in THF-t-BuOH (1:1, v/v) (10 mL). The solution was stirred in the presence of Rh(PPh3)3Cl (40 mg) under hydrogen (45 psi) for 18 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a RP-18 column using 10-100% acetonitrile in water gradient solvent system modified with 0.1% trifluoroacetic acid to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[CH:14][C:15](=[O:17])[O:16][C:11]=2[CH:10]=1.C(N(CC)CC)C.C(C1[C:36]([OH:37])=[C:35]([C:38](C)(C)C)[CH:34]=C(C)C=1)(C)(C)C.C(Cl)(=O)C(C)=C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:38][C:35](=[CH2:34])[C:36]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[CH:14][C:15](=[O:17])[O:16][C:11]=2[CH:10]=1)=[O:37]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=c1ccc2ccc(OCCCCCCO)cc2o1
Agent: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCOc1ccc2ccc(=O)oc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.2 g (16 mmol) of 7-(6-hydroxy-hexyloxy)-2H-1 -benzopyran-2-one were dissolved in 40 ml of absolute tetrahydrofuran with the exclusion of moisture, treated with 1.82 g (18 mmol) of triethylamine, 0.004 g (0.3 mmol) of 4-dimethylaminopyridine and a spatula tip of 2,6-di-tert.-butyl-p-cresol and cooled to 0° C. 1.7 ml of methacryloyl chloride were added dropwise to this solution within 10 min. The mixture was stirred at 0° C. for one hour and at room temperature for a further hour. Subsequently, the white precipitate which separated was filtered off and rinsed with tetrahydrofuran. The filtrate was evaporated to dryness and the residue was chromatographed on silica gel with acetone/cyclohexane (1:4). In this manner there were obtained 4 g of 6-(2-oxo-2H-1-benzopyran-7-yloxy)-hexyl 2-methyl-acrylate as a colourless liquid. λmax. (in CH2Cl2)=322.7 nm (ε=15110 l/mol cm).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: c1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: c1ccc(COc2ccc(-c3cccnc3)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
To a solution of 4-benzyloxyphenylboronic acid (1.48 g, 6.5 mmol) in DME (10 mL) was added 3-iodo: pyridine (1.03 g, 5.0 mmol) in DME (8 mL), potassium carbonate (2.0 g, 15 mmol) in 1:1 mixture of EtOH:water (3 mL), palladium(II) acetate (56 mg 0.25 mmol), and triphenyl phosphine (202 mg, 1.0 mmol) in DME (2 mL). The resulting mixture was warmed up to 90° C. and stirred for 16 h at that temperature. After cooling to rt, reaction mixture was poured into ice-water 200 mL) and product was extracted with EtOAc, washed with brine, filtered through pad of Celite and concentrated to a yellow solid. The crude mixture was purified by silica gel flash chromatography (20% EtOAc/Hexane) to obtain the title product as yellow solid (1.2 g, 92%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:33])([CH3:32])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].Cl>CO.O1CCCC1.O>[CH:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH:11]3[C:10]([CH3:32])([CH3:33])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:27][CH:26]=1)([CH3:31])[CH3:30]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-c3ccc(OC(C)C)cc3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1ccc(-c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 63.7 %

Procedure:
A mixture of 2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.30 g, 0.68 mmol) in methanol (2 mL) and tetrahydrofuran (15 mL), lithium hydroxide hydrate (0.28 g, 6.8 mmol) in water (1.0 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(4′-isopropoxy-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.18 g, 65%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C27H29NO3 (M+H)+: 416.5, observed: 416.1.