Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:10][Mg]Cl>O1CCCC1>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([CH3:10])([OH:9])[CH2:5][CH2:4]1
Reactant: O=C1CCC(CO)CC1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)CCC(CO)CC1
Temperature: 25 °C

Procedure:
4-(Hydroxymethyl)cyclohexanone (800 mg) in tetrahydrofuran (15 mL) was treated with 3 M methylmagnesium chloride in tetrahydrofuran (6.24 mL) at 0° C. The reaction was warmed to room temperature over 2 hours and was quenched with methanol and water. The resulting mixture was concentrated and the residue was suspended in ethyl acetate. The precipitates were filtered off and the filtrate was concentrated. The residue was purified by chromatography, eluting with 0-100% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][NH2:25]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: NNC(=O)Nc1ccccc1F
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1F

Procedure:
ninhydrin, 4-(2-fluorophenyl)-semicarbazide hydrochloride
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH:10](O)[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].C([SiH](CC)CC)C>CC#N>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(O)c1ccc(O)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: CCCCc1oc2ccccc2c1Cc1ccc(O)cc1
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
At −10° C., to a stirred solution of 4-[(2-butyl-benzofuran-3-yl)-hydroxy-methyl]-phenol (2.78 g, 9.39 mmol) in CH3CN was added portionwise triethylsilane (two ×1.50 mL, 18.78 mmol total, @ 0.5 h interval). To the reaction was added BF3 Et2O (1.19 mL, 9.39 mmol) and the reaction was stirred for 10 min. The reaction was quenched with sat. aq. K2CO3 and extracted with CH2Cl2. The organic extracts were washed with brine (3×), dried (MgSO4) and concentrated. Purification on silica gel gave 2.35 g (89%) the title compound as a white solid, mp 67-70° C. (DMSO-d6) δ0.87 (t, 3 H), 1.31 (sextet, 2 H), 1.62 (quintet, 2 H), 2.78 (t, 2 H), 3.84 (s, 2 H), 6.64 (d, 2 H), 7.02 (d, 2 H), 7.09 (dt, 1 H), 7.16 (dt, 1 H), 7.31 (d, 1 H), 7.42 (d, 1 H), 9.16 (s, 1 H). IR (KBr) 3300, 2950, 1610, 1510 and 1450 cm−1. mass spectrum (EI) mz 280M +).
Reaction SMILES: [Cl:1][C:2]([F:4])=[CH2:3].[N+](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-]>ClCCl>[Cl:1][C:2]1([F:4])[CH2:3][CH:7]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=C(F)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: ClCCl
Product: CCOC(=O)C1CC1(F)Cl
Yield: 91 %

Procedure:
16.9 mg of tetrakis(triphenylacetato) dirhodium was added to 10 ml of dichloromethane and dissolved therein. Then 370 mg of powdery Molecular Sieves 4A was added thereto. The reaction container was soaked in a dry ice/acetone bath and 1.0 g of 1-chloro-1-fluoroethylene was dissolved in the mixture. While maintaining the temperature of this solution at -35° C. to -40° C., 5.3 ml of a solution of 2.5 mmol of ethyl diazoacetate in dichloromethane was dropped thereinto under an argon gas atmosphere. The addition was made in such a manner that a half of the solution was dropped within 15 minutes and another half was dropped within 30 minutes. After the completion of the addition, the reaction mixture was slowly returned to room temperature. When analyzed by gas chromatography, it was found out that the reaction conversion ratio was 100%, the yield was 91% and the ratio of cis:trans was 1.59:1.0. The analytical data of the title product are as follows.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([O:22][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCBr
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Product: CCCCCCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Yield: 22.3 %

Procedure:
The title compound (1.2 g, 22%) was prepared as an oil from ethyl 3-(4-benzyloxyphenyl)-2-hydroxypropanoate (4.2 g, 14.0 mmol) and 1-bromohexane (3.4 g, 21.0 mmol) by an analogous procedure to that described in preparation 5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:18]C(=O)OCC4C=CC=CC=4)[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCC1Cc2cccc(-c3cccc(F)c3)c2O1)OCc1ccccc1
Agent: [Pd]
Product: NCC1Cc2cccc(-c3cccc(F)c3)c2O1
Yield: 63.5 %

Procedure:
Treatment of (−)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.330 g, 0.874 mmol) with palladium on carbon (0.033 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.135 g (55%) of (−)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. [α]D25=−19.00 (c 10.0 in methanol); mp 186-188° C.; Anal. calcd. for C15H14FNOHCl: C, 64.4; H, 5.4; N, 5.01. Found: C, 63.52; H, 5.16; N, 4.91.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[C:25]4=[N:26][NH:27][C:28](=[O:33])[C:29]5[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=54)[NH:22][CH:21]3[C:34]3[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=3)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:42][NH:43]C.[BH4-].[Na+]>CO>[C:1]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[C:25]4=[N:26][NH:27][C:28](=[O:33])[C:29]5[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=54)[NH:22][CH:21]3[C:34]3[CH:41]=[CH:40][C:37]([CH2:38][NH:43][CH3:42])=[CH:36][CH:35]=3)=[CH:18][CH:19]=2)=[O:13])[CH2:10][CH2:11]1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CNC
Reactant: CC(C)C(=O)N1CCN(C(=O)c2ccc(C3c4n[nH]c(=O)c5cccc(c45)NC3c3ccc(C=O)cc3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N3CCN(C(=O)C(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 45.5 %

Procedure:
A mixture of 4-(9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (40 mg, 0.07 mmol) and 33% dimethylamine aq solution (17 mg, 0.14 mmol) in methanol (10 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium borohydride (4 mg, 0.11 mmol) was added. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by prep-HPLC to give the compound 9-(4-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(4-((methylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7 H)-one (18 mg, yield 49%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.10-1.12 (d, J=6.8 Hz, 6H), 2.67 (s, 3H), 2.81 (brs 1H), 3.33-3.70 (m, 8H), 4.12 (s, 2H), 4.43-4.75 (d, J=7.6 Hz, 1H), 4.88 (d, J=7.4 Hz, 1H), 7.22-7.27 (m, 3H), 7.31-7.37 (m, 4H), 7.42-7.44 (d, J=8.0 Hz, 2H), 7.56-7.58 (d, J=7.2 Hz, 1H), 7.64-7.68 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 579 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C[Sn](C)(C)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[BH4-].[Na+]>>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2cnccc2c1
Reactant: C[Sn](C)(C)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Product: c1ccc(-c2ccc3c(c2)CCNC3)nc1

Procedure:
In close analogy to the procedure described above, 6-Bromo-isoquinoline is reacted with 2-trimethylstannyl-pyridine and sodium borohydride to provide the title compound.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[S:14])[NH:9][CH2:10][C:11](N)=[O:12].[CH2:16](I)[CH3:17]>>[CH2:16]([S:14][C:8]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:15])[C:11](=[O:12])[CH2:10][N:9]=1)[CH3:17]
Reactant: Cc1ccccc1NC(=S)NCC(N)=O
Reactant: CCI
Product: CCSC1=NCC(=O)N1c1ccccc1C
Yield: 57.9 %

Procedure:
The title compound was prepared by the procedure described in Example 6 using 11.2 g of 2-[3-(2-tolyl)-thioureido]-acetamide and 15.6 g of ethyl iodide. Crystallization from ethyl acetate afforded the hydrochloride salt of the title compound as a white solid (6.8 g), m.p. 156°-158° C. (dec.). Anal. Calcd. for. C12H14N2O S. HCl: C, 53.23; H, 5.58; N, 10.34. Found: C, 52.96; H, 5.49; N, 10.25. Mass spectrum (EI, M.+) m/z 234. 1H-NMR (DMSO-d6 ; 400 MHz) 88.75 (broad s, 2H), 7.43 (m, 2H), 7.35 (m, 1H), 7.30 (m, 1H), 4.53 (q, 2H), 3.18-3.20 (m, 2H), and 1.29 ppm (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]Br)[CH:5]=[C:4]([Br:10])[CH:3]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Br:10])[CH:3]=1)[CH2:8][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16]
Reactant: BrCc1cc(Br)cc(Br)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Br)cc(Br)c1
Temperature: 120 °C
Yield: 84.4 %

Procedure:
A mixture of 1,3-dibromo-5-(bromomethyl)benzene (1.1 g, ˜3.3 mmol) and potassium phthalimide (0.62 g, 3.3 mmol) in DMF (10 ml) was heated at 120° C. for 2 hours. After cooled down, a white solid precipitated. The solid was filtered and washed with ethanol, then dried in vacuum. 2-(3,5-dibromobenzyl)isoindoline-1,3-dione (1.1 g, 83%) was obtained as white solid.
Reaction SMILES: Br[C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6](=[O:23])[NH:7][C:8]1[S:9][C:10]2[CH2:16][CH2:15][O:14][C:13]3[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:12]=3[C:11]=2[N:22]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:21][C:18]1[CH:19]=[CH:20][C:12]2[C:11]3[N:22]=[C:8]([N:7]4[C:2]([CH3:25])([CH3:24])[C:3](=[O:4])[NH:5][C:6]4=[O:23])[S:9][C:10]=3[CH2:16][CH2:15][O:14][C:13]=2[CH:17]=1
Reactant: CC(C)(Br)C(=O)NC(=O)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 1.002 g (2.048 mmol) of 2-bromo-2-methyl-N-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)carbamoylpropanamide and 1.660 g (5.11 mmol) of cesium carbonate in 100 ml of N,N-Dimethylformamide was stirred at 60° C. for 2 hours. The mixture was filtered, the filtrate concentrated in high vacuum, the residue partitioned between ethyl acetate and water. pH was adjusted to 5 by addition of 5% aq citric acid. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated in vacuum to give 1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione as an off-white powder which was used in the next steps without further purification. Yield 0.812 g (97%). MS(ESI+): 408.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:15][CH2:14][CH:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[C:4]([F:32])[CH:3]=1.[C:33]([C:35]1([O:50][CH3:51])[CH2:40][CH2:39][CH:38]([CH:41]2[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][CH3:49])[CH2:43][CH2:42]2)[CH2:37][CH2:36]1)#[CH:34].N1CCCC1>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>[CH2:27]([C:10]1([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([C:34]#[C:33][C:35]3([O:50][CH3:51])[CH2:40][CH2:39][CH:38]([CH:41]4[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][CH3:49])[CH2:43][CH2:42]4)[CH2:37][CH2:36]3)=[CH:3][C:4]=2[F:32])[CH2:11][CH2:12][CH:13]([CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)[CH2:14][CH2:15]1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCC1CCC(C2CCC(C#Cc3ccc(Br)cc3F)(CCCCC)CC2)CC1
Reactant: C#CC1(OC)CCC(C2CCC(CCC)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: CCCCCC1CCC(C2CCC(C#Cc3ccc(C#CC4(OC)CCC(C5CCC(CCC)CC5)CC4)cc3F)(CCCCC)CC2)CC1

Procedure:
Analogously to Example 4, 1.913 g of 4-(4-bromo-2-fluorophenylethynyl)-4,4′-dipentylbicyclohexyl are reacted with 0.997 g of 4-ethynyl-4-methoxy-4′-propylbicyclohexyl in the presence of 0.219 g of tetrakis(triphenylphosphine)palladium(0) and 5 ml of pyrrolidine, giving 4-[4-(4,4′-dipentylbicyclohexyl-4-ylethynyl)-3-fluorophenylethynyl]-4-methoxy-4′-propyl-bicyclohexyl (C 177 N (36) I, Δε −0.26, Δn −0.015).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:22][CH3:23])[CH:8]=2)[N:3]=1.[CH3:24][NH:25][CH3:26].CO>>[CH3:23][O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:25]([CH3:26])[CH3:24])[N:11]=[C:10]2[N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13]
Reactant: CNC
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc(OC)cc23)cc1
Solvent: CO
Product: COc1ccc(N(C)c2nc(N(C)C)nc3ccc(OC)cc23)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of (2-chloro-6-methoxy-quinazoline-4-yl)-(4-methoxy-phenyl)-methyl-amine (0.12 g, 0.36 mmol), 2.0M dimethylamine in methanol (1.44 mL, 2.91 mmol) in sealed tube was stirred at 70-80° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate, brine, dried over anhydrous MgSO4, filtered and concentrated to give 90 mg of the titled compound (75% yield). 1H NMR (DMSO): δ 7.28 (d, 1H), 7.20-7.18 (dd, 2H), 7.06-7.00 (d, 1H), 7.00-6.98 (dd, 2H), 6.2 (d, 1H), 3.7(s, 3H), 3.4 (s, 3H), 3.22 (s, 3H), 3.18 (s, 6H). LC\MS: 339, (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17]Br)=[CH:5][CH:4]=1.[I-:20].[K+]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][I:20])=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: COc1ccc2cccc(CCNC(=O)CBr)c2c1
Agent: [K+]
Product: COc1ccc2cccc(CCNC(=O)CI)c2c1

Procedure:
The product of the title is obtained by treating the N-[2-(7-methoxynaphth-1-yl)ethyl]-2-bromoacetamide obtained in Example 9 with potassium iodide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[C:29]2[C:24](=[CH:25][N:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](O)=[O:31]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:21]1[CH:22]=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[N:26][CH:25]=2)[N:20]=1)=[O:31]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2cnccc2n1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2cnccc2n1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with [1,6]naphthyridine-2-carboxylic acid. MS: 416.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH:11]1[CH:6]2[CH2:7][C:8]([CH3:19])([CH3:18])[CH2:9][CH2:10]1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH3:28].N#N.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH:12]([C:25]1[CH:24]=[CH:23][C:22]([O:27][CH3:28])=[CH:21][CH:26]=1)[CH:11]1[CH:6]2[CH2:7][C:8]([CH3:19])([CH3:18])[CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1)C1CC(C)(C)CCC1CC2=O
Reactant: COc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: N#N
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C2C(=O)c3ccc(OC)cc3C3CC(C)(C)CCC32)cc1
Yield: 89.6 %

Procedure:
Using a 2 neck v shaped flask, combine 6-Methoxy-3,3-dimethyl-2,3,4,4a,10,10a-hexahydro-1H-phenanthren-9-one (1.3 g, 4.9 mmol), and 4 bromoanisole (0.16 ml, 4.9 mmol) in dioxane (40 ml) exchange with N2 add sodium t-butoxide, Add Pd[P(C4H9)3]2 exchange with N2. Heat at 80° stirring over night. Keeping reaction under N2 quench with acetic acid (6 ml). Dilute with ethyl acetate (50 ml), wash with saturated aqueous sodium bicarbonate 3× (50 ml), with brine (40 ml), dry, and concentrate. Chromatograph residue on an biotage eluting with 0-10% ethyl acetate in hexanes to give the title compound (1.6 g, 90%): 1H NMR (CDCl3) δ 8.02-7.99 (d, 1H), 7.07-7.05 (d, 2H), 6.9-6.88 (d, 2H), 6.85-6.82 (dd, 1H), 6.69-6.68 (d, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.17-3.12 (m, 1H), 2.68-2.62 (m, 1H), 1.68-1.60 (m, 1H), 1.52-1.44 (m, 3H), 1.41-1.37 (m, 1H), 1.30-1.24 (m, 1H), 1.18-1.13 (m, 1H), 1.1 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:14]1[C:24]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:23][C:17]([C:18](OCC)=[O:19])=[CH:16][C:15]=1[S:29][CH3:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.Cl>C(OCC)C.O>[CH2:7]([C:14]1[C:24]([S:25](=[O:28])(=[O:27])[NH2:26])=[CH:23][C:17]([CH2:18][OH:19])=[CH:16][C:15]=1[S:29][CH3:30])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1cc(SC)c(Cc2ccccc2)c(S(N)(=O)=O)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CSc1cc(CO)cc(S(N)(=O)=O)c1Cc1ccccc1
Reaction time: 3 h

Procedure:
To a stirred mixture of lithium aluminium hydride (24 g) and dry diethyl ether (500 ml), a solution of ethyl 4-benzyl-3-methylthio-5-sulfamylbenzoate (85 g) in dry diethyl ether (3 liters) is dropwise added during 1-1.5 hours. After additional stirring for 3 hours the mixture is cooled, and ethyl acetate (60 ml) followed by water (100 ml) and 4 N hydrochloric acid (1 liter) are very cautiously added dropwise. The organic layer is separated, washed with 4 N hydrochloric acid and with water, and dried in the presence of magnesium sulphate. After filtration, the solvents are removed in vacuo to yield crude 4-benzyl-3-methylthio-5-sulfamylbenzylalcohol. After recrystallization from ethanol it is obtained with a melting point of 190°-192° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][OH:20].O>CN(C=O)C>[OH:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCCCO)c1
Yield: 96.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (366 mg, 3 mmol) in anhydrous DMF (7 ml), under nitrogen atmosphere, K2CO3 (829 mg, 6 mmol), and, after 10 minutes, 3-bromo-1-propanol (500 mg, 3.6 mmol) were added. The mixture was heated to reflux for 2 hours, then water was added and the product was extracted with CH2Cl2. The organic layers were washed with water and with NaCl saturated solution, dried on Na2SO4. After evaporation of the solvent the crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate 2/1); 520 mg (yield 95%) of title product were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl.Cl[CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22]>>[N+:13]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-:15])=[O:14]
Reactant: CCOC(=O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCOC(=O)c1cc(OCCN(CC)CC)ccc1[N+](=O)[O-]

Procedure:
Prepared analogously to intermediate product Z5a from ethyl 5-hydroxy-2-nitrobenzoate and (2-chloroethyl)-diethyl-amine-hydrochloride
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC(N(C)C)=C(C)C.[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9]([NH:11][CH3:12])=[CH:10][C:2]=2[F:1])=[CH:27][CH:26]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-4-methylamino-5-nitro-benzoic acid (0.500 g, 2.34 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (0.371 mL, 2.80 mmol) and DCM (50 mL) is stirred for 30 min, then 4-bromoaniline (0.402 mg, 2.34 mmol) and DIPEA (0.549 mL, 3.15 mmol) are added and it is stirred for 2 h. The mixture is concentrated, water is added and the precipitate is filtered, washed with water and dried to give the subtitle compound.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>CCO>[Br:1][C:2]1[C:3]([NH:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NC1CCCC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Clc1ncc(Br)c(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
In a large sealed tube is added 5-bromo-2,4-dichloropyrimidine (3 g, 13.2 mmol) in 100 mL of EtOH. Then cyclopentyl amine (1.95 mL, 19.75 mmol) and N,N′-diisopropylethylamine (3.36 mL, 19.8 mmol) are added to the solution at rt. The solution is then stirred rt overnight. Solvent is evaporated and the crude is purified using silica gel chromatography (15% ethyl acetate/85% hexane) to give (5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine as a white solid (3.25 g, 89%). MS (ESI) m/z 278.4 (M+H)+
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[NH:24][C@@H:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1.[O:36]=[C:37]1[NH:42][C:41]2[CH:43]=[C:44]([C:47](O)=[O:48])[CH:45]=[CH:46][C:40]=2[O:39][CH2:38]1.CCN(C(C)C)C(C)C>C(OC(C)=O)CCC.CCOC(C)=O>[Cl:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([C:47]([C:44]3[CH:45]=[CH:46][C:40]4[O:39][CH2:38][C:37](=[O:36])[NH:42][C:41]=4[CH:43]=3)=[O:48])[C@@H:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: CCOC(=O)C[C@H]1COc2cc(Cl)ccc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCOC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H]1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 140 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
T3P (50% solution in EtOAc, 146 g, 230 mmol) was added into a solution of ethyl [(3S)-7-chloro-3,4-dihydro-2H-1,4-benzoxazin-3-yl]acetate (Intermediate 20a, 29.4 g, 115 mmol) in n-BuOAc (100 mL), 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (22.7 g, 118 mmol) and DIPEA (44.5 g, 345 mmol) at 20° C. The resulting mixture was stirred at 140° C. for 24 h. The reaction mixture was cooled and diluted with of EtOAc (500 mL). The resulting mixture was washed with 200 mL of saturated sodium bicarbonate, 200 mL of 1 M citric acid and 200 mL of 1 M HCl. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was applied onto a silica gel column and eluted with EtOAc/PE (1/10 to 1/1). The pure fraction was concentrated in vacuo to afford the title compound (41 g, 83%) as a yellow solid.