Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)=[CH:10][C:9]=1[F:19])(=[O:5])=[O:4])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[C:31]([CH2:32][NH2:33])=[CH:30][C:29]([C:34]([F:37])([F:36])[F:35])=[N:28]2)[CH:24]=[CH:25][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>O1CCOCC1>[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[C:31]([CH2:32][NH:33][C:15](=[O:17])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[C:9]([F:19])[CH:10]=3)[CH3:18])=[CH:30][C:29]([C:34]([F:35])([F:36])[F:37])=[N:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: CCS(=O)(=O)NCc1ccc(C(C)C(=O)O)cc1F
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CCS(=O)(=O)NCc1ccc(C(C)C(=O)NCc2cc(C(F)(F)F)nn2-c2cccc(Cl)c2)cc1F
Reaction time: 8 h

Procedure:
2-(4-(ethyl-sulfonamidomethyl)-3-fluorophenyl)propanoic acid (60 mg, 0.207 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (63 mg, 0.228 mmol) were dissolved and mixed in 1,4-dioxane followed by addition of HOBt (42 mg, 0.310 mmol) and EDC (60 mg, 0.313 mmol) and TEA (0.07 mL, 0.518 mmol). The reaction mixture was stirred for overnight and then quenched by water and extracted with EtOAc. Drying (MgSO4) and evaporation of the ethyl acetate followed and the residue was purified by CC (EtOAc/n-hexane) to give the example B17 in pure form (104 mg, 92%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21]>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([C:20]([O:19][CH3:18])=[O:21])[CH:27]=2)=[CH:3][CH:4]=1)([CH3:17])[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: COC(=O)c1cccc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 65 %

Procedure:
Prepared in a similar manner to Example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 3-(methoxycarbonyl)phenylboronic acid. Yield: 65%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m, 1H), 3 (t, 2H), 3.9 (s, 1H), 5.2 (broad, 1H), 7.4-7.56 (m, 3H), 7.6 (d, 2H), 7.8 (d, 1H), 8.1 (dd, 1H), 8.3 (d, 1H). MS (M+H, 354).
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(O)(=O)C.O>O>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][CH:3]=[O:2])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)#[N:18]
Reactant: COC=Cc1ccc(-c2ccc(C#N)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccc(-c2ccc(CC=O)cc2)cc1
Temperature: 100 °C
Yield: 104.2 %

Procedure:
A mixture of 4.9 g of 4'-(2-methoxyvinyl)-4-biphenylcarbonitrile and 80 ml of glacial acetic acid/water (vol. 2:1) was heated to reflux for 1.5 hours at 100° C. bath temperature. The reaction mixture was subsequently poured into 150 ml of water and extracted three times with 100 ml of methylene chloride each time. The organic phases were washed with 100 ml of water and with 100 ml of saturated sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated. There were obtained 4.8 g of (4'-cyano-4-biphenylyl)acetaldehyde as a yellowish, crystalline residue which was processed without additional purification; Rf-value (toluene/ethyl acetate vol. 90:10) 0.37.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10].[I-:11].[Na+].O>CC(C)=O>[I:11][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10]
Reactant: C=Cc1ccccc1CCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=Cc1ccccc1CI
Yield: 95 %

Procedure:
Dissolve 1-chloromethyl-2-vinyl-benzene (4.0 g, 26 mmol) in acetone (100 mL) and add sodium iodide (4.5 g, 30 mmol). Heat at gentle reflux for 30 minutes. Cool, add water (150 mL) and extract with pentane (200 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give 1-iodomethyl-2-vinyl-benzene (95%).
Reaction SMILES: C(O)(=O)C.[CH3:5][N:6]([CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH:15]=2)[CH2:10]1)[CH3:7]>[Zn].C1COCC1>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH:9]([CH2:8][N:6]([CH3:5])[CH3:7])[CH2:18][CH2:17]3)=[CH:22][CH:23]=1
Reactant: CN(C)CC1CCc2cc(OCc3ccc([N+](=O)[O-])cc3)ccc2C1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Reaction time: 6 h
Yield: 60.3 %

Procedure:
After acetic acid (6 ml) was added to THF solution (12 ml) of 2-[(N,N-dimethylamino)methyl]-6-(4-nitrobenzyloxy)tetralin (1.91 g) under ice-cooling, zinc powder (3.67 g) was further added, which was stirred for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated. 10% aqueous potassium carbonate solution and ethyl acetate were added to the residue, the precipitate was removed by celite filtration, and the filtrate was extracted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using aluminum column chromatography (development solvent; hexane˜hexane:ethyl acetate=4:1) to give the titled compound (1.05 g).
Reaction SMILES: [CH:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.F[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([CH3:23])(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C>CC#N>[F:19][C:17]1[CH:18]=[CH:13][C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:15]([NH:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:16]=1
Reactant: NC1CCCc2ccccc21
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(F)cc1NC1CCCc2ccccc21
Yield: 114.7 %

Procedure:
A solution of 1,2,3,4-tetrahydronaphthalen-1-amine (0.82 mL, 5.73 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (1.1 g, 5.73 mmol) and diisopropylethylamine (2.0 mL, 11.46 mmol) in CH3CN (15 mL) was stirred at 60° C. for 48 h. The solvent was concentrated in vacuo, the residue was taken up in dichloromethane and washed with water and brine, dried, and concentrated under reduced pressure to yield 2.1 g of a yellow oil. The residue was purified by PTLC (20% ethyl acetate in hexanes) to give 720 mg (39%) of the desired aniline: 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, 1H), 7.28-7.13 (m, 3H), 6.60 (dd, 1H), 6.51-6.45 (m, 2H), 4.62 (dd, 1H), 2.96 (s, 3H), 2.91-2.74 (m, 2H), 2.05-1.98 (m, 2H), 1.91-1.85 (m, 2H). MS (ESI) m/z: Calculated: 319.39; Observed: 661.0 (2M++23).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([OH:28])=O)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[O:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][NH2:40]>>[O:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][NH:40][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([C:21]2[CH:20]=[CH:19][C:18]3[N:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:32])=[O:6])[CH:9]=4)[CH:15]=[N:16][C:17]=3[CH:22]=2)[CH:24]=1
Reactant: NCC1CCCO1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cccc(C(=O)O)c4)ccc32)c1
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cccc(C(=O)NCC5CCCO5)c4)ccc32)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 starting from 3-{1-[3-({[(2,2,2-trifluoroethyl)amino]-carbonyl}amino)-phenyl]-1H-benzimidazol-5-yl}benzoic acid and 2-tetrahydrofuranmethanamine, (Aldrich, Cat. No. 131911). LCMS (M+H)+: m/z=538.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)[C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18]C)=[O:17])=[CH:8][CH:7]=1)[CH3:2].[OH-].[Li+]>C1COCC1.O>[CH2:1]([N:3]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:31]=1)[C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)Cc1ccc(SCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1ccc(C(F)(F)F)cc1)C(=O)Cc1ccc(SCc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
Methyl 2-({[4-(2-{ethyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethyl)phenyl]thio}methyl)benzoate (640 mg, 1.276 mmol) was dissolved in THF (20 ml). Lithium hydroxide (61 mg, 2.552 mmol) in water (10 ml) was added. The mixture was stirred at room temperature and the reaction was followed by LC-MS. After 24 hours, more lithium hydroxide (30 mg) and water (10 ml) were added. After in total 70 hour, LC-MS showed the reaction was complete. The mixture was evaporated to remove THF. The residue was washed with diethyl ether, then acidified with 10% HCl, pH=2, and extracted with EtOAc (×2). The extracts were combined and washed with brine, dried with magnesium sulphate and evaporated. Chromatography of the residue on a column (ISOLUTE SI, 5 g/25 ml), using DCM and then MeOH/DCM (0.5:99.5, then 1:99) as eluant, gave the title compound (510 mg), yield 82%.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Si:11]([O:18][C@@H:19]([CH3:25])[C:20](OCC)=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C(OCC)C>[Si:11]([O:18][C@@H:19]([CH3:25])[CH2:20][OH:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: C[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
Diisobutylaluminum hydride (1M in DCM) (41.4 mL, 41.42 mmol) was added dropwise to a stirred solution of (S)-ethyl 2-(tert-butyldimethylsilyloxy)propanoate (CAS no. 106513-42-2) (5 mL, 18.83 mmol) in diethyl ether (25 mL) at ˜78° C. under nitrogen. The resulting mixture was stirred at r.t. for 2 hours. The reaction mixture was carefully quenched with 20% Rochelle's solution (>100 ml) and at −78° C. and allowed to warm to r.t. After 2 hours of vigourous stirring the mixture was extracted with Et2O ×2, the organic layer was dried (MgSO4), filtered and evaporated to afford colourless liquid, (S)-2-(tert-butyldimethylsilyloxy)propan-1-ol (3.50 g, 98%). 1H NMR (400 MHz, CDCl3) δ 0.00 (6H, s), 0.81 (9H, s), 1.03 (3H, d), 1.71-1.90 (1H, m), 3.24-3.33 (1H, m), 3.35-3.44 (1H, m), 3.78-3.87 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][NH:7][C:8](=[O:42])[C:9]2[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([C:16]3[C:17]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])=[CH:18][C:19]4[O:23][C:22]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[C:21]([C:31](=[O:34])[NH:32][CH3:33])[C:20]=4[CH:35]=3)[N:10]=2)=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:53](Cl)([O:55]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:8](=[O:42])[C:9]3[N:10]=[C:11]([C:16]4[C:17]([N:36]([CH3:41])[S:37]([CH3:40])(=[O:38])=[O:39])=[CH:18][C:19]5[O:23][C:22]([C:24]6[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=6)=[C:21]([C:31]([NH:32][CH3:33])=[O:34])[C:20]=5[CH:35]=4)[CH:12]=[CH:13][C:14]=3[O:15][C:53]2=[O:55])=[CH:43][CH:44]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(O)c(C(=O)NCc4ccc(F)cc4)n3)cc12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4oc(=O)n(Cc5ccc(F)cc5)c(=O)c4n3)cc12
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of N-(4-fluorobenzyl)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-3-hydroxypicolinamide (30 mg, 0.05 mmol) and Et3N (11 mg, 0.10 mmol) in CH2Cl2 (5 mL) was stirred at RT under N2 atmosphere, and then triphosgene (18 mg, 0.06 mmol) was added portionwise. The mixture was stirred at RT for 4 h. The solvent was removed by rotary evaporator. After purified by prep-TLC (DCM:MeOH=60:1), 5-(3-(4-fluorobenzyl)-2,4-dioxo-3,4-dihydro-2H-pyrido[2,3-e][1,3]oxazin-6-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide was obtained. (15 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 7.97˜8.05 (m, 2H), 7.92 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 7.52˜7.63 (m, 3H), 7.19 (t, J=8.4 Hz, 2H), 7.01 (t, J=8.4 Hz, 2H), 6.14 (d, J=4.4 Hz, 1H), 5.20 (s, 2H), 3.24 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.95 (s, 3H). MS (M+H)+: 647.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:35])[C@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1[CH:48]1[N:52]([C:53]([O:55][CH2:56][CH:57]=[CH2:58])=[O:54])[NH:51][C:50](=[O:59])[CH2:49]1)=[O:41])[CH:37]=[CH2:38]>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:18]2[C@H:19]([CH3:35])[C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:44][C@H:43]1[CH:48]1[N:52]([C:53]([O:55][CH2:56][CH:57]=[CH2:58])=[O:54])[NH:51][C:50](=[O:59])[CH2:49]1)=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1NC(=O)CC1[C@@H]1C[C@H](S)CN1C(=O)OCC=C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C3CC(=O)NN3C(=O)OCC=C)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 43.1 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (330 mg, 0.66 mmol) and (2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)-4-mercaptopyrrolidine (234 mg, 0.66 mmol) to obtain allyl (1R,5S,6S)-2-[(2S,4S)-N-allyloxycarbonyl-2-(1-allyloxycarbonyl-3-pyrazolidinon-5-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (172 mg, yield: 43.1%).
Reaction SMILES: Br[CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C=O)C>[N:14]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:13])=[N+:15]=[N-:16]
Reactant: CCCCCCCCCCC(O)Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 24 h
Yield: 107.2 %

Procedure:
To a 250 mL round-bottom dry flask was added anhydrous DMF (60 mL), 11 bromo-1-undecanol (10 g, 39.8 mmol) and NaN3 (2.85 g, 43.8 mmol). The solution was stirred with a magnetic bar for 24 hours at ambient temperature and quenched with DI water (60 mL). The solution was extracted with CH2Cl2 (3×40 mL), re-extracted with DI water (2×50 mL), dried with sodium sulfate overnight, and filtered. After the removal of the solvent by a rotoevaporator, a clear, colorless liquid (9.1 g, 93.4%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([O-:3])=[O:2].C([O-])(C)(C)C.[K+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O>[CH2:39]([O:38][C:36]([CH2:35][N:17]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:37])[CH3:40]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)Nc2c([N+](=O)[O-])cc([N+](=O)[O-])c3ccccc23)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(c1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
60 g (155 mmol) of N-(2,4-dinitro-1-naphthyl)-4-methylphenylsulfonamide (J. Soc. Chem. 1935, 1855) were dissolved in 500 ml of anhydrous dimethylformamide under protective gas and 19.1 g (170 mmol) of potassium tert-butanolate were added a little at a time. The mixture was stirred at room temperature for about 30 minutes, and then 25.9 g (155 mmol) of ethyl bromoacetate dissolved in 50 ml of anhydrous dimethylformamide were added dropwise. The mixture was then heated at 100° C. for 90 minutes and, after cooling, poured into ice-water, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was heated with a mixture of 50 ml of toluene and 100 ml of ethanol and the resulting crystals were filtered off with suction to yield 55.7 g (76%) of the product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([Cl:19])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl.C(OCC)(=O)C>C1COCC1>[Cl:19][C:8]1[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(Cc2ccc(F)cc2)c(Cl)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cc2ccc(F)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-4-(4-fluorobenzyl)-pyridine-2-carboxylic acid methyl ester (190 mg, 0.68 mmol) in THF (10 mL) was added sodium hydroxide solution (1.36 mL, 1 N). The resulting solution was stirred at room temperature for 2 hours, and afterwards acidified with hydrochloric acid (15 mL, 1N) and poured into ethyl acetate (50 mL). The phases were separated and the water phase was extracted with additional ethyl acetate; the organic portions were combined, dried over Na2SO4, filtered and concentrated. The crude material (186 mg, quant.) a white solid, was sufficiently pure to be used in the next step without further purification. MS (ESI, m/z): 264.0 (M−H−).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]12[CH2:9][C:6]([NH2:10])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.FC(F)C12CCC(N)(CC1)CC2.[C:24]([N:26]=[C:27](OCC)[C:28]([CH3:37])([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29])#[N:25]>>[C:24]([N:26]=[C:27]([NH:10][C:6]12[CH2:9][C:3]([CH:2]([F:11])[F:1])([CH2:4][CH2:5]1)[CH2:8][CH2:7]2)[C:28]([CH3:37])([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29])#[N:25]
Reactant: CCOC(=NC#N)C(C)(C)Oc1ccccc1
Reactant: NC12CCC(C(F)F)(CC1)C2
Agent: NC12CCC(C(F)F)(CC1)CC2
Product: CC(C)(Oc1ccccc1)C(=NC#N)NC12CCC(C(F)F)(CC1)C2

Procedure:
The titled compound was prepared using the procedure described in Example 85 substituting 4-(difluoromethyl)bicyclo[2.2.1]heptan-1-amine (BA-5) for 4-(difluoromethyl)bicyclo[2.2.2]octan-1-amine (BA-4) and ethyl N-cyano-2-methyl-2-phenoxypropanimidoate (CI-1) for Example 8B. 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (s, 1H), 7.9 (t, J=7.9 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 6.94 (d, J=7.6 Hz, 2H), 5.82 (t, J=56.4 Hz, 1H), 2.0 (m, 8H), 1.72 (s, 6H), 1.6-2.0 (m, 2H); LCMS (ESI+) m/z 348.2 (M+H)+.
Reaction SMILES: Cl.[C:2]1(=[O:13])[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>CN(C=O)C>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[N:10]1[CH2:11][CH2:12][C:7]2([C:2](=[O:13])[NH:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][CH2:9]1
Reactant: O=C1NCCCC12CCNCC2
Reactant: Clc1nc2ccccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCCC12CCN(c1nc3ccccc3o1)CC2
Temperature: 60 °C
Yield: 71.5 %

Procedure:
To the stirred solution of 2,9-diazaspiro[5.5]undecan-1-one hydrochloride [1187173-73-4] (100 mg, 0.49 mmol) in DMF (3 mL) was added K2CO3 (203 mg, 1.47 mmol) and 2-chloro benzoxazole [615-18-9] (82.8 mg, 0.54 mmol). The mixture was heated at 60° C. for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the crude mixture water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid which was washed with diethyl ether and n-pentane to yield the title compound as solid (100 mg, 72%). [LCMS RtF=0.36 min, [M+H]+=286.1]
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:12])[CH:9]=[CH:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C(C(=O)CC=C)=CC=CN=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>C(O)C>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:32]2[C:2]3[C:7](=[CH:6][CH:5]=[CH:4][N:3]=3)[C:8](=[O:12])[CH2:9][CH:10]2[CH3:11])=[CH:29][CH:28]=1
Reactant: CC=CC(=O)c1cccnc1Cl
Reactant: COc1ccc(CN)cc1
Agent: C=CCC(=O)c1cccnc1Cl
Solvent: CCO
Product: COc1ccc(CN2c3ncccc3C(=O)CC2C)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
[Step 3] 2.2 g of the mixture of 1-(2-chloropyridin-3-yl)but-2-en-1-one and 1-(2-chloropyridin-3-yl)but-3-en-1-one and 4-methoxybenzylamine were dissolved in 30 mL of ethanol and stirred overnight at 70° C. Following completion of the reaction, the solution was concentrated under reduced pressure and water was added to the resulting residue followed by extracting three times with chloroform. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:3) to obtain 2.7 g of 1-(4-methoxybenzyl)-4-oxo-2-methyl-2,3-dihydro-1H-[1,8]-naphthyridine in the form of a yellow oil (80%).
Reaction SMILES: [N:1]12[CH2:14][CH2:13][N:7]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2.[CH2:15]1[O:17][CH:16]1[CH2:18][OH:19]>>[OH:17][CH:16]([CH2:18][OH:19])[CH2:15][N:10]1[CH2:9][CH2:8][N:7]2[CH2:13][CH2:14][N:1]([CH2:2][CH2:3][N:4]([CH2:15][CH:16]([OH:17])[CH2:18][OH:19])[CH2:5][CH2:6]2)[CH2:12][CH2:11]1
Reactant: OCC1CO1
Reactant: C1CN2CCNCCN(CCN1)CC2
Product: OCC(O)CN1CCN2CCN(CC1)CCN(CC(O)CO)CC2

Procedure:
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.4) and glycidol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:19]=1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([Cl:49])[C:35]=1[OH:50]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[CH:19]=2)=[CH:3][C:2]([C:38]2[CH:39]=[C:34]([Cl:33])[C:35]([OH:50])=[C:36]([Cl:49])[CH:37]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN1CCN(CCc2cccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)c2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CN1CCN(CCc2cccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)c2)CC1
Yield: 74.2 %

Procedure:
Following general procedure F, {6-bromo-4-[3-(2-(4-methylpiperazin-1-yl)ethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (56 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (48 mg, 0.165 mmol) to afford the desired product (47 mg, 74%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.25 (s, 1H), 7.89 (s, 2H), 7.69 (s, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.13-6.94 (m, 4H), 2.97-2.84 (m, 1H), 2.82-2.72 (m, 2H), 2.66-2.51 (m, 10H), 2.43 (s, 3H), 1.32-1.06 (m, 4H). ESI MS m/z 575 [C32H32C12N4O2+H]+; HPLC 95.1% (AUC), tR=10.37 min.