Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH2:25]Cl)[CH:24]=1)[CH2:12][CH2:11]2>CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([CH2:25][O:4][CH:2]([CH3:3])[CH3:1])[CH:24]=1)[CH2:12][CH2:11]2
Reactant: CC(C)O
Reactant: O=C1c2ccc(Cl)cc2CCN1c1cncc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To solution of propan-2-ol (3.6 mg, 0.06 mmol) in dry DMF (1 mL) was added NaH (1.5 mg, 0.06 mmol) at 0° C. The reaction mixture was stirred at room temperature for 5 min before 6-chloro-2-(5-chloromethyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (15 mg, 0.05 mmol, example 140 [A]) was added. The resulting reaction mixture was then stirred at room temperature for 1 hour before it was poured into ice-water and extracted with EtOAc (2×5 mL). The organic layer was dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by prep-HPLC to give title compound (8 mg, 48%) as a white solid. MS: 331.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
4-Nitrophenyl sulfonyl chloride (1.1 g, 5.4 mmol) was added in one portion to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.9 mmol) and diisopropylethylamine in THF (10 ml). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour, after which time the solvent was removed under vacuum to give the title compound (1.92 g, 100% yield) as an orange solid which was used without further purification. Tr=2.00 min m/z (ES+) (M+Na+) 408.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[F:19][C:20]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=1N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[F:19][C:20]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=1[NH:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:6]3[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]3=2)[N:14]=[CH:15][N:16]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: COc1ccc(N)c(F)c1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)c(F)c1
Yield: 85 %

Procedure:
Prepared from VII and 2-fluoro-4-methoxyaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 85%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2844, 2226, 1731, 1649, 1613, 1583, 1507, 1493, 1460, 1445, 1379, 1356, 1305, 1263, 1212, 1168, 1153, 1129, 1090, 1027, 980, 947, 841, 830, 818; 19F NMR (282 MHz, DMSO-d6) δ −120.02; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.15 (s, 1H), 7.77 (d, 1H, J=9.0 Hz), 7.30 (s, 1H), 6.92 (m, 1H), 6.80 (d, 2H, J=9.0 Hz); HRMS calcd for C17H11N5OSF (M+H+): 352.0668, found 352.0658.
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=1)=[CH:8][C:7]([C:26]([O:28]C)=[O:27])=[CH:6][CH:5]=2.CO.[OH-].[Na+]>O>[OH:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=1)=[CH:8][C:7]([C:26]([OH:28])=[O:27])=[CH:6][CH:5]=2
Reactant: COCCOc1ccc2c(-c3c(O)[nH]c4ccc(C(=O)OC)cc34)ncnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCOc1ccc2c(-c3c(O)[nH]c4ccc(C(=O)O)cc34)ncnc2c1
Temperature: 40 °C
Yield: 85.1 %

Procedure:
To a mixture of methyl 2-hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylate (5.15 g, 13.1 mmol), methanol (100 mL) and water (50 mL) was added aqueous sodium hydroxide (92 mL, 1 M) and the reaction mixture was stirred at 40° C. over night. Methanol was removed in vacuo and the basic aqueous layer was acidified with 1 M hydrochloric acid and stirred for 30 min. The precipitate formed was filtered off, washed with hydrochloric acid (50 mL, 1 M) and water (2×50 mL) and dried in vacuo at 50° C. over night. The crude product was stirred in methanol at room temperature over night. The solid was filtered off to give 4.23 g (85% yield) of the title compound as an orange solid: MS (AP+) m/z 380.3 (M++1).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].[NH2:19][C:20]([NH2:22])=[S:21]>CN(C=O)C>[NH2:22][C:20]1[S:21][CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=[O:17])[N:19]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)CCCN1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Product: Nc1nc(CCCN2C(=O)c3ccccc3C2=O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
1-bromo-5-phthalimido-2-pentanone (0.500 g, 1.61 mmol) was dissolved in DMF (3.5 mL) at 0° C. and thiourea (0.135 g, 1.77 mmol) was added drop-wise as a solution in DMF (0.50 mL). The solution was allowed to warm to room temperature and stirring was continued for 2 h at which time the DMF was removed under reduced pressure and the resulting slurry was made alkaline with 10% K2CO3 (100 mL). The aqueous solution was then extracted with EtOAc (3×40 mL) and the organic layer was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to obtain 51 (448 mg, 97%) as a fine white powder in its freebase form: 1H NMR (300 MHz, DMSO-d6) δ 7.85 (m, 4H), 6.78 (s, 2H), 6.13 (s, 1H), 3.56 (t, 2H, J=6.9 Hz), 2.42 (t, 2H, J=7.5 Hz), 1.88 (quint., 2H, J=7.5 Hz); 13C NMR (75 MHz, DMSO-d6) δ 168.01, 167.87, 151.20, 134.25, 131.61, 122.89, 100.17, 37.27, 28.70, 27.09; HRMS (ESI) calcd for C14H14N3O2S (MH+) 288.0801. found 288.0799.
Reaction SMILES: C1(C)C=CC=CC=1.C[Al](C)C.[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH2:30][CH2:31][C:32]2[N:42]=[CH:41][CH:40]=[CH:39][C:33]=2[C:34](OCC)=[O:35])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O.ClCCl>[O:35]=[C:34]1[C:33]2[CH:39]=[CH:40][CH:41]=[N:42][C:32]=2[CH2:31][CH2:30][CH2:29][N:28]1[CH:25]1[CH2:24][CH2:23][N:22]([C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:21])[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cccnc1CCCNC1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(N2CCCc3ncccc3C2=O)CC1
Yield: 56.1 %

Procedure:
A 2 M toluene solution (14.6 mL) of trimethylaluminum was added at 0° C. to a mixture of ethyl 2-(3-((1-((benzyloxy)carbonyl)piperidin-4-yl)amino)propyl)nicotinate (2.4 g) and dichloromethane (60 mL), and the resultant mixture was stirred at room temperature for 36 hours. Water was added to the reaction mixture, and then, the mixture was neutralized by the addition of hydrochloric acid. The organic layer was separated, and then, the aqueous layer was subjected to extraction with dichloromethane. Combined organic layers were washed with water and saturated saline and dried over sodium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol/dichloromethane) to obtain the title compound (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:21][C:22]([F:27])([F:26])[C:23](O)=[O:24].ClC1C=C(Cl)C=CC=1C1NC(=O)C2N(N=C(CN3CCOCC3)C=2)C=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:5]([C:23](=[O:24])[C:22]([F:27])([F:26])[F:21])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Reactant: O=C(O)C(F)(F)F
Agent: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cn2nc(CN3CCOCC3)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C(=O)C(F)(F)F
Temperature: -50 °C
Reaction time: 2 h

Procedure:
8 g (35 mmol) of tert-butyl (6-chloropyridin-2-yl)carbamate (Example 24A) were initially charged in 100 ml of THF and cooled to −50° C. 55 ml (87 mmol) of butyllithium (1.6N) were added dropwise. After the dropwise addition had ended, the reaction was slowly warmed to −10° C. and stirred at 0° C. for 2 h. The mixture was then cooled again to −40° C., and 12.8 g (70 mmol) of 4-(trifluoroacetyl)morpholine (Example 21A), dissolved in 4 ml of THF, were added. The reaction solution was stirred at −40° C. for 1 h, and, at −40° C., poured into 1 l of ethyl acetate and 350 ml of ammonium chloride solution and extracted. The organic phase was separated off, dried over magnesium sulfate and concentrated on a rotary evaporator. The reaction mixture was chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 9 g (79% of theory) of the product as an oil.
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>[OH-].[Na+].CCOC(C)=O>[OH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: NCCc1ccc(O)cc1
Reactant: C1CC2OC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Oc1ccc(CCNC2CCCC2O)cc1
Reaction time: 6 h

Procedure:
Stir a mixture of cyclopentene oxide (482.0 mg, 5.73 mmol) and tyramine (943.2 mg, 6.88 mmol) in 1.0 N NaOH (20 mL) at room temperature for 64 hours, at 45-55° C. for 6 hours, and at 100° C. for 18 hours. Quench the reaction with saturated aqueous NH4Cl (40 mL) and take it up in EtOAc (50 mL). Separate the layers after shaking. Wash the organic layer with H2O and brine (50 mL each). Back-extract the aqueous layers with CH2Cl2, EtOAc and CH2Cl2 (50 mL each). Adjust the pH of the combined aqueous layers to alkaline and concentrate. Suspend the residue in 10:40:50 2.0 M NH3 in MeOH/CH2Cl2/EtOAc and decant off the supernatant. Dissolve the residual solid in H2O and extract it with 10:40:50 2.0 M NH3 in MeOH/CH2Cl2/EtOAc (100 mL) and 10:90 2.0 M NH3 in MeOH/CH2Cl2. Combine all the organic layers and concentrate. Dissolve the residue in a small amount of MeOH and purify by flash chromatography, eluting with 10:40:50 2.0 M NH3 in MeOH/CH2CL2/EtOAc to afford the title compound as a 1:3 cis/trans isomeric mixture (566 mg, 45%): MS ES+ 222.0 (M+H)+, HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=4.72 min, 76% and 6.52 min, 24%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14](OCC)=[O:15])=[C:10]1[C:19]([O:21]CC)=O.O.[NH2:25][NH2:26]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:19](=[O:21])[NH:25][NH:26][C:14](=[O:15])[C:11]=2[CH:12]=[CH:13]1
Reactant: CCOC(=O)c1ccn(-c2ccc(C)cc2C)c1C(=O)OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(-n2ccc3c(=O)[nH][nH]c(=O)c32)c(C)c1
Yield: 88.7 %

Procedure:
To a solution of diethyl 1-(2,4-dimethylphenyl)-1H-pyrrole-2,3-dicarboxylate (0.5 g, 1.59 mmol) in ethanol (5 ml) was added hydrazine monohydrate (0.38 ml, 7.93 mmol) and the mixture was heated under reflux for 14 hours. During the reaction, additional hydrazine monohydrate (0.2 ml×3) was added to the mixture. The solvent was removed in vacuo and the residue was treated with 2N hydrochloric acid at 80° C. for 20 min. After cooling, crystals were collected by filtration, washed with water and dried to give 0.36 g (89%) of the title compound.
Reaction SMILES: [F:1][CH2:2][C:3]([O:5]CC)=O.[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[CH2:11][Mg]Cl>C(OCC)C.[Cl-].[NH4+]>[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[CH2:11][C:3](=[O:5])[CH2:2][F:1]
Reactant: CCOC(=O)CF
Reactant: Cl[Mg]Cc1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: O=C(CF)Cc1ccc(Cl)cc1Cl
Temperature: -60 °C
Reaction time: 5 h
Yield: 49 %

Procedure:
To a stirred solution of ethyl fluoroacetate (0.33 ml; 3.3 mmol) in dry diethyl ether (3.3 ml) under argon at −76° C. was added dropwise a 0.25 M solution of 2,4-dichlorobenzylmagnesium chloride in diethyl ether (20 ml; 5 mmol). The suspension was stirred at −60° C. during 5 h. The mixture was poured in ammonium chloride sat. solution and extracted three times with diethylether. Organics were combined, dried over sodium sulfate and evaporated to a resin which was subject to flash chromatography (eluant: c-hexane/ethyl acetate 99:1 to 70:30) to afford 0.36 g (49% of theory) of 1-(2,4-dichloro-phenyl)-3-fluoro-propan-2-one as a pale yellow solid (melting point: 48-52° C.).
Reaction SMILES: [CH2:1](SC1C(NC(=O)C=1)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:15](#N)[CH3:16]>>[C:3]1([C:15]([C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=2)=[CH2:16])[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=1
Reactant: CC#N
Reactant: CCCCCCSC1=CC(=O)NC1=O
Product: C=C(c1ccccc1)c1ccccc1

Procedure:
Hexylsulfanylmaleimide (25 mg, 0.116 mmol) was dissolved in acetonitrile (21 mL) and 1,1-diphenylethyene (203 μL, 1.16 mmol) to provide a 0.005M solution. The resulting solution was degassed for 30 minutes and irradiated in pyrex glassware for 5 minutes with stirring. Solvent was removed in vacuo and purification by flash chromatography (gradient elution in petroleum ether to 30% ethyl acetate in petroleum ether) afforded the desired compound as a colourless oil (30 mg, 0.075 mmol) in 64% yield. δH (600 MHz, CDCl3) 8.15 (s, 1H, NH), 7.42 (m, 2H, 2×H-8), 7.36-7.21 (m, 8H, 8×Ar—H), 3.54 (dd, 1H, J=10.3 and 12.9, HH-6), 3.34 (dd, 1H, J=5.7 and 10.3, H-7), 3.18 (dd, 1H, J=5.8 and 12.9, HH-6), 2.43 (dt, 1H, J=7.3 and 11.0, HH-17), 2.34 (dt, 1H, J=7.4 and 11.0, HH-17), 1.40-1.34 (m, 2H, H2-16), 1.26-1.20 (m, 4H, H2-14 and H2-15), 1.18-1.13 (m, 2H, H2-13), 0.84 (t, 3H, J=7.5, H3-12); δC (150 MHz, CDCl3) 177.16 (C═O), 175.87 (C═O), 142.09 (2×Ar), 141.80 (2×Ar), 128.17 (2×Ar—H), 128.13 (2×Ar—H), 128.10 (2×Ar—H), 128.06 (2×Ar—H), 127.44 (Ar—H), 127.32 (Ar—H), 63.03 (C5), 57.20 (C4), 44.38 (C7), 35.17 (C6), 31.35 (CH2), 30.07 (C17), 28.77 (CH2), 28.71 (CH2) 22.53 (CH2), 14.11 (C12); IR (oil, cm−1) 2927 (m) 1772 (w), 1709 (s); MS (ES−) m/z (relative intensity): 392 ([M], 10), 212 (100); Exact Mass Calcd for [C24H26NO2S] requires m/z 392.1684 Found 392.1674 (ES−).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:21][P:22]([O:28]CCCC)[O:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:19][CH3:20]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][P:22](=[O:28])([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCCCOP(OCCCC)OCCCC
Product: CCCCOP(=O)(Cc1ccc(OCc2ccccc2)cc1)OCCCC
Temperature: 50 °C

Procedure:
A mixture of 4-benzyloxybenzyl chloride (4.99 g) and tri-n-butylphosphite is heated at 50° C. for about 4 hours while removing butyl chloride. The mixture is cooled to room temperature and the crude product purified by HPLC on silica, eluting with 25% ethyl acetate in hexane, to give dibutyl 4-benzyloxybenzylphosphonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=1[N+:17]([O-])=O.C1CCCCC1.C(OCC)(=O)C>[Pd].C(O)C.C1COCC1>[C:13]([O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH2:17])[CH:4]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(Cl)c(N)c1
Reaction time: 12 h

Procedure:
At room temperature, 500 mg of palladium on carbon (10%) were added to a solution of 6.74 g (23.76 mmol) of tert-butyl (2E)-3-(4-chloro-3-nitrophenyl)prop-2-enoate in 200 ml of ethanol and 20 ml of THF, and the mixture was hydrogenated under atmospheric pressure for 12 h. After the reaction had gone to completion (monitored by TLC; mobile phase cyclohexane/ethyl acetate 1:1), the reaction solution was filtered through kieselguhr and the filtrate was concentrated under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1→2:1). This gave 1.40 g (5.47 mmol, 23% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.Cl>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC=C(C(=O)O)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC=CC(C(=O)O)C1
Yield: 96.9 %

Procedure:
A solution of 1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid (6.5 g, 28.6 mmol) in dry tetrahydrofuran (150 ml) was added dropwise to a mixture of 2.5 M butyllithium in hexane (25 ml, 62.5 mmol) and diisopropylamine (6.37 g, 63.1 mmol) in dry tetrahydrofuran (150 ml) at <-65° C. Stirring was continued for 20 min. -10°C. The mixture was poured into 1 M aqueous HCl (100 ml) while cooling with ice. The resulting mixture was extracted several times with ethyl acetate (a total of 500 ml). The organic layer was dried over magnesium sulphate and evaporated to dryness in vacuo to give 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid (Yield: 6.3 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.C(O)(=O)C(O)=O.[CH2:30]1[C:33]2([CH2:36][NH:35][CH2:34]2)[CH2:32][O:31]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:35]2[CH2:36][C:33]3([CH2:30][O:31][CH2:32]3)[CH2:34]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1NCC12COC2
Agent: O=C(O)C(=O)O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CC3(COC3)C2)cn1
Yield: 76 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 2-oxa-6-aza-spiro[3.3]heptane oxalate instead of methylamine, to the title compound (96 mg, 76%) which was obtained as an off white solid. MS: m/e=392.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])/[CH2:7][CH2:6]2>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2
Reactant: COC(=O)/C=C1\CCc2cc(OC)ccc21
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CCc2cc(OC)ccc21
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a mixture of 10% Pd—C (200 mg) in methanol (10 mL) under an atmosphere of nitrogen, methyl (2E)-(5-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetate (2.00 g, 9.16 mmol, from Step A) was added as a solid. The mixture was evacuated and filled with 1 atmosphere of H2. After 1 hr, the mixture was filtered through a pad of Celite® and the filtrate concentrated in vacuo. The residue was azeotroped with toluene to afford 2.00 g of the title compound: 1H NMR (CDCl3) δ 1.78-1.84 (m, 1H), 2.40-2.50 (m, 2H), 2.79 (dd, 1H, J=5.7, 15.3 Hz), 2.87-2.98 (m, 2H), 3.57-3.60 (m, 1H), 3.77 (s, 3H), 3.83 (s, 3H), 6.77 (dd, 1H, J=2.3, 8.2 Hz), 6.83 (d, 1H, J=1.9 Hz), 7.12 (d, 1H, J=8.2 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:10][C:11]2[C:12](=[C:14]([C:18]([OH:20])=O)[CH:15]=[CH:16][CH:17]=2)[N:13]=1.Cl.Cl.[NH2:24][C@H:25]1[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:27]12[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28]1)[C@H:25]([NH:24][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[N:2]([CH3:1])[CH3:21])=[N:13][C:12]=13)=[O:20])[CH2:26]2
Reactant: CN(C)c1ccccc1-c1nc2c(C(=O)O)cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)c1ccccc1-c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.7 %

Procedure:
A mixture of 2-(2-(dimethylamino)phenyl)benzo[d]oxazole-4-carboxylic acid (100 mg, 0.35 mmol), (S)-(−)-3-aminoquinuclidine dihydrochloride (70 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol) and 1-hydroxybenzotriazole (95 mg, 0.70 mmol) in DMF (1 mL) was stirred for 5 min at room temperature, then triethylamine (0.19 mL, 1.4 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with dichloromethane (20 mL), then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (3×15 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 89:10:1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(2-dimethylaminophenyl)benzoxazole-4-carboxamide (46 mg, 34%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.60 (d, J=7.0 Hz, 1H), 8.19 (dd, J=7.5, 1.0 Hz, 1H), 7.99 (dd, J=8.0, 2.0 Hz, 1H), 7.71 (dd, J=8.0, 1.0 Hz, 1H), 7.49-7.42 (m, 2H), 7.13 (d, J=8.5 Hz, 1H), 7.03 (t, J=8.5 Hz, 1H), 4.28-4.26 (m, 1H), 3.49 (ddd, J=11.5, 9.5, 2.0 Hz, 1H), 3.10-2.85 (m, 4H), 2.85 (s, 6H), 2.77 (dd, J=14.0, 4.5 Hz, 1H), 2.15-2.11 (m, 1H), 2.04-1.98 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.51 (m, 1H); MS (ESI+) m/z 391 (M+H); HPLC>99% (AUC), tR=12.81 min.
Reaction SMILES: C(OC(C1C=NC2C(C=1[Cl:16])=NC(F)=CC=2)=O)C.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1O)=[CH:30][N:29]=[C:28]([Cl:34])[CH:27]=2)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][C:26]2[C:31]([C:32]=1[Cl:16])=[CH:30][N:29]=[C:28]([Cl:34])[CH:27]=2)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cnc2cc(Cl)ncc2c1O
Reactant: CCOC(=O)c1cnc2ccc(F)nc2c1Cl
Product: CCOC(=O)c1cnc2cc(Cl)ncc2c1Cl

Procedure:
The title compound was prepared following the procedure described for 4a using 7-chloro-4-hydroxy-[1,6]naphthyridine-3-carboxylic acid ethyl ester (11). 1H-NMR (CDCl3) δ (ppm): 1.47 (3H, t, J=7.14 Hz), 4.53 (2H, q, J=7.14 Hz), 8.02 (1H, s), 9.37 (1H, s), 9.62 (1H, s). m/z 272.2 (MH+).