Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>ClCCl>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:29])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: CN1CCC(C(=O)Cl)CC1
Reactant: NCc1nccnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC(C(=O)NCc2nccnc2Cl)CC1
Yield: 83 %

Procedure:
To a solution of 2-aminomethyl-3-chloropyrazine hydrochloride (content 70%; 7.85 mmol, 1.7 g) in N,N-diisopropylethylamine (39.3 mmol, 6.84 ml) and dichloromethane (30 ml) at 0° C. was added carefully 1-methylpiperidine-4-carbonyl chloride hydrochloride (9.42 mmol, 2.2 g). Then the cooling bath was removed. After two hours saturated aqueous sodium hydrogencarbonate solution (40 mL) was added and extracted five times with dichloromethane (30 mL). The organic extracts were combined, dried and concentrated and co-evaporated twice with toluene to give N-((3-chloropyrazin-2-yl)methyl)-1-methylpiperidine-4-carboxamide (1.75 g)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C:18]([OH:20])=O)[CH:15]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH:25][C:18](=[O:20])[CH2:17][CH2:16][N:14]1[CH:15]=[C:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH:12]=[N:13]1
Reactant: O=C(O)CCn1cc(-c2c[nH]c3cc(F)ccc23)cn1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)CCn1cc(-c2c[nH]c3cc(F)ccc23)cn1
Yield: 14.6 %

Procedure:
Following the general method as outlined in Example 39, starting from 3-(4-(6-fluoro-1H-indol-3-yl)-1H-pyrazol-1-yl)propanoic acid (Example 24; 110 mg; 0.40 mmol) and N,N-dimethylethylenediamine (0.08 mL; 0.8 mmol), 20 mg (15%) of the title product was obtained as a yellow solid purified by preparative HPLC.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1([C:13]2[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[C:23]1[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=1>COCCOC.O.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>[CH:7]1([C:13]2[CH:18]=[CH:17][C:16]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
A mixture of 2M aqueous sodium carbonate solution (0.396 mL), tetrakis(triphenylphosphine)palladium(0) (30.5 mg), 4-cyclohexylphenylboronic acid (140 mg) and 3-bromopyridin-2-amine (91 mg) in 1,2-dimethoxyethane (20 mL) and water (5 mL) was stirred overnight under a nitrogen atmosphere at 80° C. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (57.4 mg) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2](=[CH2:12])[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.[Br:13][C:14]([Br:24])=[CH:15][C@H:16]1[C@@H:18]([C:19](Cl)=[O:20])[C:17]1([CH3:23])[CH3:22].N1C=CC=CC=1>C1C=CC=CC=1>[Br:13][C:14]([Br:24])=[CH:15][C@H:16]1[C@@H:18]([C:19]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH2:3][C:2]([Cl:1])=[CH2:12])=[CH:5][CH:6]=2)=[O:20])[C:17]1([CH3:22])[CH3:23]
Reactant: C=C(Cl)Cc1ccc(CO)cc1
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Br)Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: C=C(Cl)Cc1ccc(COC(=O)[C@@H]2[C@H](C=C(Br)Br)C2(C)C)cc1
Reaction time: 16 h

Procedure:
The alcohol of Example 2 (0.078 g) in benzene (2 ml) is added to (IR)cis 3-(2,2-dibromovinyl)2,2-dimethylcyclopropane carbonyl chloride (0.135 g) in benzene (3 ml). Pyridine (0.06 ml) is then added and the mixture stirred at 20° for 16 hours. This is chromatographed on florisil and the fraction eluted by 7% ether in petrol evaporated to a residue of 0.19 g (96%) ester, nD20 1.5692.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([OH:10])=O)=[CH:5][O:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][CH:54]([NH:57][C:58]2[C:63]([N+:64]([O-])=O)=[CH:62][N:61]=[C:60]3[N:67]([S:70]([C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)(=[O:72])=[O:71])[CH:68]=[CH:69][C:59]=23)[CH2:53][CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[C:44]([O:48][C:49]([N:51]1[CH2:52][CH2:53][CH:54]([NH:57][C:58]2[C:63]([NH:64][C:8](=[O:10])[CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][CH:5]=3)=[CH:62][N:61]=[C:60]3[N:67]([S:70]([C:73]4[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=4)(=[O:71])=[O:72])[CH:68]=[CH:69][C:59]=23)[CH2:55][CH2:56]1)=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1nocc1CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nocc1CC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-(3-Methylisoxazol-4-yl)acetic acid (0.223 g, 1.58 mmol), HATU (0.600 g, 1.58 mmol), and diisopropylethylamine (0.300 ml, 1.72 mmol) were added sequentially to a solution of 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl amino)-piperidine-1-carboxylic acid tert-butyl ester (0.677 g, 1.44 mmol, prepared as described in Example 115) in a 6:1 mixture of CH2Cl2 and DMF (7 ml) at 25° C. The reaction mixture was stirred for 14 h at 25° C., then saturated NaHCO3 (7 ml) was added and the mixture was vigorously shaken by hand for 1 min. The phases were separated using a phase separation column (Biotage) and the organic layer was concentrated under reduced pressure to give crude 4-{1-benzenesulfonyl-5-[2-(3-methyl-isoxazol-4-yl)-acetylamino]-1H-pyrrolo[2,3-b]pyridin-4-ylamino}-piperidine-1-carboxylic acid tert-butyl ester as a brown oil. LCMS (Method G, ESI): RT=0.99 min, m+H=595.4. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.O>C1COCC1.CN(C=O)C>[C:10]([C:9]1[CH:14]=[CH:15][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=1)([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CC#N)cc1
Yield: 76 %

Procedure:
Part A: To a stirred solution of 7.5 g(153 mmol) sodium cyanide in 75 mL of THF was added 40 mL of DMF followed by 11.5 g(50.2 mmol) of of methyl 4-(bromomethyl)benzoate in 30 mL of DMF over 10 min. The solution was stirred 18 and treated with 100 mL water. The mixture was filtered, rinsed with water, and air-dried briefly to give 6.7 g (76%) of 4-(carbomethoxy)phenylacetonitrile as a white solid. 1H NMR (300 MHz, DMSO) δ 7.95(d, 2H, J=8.4 Hz); 7.47(d, 2H, J=8.5 Hz); 4.14(s, 2H); 3.82(s, 3H). Part B: The above nitrile ester was stirred with 120 mL of 6 N aq. HCl for 18 h at reflux and then cooled. The mixture was diluted with 160 mL water and then filtered. The white solid was rinsed with water, air-dried briefly, and placed in a vacuum oven at 75° C. for 1 h. This affords 6.89 g (100%) of 4-(carboxy)phenylacetic acid. 1H NMR (300 MHz, DMSO) δ 7.92(d, 2H, J=8.5 Hz); 7.49(d, 2H, J=8.4 Hz); 3.63(s, 2H)
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][C:35](O)=[O:36]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][CH:29]5[CH2:30][O:31][CH2:32][CH2:33][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)CC1COCCO1
Agent: Cl
Product: O=C(CC1COCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (130 mg, 95%), MS (ISP) m/z=459.5 [(M+H)+], mp 194.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (132 mg, 0.3 mmol) and rac-(1,4-dioxan-2-yl)-acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[CH3:13][N:14]([CH3:29])[CH2:15][CH2:16][O:17][C:18]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:24][C:21]2[CH:22]=[N:23][C:18]([O:17][CH2:16][CH2:15][N:14]([CH3:29])[CH3:13])=[C:19]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CN(C)CCOc1ncc(N)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCOc1ncc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 16 h
Yield: 63.6 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (100 mg, 0.429 mmol), 6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-amine (107 mg, 0.429 mmol) and HATU (245 mg, 0.644 mmol) in DCM (15 mL) was added DIEA (0.225 mL, 1.287 mmol). The resulting mixture was stirred at 20° C. for 16 h. The mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM/MeOH=10/1) to yield a brown oil of 2-(4-bromo-2-fluorophenyl)-N-(6-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)acetamide (130 mg, 0.273 mmol, 63.7% yield): 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H), 7.38-7.26 (m, 4H), 4.62 (t, J=5.4 Hz, 2H), 3.75 (s, 2H), 3.08 (t, J=5.2 Hz, 2H), 2.56 (s, 6H); ES-LCMS m/z 464.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13](=[O:15])[CH3:14])=[C:7]([OH:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[C:1]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([C:13](=[O:15])[CH3:14])=[C:7]([O:16][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(C)=O)c(O)cc1C(C)(C)C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C(C)(C)C)c(OC)cc3C(C)=O)c2cc1OC
Temperature: 140 °C
Reaction time: 24 h
Yield: 12.7 %

Procedure:
1-(4-Tert-butyl-2-hydroxy-5-methoxyphenyl)-ethanone (30 mg), 4-chloro-6,7-dimethoxyquinoline (87 mg), and 4-dimethylaminopyridine (48 mg) were suspended in o-dichlorobenzene (4 ml) to prepare a suspension which was then stirred at 140° C. for 24 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (7 mg, yield 13%).
Reaction SMILES: C([O-])(=O)C.[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][C:16]1[NH:20][CH:19]=[CH:18][NH+:17]=1.[S:21](=[O:25])(=[O:24])([OH:23])[OH:22]>>[S:21](=[O:23])(=[O:22])([OH:25])[OH:24].[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][C:16]1[NH:20][CH:19]=[CH:18][N:17]=1
Reactant: c1ccc2c(c1)OCC(Cc1[nH]cc[nH+]1)O2
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Product: c1ccc2c(c1)OCC(Cc1ncc[nH]1)O2

Procedure:
2-(1,4-benzodioxan-2-ylmethyl)imidazolium acetate (1.0 g) is dissolved in 50 ml 50% aqueous sulfuric acid, and the solution evaporated to dryness. The product is suspended in ethanol and filtered, air dried and recrystallized from methanol/acetone to yield 2-(1,4-benzodioxan-2-ylmethyl)imidazole bisulfate.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[OH-].[Na+].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.C(O)C>[CH:13](=[C:3]1[C:4](=[O:10])[CH:5]2[CH2:8][CH2:9][N:2]1[CH2:7][CH2:6]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1C(=Cc2ccccc2)N2CCC1CC2

Procedure:
To quinuclidine-3-one hydrochloride (Aldrich Chemical Co.) (49.9 g) in water (200 ml) was added sodium hydroxide (12.5 g, 0.310 mol). The aqueous layer was extracted with dichloromethane (2×200 ml) and the combined organic layers dired (Na2CO3), filtered, and evaporated in vacuo to give a colourless oil. The oil (38.64 g) was dissolved in ethanol (400 ml) and sodium hydroxide (3 g) added, followed by benzaldehyde (32.8 g). The reaction mixture was heated at reflux for 2 h. On cooling the product crystallized from the solution as a yellow solid. 1H NMR (CDCl3) δ 1.96-2.08 (4H, m), 2.62-2.66 (1H, m), 2.92-3.24 (4H, m), 7.02 (1H, s), 7.32-7.42 (3H, m), 8.00-8.04 (2H, m).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@H:19]1[CH2:23][CH2:22][N:21](/[N:24]=[CH:25]/[C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[C:27]=2[CH3:35])[C@@H:20]1[CH2:36][OH:37])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C(Cl)Cl>[Si:11]([O:18][C@H:19]1[CH2:23][CH2:22][N:21](/[N:24]=[CH:25]/[C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[C:27]=2[CH3:35])[C@@H:20]1[CH:36]=[O:37])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: Cc1c(/C=N/N2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]2CO)ccc(C#N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(/C=N/N2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]2C=O)ccc(C#N)c1Cl
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (1.92 mL, 0.022 moles) in dry DCM (25 mL) at −78° C. was added DMSO (3.12 mL, 0.044 moles) and stirred for 30 min. Then to the reaction mixture at the same temperature was added a solution of 4-((E)-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidin-1-ylimino)methyl)-2-chloro-3-methylbenzonitrile (IVa) (7.5 g, 0.0184 moles) in 100 mL DCM and continued stirring for 1 h. The reaction mixture was quenched with triethylamine (13 mL) at −30° C. and stirred for 1 h. Then it was diluted with DCM and washed with water, brine, dried over Na2SO4 and concentrated to get the title compound which was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH:8]=[C:9]=[CH2:10])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[ClH:11].[CH2:12](O)[CH3:13]>>[ClH:11].[NH2:1][CH:2]([CH:8]=[C:9]=[CH2:10])[CH2:3][CH2:4][C:5]([O:7][CH2:12][CH3:13])=[O:6]
Reactant: CCO
Reactant: C=C=CC(N)CCC(=O)O
Agent: Cl
Product: C=C=CC(N)CCC(=O)OCC
Reaction time: 8 h

Procedure:
To 4-amino-5,6-heptadienoic acid in anhydrous ethanol at 0° C. was added gaseous HCl. The reaction was left overnight at room temperature and then evacuated to a residue. This was taken in ethyl acetate, decolorized with charcoal, and then crystallization accomplished from ethyl acetate-ether to give the title compound. mp. 81°-83° C.; IR (KBr): 1952, 1710 cm-1. 'H NMR (δD2O): 1.3 (t, 3H, J=6.9 Hz, CH3), 1.9-2.8 (m, 4H, CH2CH2), 3.95 (m, 1H, CHN), 4.2 (q, 2H, J=6.9 Hz, OCH2), 5.0-5.4 (m, 3H H2C=C=CH). Anal. Calcd. for C9H16ClNO2 : C, 52.56, H, 7.84, N, 6.87; Found: C, 52.45, H, 7.95, N, 6.98.
Reaction SMILES: [I-].[K+].[CH2:3]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH3:4].[CH3:12][CH:13]([CH3:16])[CH2:14]O>O.ClCCl>[CH2:3]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][CH2:12][CH:13]([CH3:16])[CH3:14])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CC(C)CO
Reactant: CCc1ccc(N)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCc1ccc(NCC(C)C)cc1
Temperature: 150 °C
Reaction time: 0.05 h

Procedure:
To potassium iodide (5342 mg, 32.2 mmol), [Cp*IrCl2]2 (128 mg, 0.161 mmol) and 4-ethylaniline (2 mL, 16.09 mmol) at room temperature, was added 2-methylpropan-1-ol (5.94 mL, 64.4 mmol), followed by water (10 mL). The reaction vessel was sealed and heated by microwaves (Biotage Initiator) to 150° C. for 90 minutes. After cooling the reaction mixture was diluted with water (10 mL) and dichloromethane (20 mL) then stirred vigorously for 3 minutes. The organic phase was separated by hydrophobic frit. The aqueous phase was diluted with further dichloromethane (10 mL) and again stirred vigorously for 2 minutes, then the organics separated by hydrophobic frit. The combined organic fractions were evaporated in vacuo to give the crude product as a brown oil. The crude was purified by silica (Si) chromatography (0-50% dichloromethane-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give the required product, 2.612 g, as a pale yellow oil. LCMS [LCMS1] Rt 0.96 min, m/z (ES+) 178 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])[O:5][CH:6]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[CH:3]=[C:4]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])[O:5][CH:6]=2)[CH:21]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)co1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(-c2cccnc2)co1

Procedure:
The title compound was prepared by a method analogous to that described in Example 12 from (R)-3′-(4-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and pyridine-3-boronic acid. The title compound (105 mg) was obtained as a pale solid, m/z 326 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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.[Pd]>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([CH:25]=[O:26])[CH:32]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Temperature: 160 °C

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (200 mg, 0.483 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added (3-formylphenyl)boronic acid (317 mg, 1.93 mmol), and Cs2CO3 (315 mg, 0.97 mmol) in a microwave tube. The reaction mixture was degassed for 5 min before addition of tetrakis (triphenylphosphosphine) palladium (0) (48 mg, 0.043 mmol). The reaction was heated in a microwave for 30 min at 160° C. The organic layer was separated and concentrated. The residue was dissolved in MeOH until solid precipitated to yield 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([CH3:18])[CH:12]=1>>[CH3:18][C:13]1[CH:12]=[CH:11][C:16]([O:17][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[CH:15][CH:14]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: Cc1ccc(O)cc1
Product: Cc1ccc(Oc2ccc3[nH]ccc3c2)cc1

Procedure:
Prepared by Procedure J and Scheme U using 5-bromo-1H-indole and p-cresol: ESMS m/e: 224.0 (M+H)+.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][C:15](=O)[CH:14]=[CH:13]2)(=O)C(C)(C)C.[H-].[Na+].C([O:40][C@@H:41]([C:45]1[C:46](C2C=CC(Cl)=CC=2)=[C:47]2[C:52](=[CH:53][C:54]=1C)N1N=NN=C1C=C2)C(O)=O)(C)(C)C>CN(C=O)C>[CH2:41]([O:40][C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][C:19]([CH3:20])=[C:10]([C@H:9]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])[CH2:8][OH:7])[C:11]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:16]=1)[C:45]1[CH:46]=[CH:47][CH:52]=[CH:53][CH:54]=1
Reactant: Cc1cc2c(ccc3nnnn32)c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nc(OCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To the solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (8J) (16 mg, 0.03 mmol) in DMF (1 mL) was added sodium hydride (7 mg, 60% oil, 0.17 mmol). The mixture was stirred for 30 minutes, and benzyl bromide (64, 0.05 mmol) was added. The mixture was stirred another 90 minutes, and was quenched with water, and left for 12 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethanol (3.1 mg). LCMS-ESI+ (m/z): [M-FH]+ calcd for C29H30ClNO3: 476.2. Found: 476.1. (S)-1-Benzyl-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one was also isolated 6.1 mg LCMS-ESI+ (m/z): [M+H]+ calcd for LCMS-ESI+ (m/z): [M+H]+ calcd for C29H31ClNO3: 476.2. Found: 476.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([S:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:27]([F:30])([F:29])[F:28]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:15][C:4]2[C:5]([S:8][C:9]3[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:24])=[O:25])=[CH:19][C:18]=1[C:27]([F:30])([F:28])[F:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)cnc1Sc1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Sc1ccncc1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-chloro-2-(pyridin-4-ylsulfanyl)-pyridin-3-ylamine (100 mg, 0.42 mmol) in anhydrous pyridine (0.5 mL) was added drop wise a solution of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (117 mg, 0.42 mmol) in pyridine (0.25 mL). The resulting mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc and brine. The aqueous portion was separated and extracted with EtOAc. The combined extracts were dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was treated with 0.3 M aqueous NaOH and washed with CH2Cl2. The aqueous portion was acidified with conc HCl to pH 3 and extracted with EtOAc. The combined extracts were dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was separated by preparative HPLC (20→80% gradient of ACN-water) and pure product fractions were lyophilized to provide pure product as a solid. Mass spectrum m/z: 480.0 (M+H).