Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([O-:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCCC1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
To a solution of methyl trans-4-[(1R or 1S)-1-hydroxy-1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)ethyl]cyclohexanecarboxylate (83 mg, 0.161 mmol) in methanol (1.5 ml) was added sodium hydroxide (1.0 M in water, 560 μl, 0.560 mmol). The mixture was then heated to a temperature of 80° C. for 60 minutes. The reaction was subsequently allowed to cool to room temperature and the pH was lowered to 5-6 by dropwise addition of hydrochloric acid (2N in water). The resulting suspension was filtered to afford trans-4-((1R or 1S)-1-hydroxy-1-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)-2,3′-bipyridin-6′-yl)ethyl)cyclohexanecarboxylic acid (52 mg, 0.104 mmol, 64.4% yield) as a colorless solid. MS ESI calcd. for C26H28F3N4O3 [M+H]+ 501. found 501. 1H NMR (500 MHz, DMSO-d6) δ 11.94 (br s, 1H), 10.21 (s, 1H), 9.12 (s, 1H), 8.58 (s, 1H), 8.49 (d, J=5.1 Hz, 1H), 8.33 (d, J=8.3 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.45 (s, 1H), 7.29 (s, 1H), 7.20 (d, J=5.1 Hz, 1H), 5.05 (s, 1H), 2.35 (s, 3H), 2.05-1.66 (m, 5H), 1.43 (s, 3H), 1.15-1.0 (m, 5H). rhSyk IC50=<0.5 nM
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[C:5](F)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+].OC(C(F)(F)F)=O.FC1C=C(CN)C=[N:31]C=1>C1COCC1.CCOC(C)=O>[N+:10]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:31])([O-:12])=[O:11]
Reactant: NCc1cncc(F)c1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,4,5-tri-fluoronitrobenzene (2.864 g, 0.016 mol), K2CO3 (2.236 g, 0.0161 mol) and (5-fluoropyridin-3yl)methanamine TFA salt (1.02 g, 50% LC-MS) were dissolved in THF (25 mL) and stirred at room temperature for 16 hours. The reaction mixture was then diluted with EtOAc (100 mL) and washed with H2O. The organic phase was dried and concentrated under vacuum to give the ortho-substitution product, 4,5-difluoro-N-(5-fluoropyridin-3-yl) methyl)-2-nitroaniline as a yellow solid. 1H NMR (400 MHz, DMSO-d6), δ: 8.72 (br, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 8.15 (dd, J=10 Hz, 8.8 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H), 6.83 (dd, J=12.8 Hz, 7.8 Hz, 1H), 4.71 (s, 2H). MS (M+1): 284
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:7]([F:32])=[C:8]([CH:20]=[CH:21][C:22]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)[O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[N:11]=1.Cl.O>O1CCCC1>[F:32][C:7]1[C:6]([CH:2]=[O:1])=[C:22]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)[CH:21]=[CH:20][C:8]=1[O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[N:11]=1
Reactant: COc1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C3OCCO3)c2F)ccc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2F)ccc1C#N
Temperature: 25 °C
Yield: 73.9 %

Procedure:
A solution of 6-(3-(1,3-dioxolan-2-yl)-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methoxynicotinonitrile (2.18 g, 4.93 mmol) in tetrahydrofuran (6 mL) was added 3 M HCl (3 mL). The solution was refluxed for four hours. The solution was cooled to room temperature and water was added. The solution was extracted with ethyl acetate. The organic layer was washed with water, then washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to give 6-(2-fluoro-3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methoxynicotinonitrile (1.45 g, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:18][C:19]1[C:24]2[B:25]([OH:28])[O:26][CH2:27][C:23]=2[CH:22]=[C:21]([OH:29])[CH:20]=1>>[Cl:1][C:2]1[C:3]([O:29][C:21]2[CH:20]=[C:19]([CH3:18])[C:24]3[B:25]([OH:28])[O:26][CH2:27][C:23]=3[CH:22]=2)=[N:4][C:5]([O:10][CH2:11][CH2:12][O:13][CH:14]([CH3:16])[CH3:15])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(C)OCCOc1nc(Cl)c(Cl)cc1C#N
Reactant: Cc1cc(O)cc2c1B(O)OC2
Product: Cc1cc(Oc2nc(OCCOC(C)C)c(C#N)cc2Cl)cc2c1B(O)OC2

Procedure:
This compound was prepared from 5,6-dichloro-2-(2-isopropoxyethoxy)nicotinonitrile and 7-methylbenzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.02 (d, J=4.8 Hz, 6H), 2.44 (s, 3H), 3.45-3.56 (m, 3H), 4.21-4.23 (m, 2H), 5.02 (s, 2H), 7.03 (s, 1H), 7.11 (s, 1H), 8.58 (s, 1H), 10.0 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14]3([C:17](OCC)=[O:18])[CH2:16][CH2:15]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14]3([CH2:17][OH:18])[CH2:15][CH2:16]3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(Nc2nc(-c3ccc(Br)cc3)cs2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC1(Nc2nc(-c3ccc(Br)cc3)cs2)CC1
Reaction time: 1 h
Yield: 14.1 %

Procedure:
A solution of ethyl 1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclopropane carboxylate (3.91 g, 10.6 mmol), prepared in the previous step, in 50 mL of anhydrous tetrahydrofuran was added under nitrogen dropwise to a suspension of lithium aluminum hydride (1.00 g, 26.3 mmol) in 20 mL of anhydrous tetrahydrofuran at ice-bath temperature. After the addition, the cooling bath was removed and the stirring continued for 1 h. Water (1 mL) was slowly added to the reaction, followed by the addition of 1 mL of 15% NaOH and then 3 mL of water. After the additions, the reaction was stirred for 1 h. The reaction was diluted with ethyl acetate and filtered through the Celite™ reagent. The filtrate was extracted two times with water, dried (anhydrous MgSO4), filtered and the solvent removed under reduced pressure to give a crude residue. The residue was taken up in methylene chloride, applied to a Biotage FLASH 40+™ cartridge and the methylene chloride allowed to evaporate. Purification of the residue on the samplet on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of 5% methylene chloride-hexane to 100% methylene chloride gave a material which was recrystallized from methylene chloride to give (1-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}cyclopropyl)methanol (0.4867 g, 14%) as a white solid mp 129-131° C.; MS (ES) m/z 324.9.
Reaction SMILES: [N+:1]([CH:4]([CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)[C:5]([O:7]CC)=[O:6])([O-])=O.O.[ClH:26]>C(O)C.[Pd]>[ClH:26].[NH2:1][CH:4]([CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C1c2ccccc2C=Cc2ccccc21)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC(C(=O)O)C1c2ccccc2CCc2ccccc21

Procedure:
Ethyl α-nitro-5H-dibenzo[a,d]cycloheptene-5-acetate (13 g, 40 mmol) (Example 4, Step A) is dissolved in 150 mL of ethanol, 40 mL of water, and 3.5 mL of concentrated hydrochloric acid and hydrogenated with 2.0 g of 20% palladium on carbon (52 psi, 30 hours). The filtered solution is stripped and a white solid washed with diethyl ether, dried at 50° C./2 mm Hg. The crude product is used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:19][C@H:20]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:19][C@H:20]([C:22]2[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[CH:24][CH:23]=2)[CH3:21])=[O:9])[C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)cnc1Oc1ccc(F)cc1
Reactant: C[C@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(4-fluorophenoxy)nicotinic acid and tert-butyl 4-[(1S)-1-aminoethyl]benzoate (step 3): 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.7 Hz), 8.14 (1H, br.s), 8.13 (1H, d, J=2.7 Hz), 7.95 (2H, d, J=8.3 Hz), 7.39 (2H, d, J=8.3 Hz), 7.17–7.11 (4H, m), 5.36 (1H, dq, J=7.2, 7.0 Hz), 1.59 (3H, d, J=7.0 Hz), 1.58 (9H, s); MS (ESI) m/z 415 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([CH3:7])[CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH3:30])[CH:21]=1.C(Cl)(Cl)Cl>CN(C)C=O.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>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([CH3:7])[CH:6]=2)=[C:22]([O:29][CH3:30])[CH:21]=1
Reactant: CCOC(=O)c1cc(Br)cn1C
Reactant: COc1cc(Cl)ccc1B(O)O
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: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2OC)cn1C
Yield: 254.5 %

Procedure:
Ethyl 4-bromo-1-methyl-1H-pyrrole-2-carboxylate (5.00 g, 21.6 mmol) prepared in the Step 10-1-2 was dissolved in N,N-dimethylformamide (20 ml)/water (5 ml), and sodium carbonate (6.87 g, 64.8 mmol), tetrakis(triphenylphosphine)palladium (120 mg, 0.1 mmol) and 4-chloro-2-methoxyphenylboronic acid (8.04 g, 4.32 mmol) was added to the solution. The mixture was heated under reflux for 5 hours. After the mixture was allowed to cool, water and chloroform was added to the mixture. The organic phase was collected by separation and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (3.23 g, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][N:8]2[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.Cl[C:17]1[C:18]2[CH2:26][N:25]([C:27]3[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=3)[CH2:24][CH2:23][C:19]=2[N:20]=[CH:21][N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[Cl:33][C:32]1[C:27]([N:25]2[CH2:24][CH2:23][C:19]3[N:20]=[CH:21][N:22]=[C:17]([NH:1][C:2]4[CH:10]=[C:9]5[C:5]([C:6]([CH3:15])([CH3:14])[CH2:7][N:8]5[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=4)[C:18]=3[CH2:26]2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)N1CC(C)(C)c2ccc(N)cc21
Reactant: Clc1cccnc1N1CCc2ncnc(Cl)c2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N1CC(C)(C)c2ccc(Nc3ncnc4c3CN(c3ncccc3Cl)CC4)cc21
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A mixture of 1-(6-amino-3,3-dimethylindolin-1-yl)ethanone (80 mg), 4-chloro-6-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (80 mg), and CH3CN (5 mL) was run in a Microwave Reactor at 180° C. for 1 h. After cooling, the mixture was treated with sat. aq. Na2CO3 and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column to give a light yellow solid (75 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[S:21][CH:22]=[C:23]([CH:25]([CH3:27])[CH3:26])[N:24]=3)[CH:15]=[CH:14][N:10]2[C:11](=[O:13])[CH:12]=1)(=O)=O.B1([C:36]2[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=2)OCCCO1.[Br-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O1CCOCC1>[CH:25]([C:23]1[N:24]=[C:20]([CH2:19][CH2:18][C:16]2[CH:15]=[CH:14][N:10]3[C:11](=[O:13])[CH:12]=[C:7]([C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[N:8]=[C:9]3[CH:17]=2)[S:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CC(C)c1csc(CCc2ccn3c(=O)cc(OS(=O)(=O)C(F)(F)F)nc3c2)n1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)c1csc(CCc2ccn3c(=O)cc(-c4cccnc4)nc3c2)n1
Temperature: 85 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
2-Trifluoromethanesulfonyloxy-8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one(499 mg), pyridine-3-boronic acid 1,3-propanediol cyclic ester (364 mg), palladium tetrakistriphenylphosphine (65 mg), potassium bromide (146 mg) and potassium carbonate (231 mg) were added with dioxane(8 ml) and stirred overnight at 85° C. under nitrogen atmosphere. The reaction mixture was cooled and then added with ethyl acetate. Insoluble solids were removed by filtration, and the solvent of the filtrate was evaporated. The residue was purified by silica gel column chromatography to obtain the title compound (400 mg).
Reaction SMILES: [F:1][CH:2]([F:22])[CH:3]([C:5]1[CH:6]=[C:7]([C:19](O)=[O:20])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)[OH:4].[CH3:23][C:24]1[N:28]=[C:27]([C@H:29]([NH2:31])[CH3:30])[O:26][N:25]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][CH:2]([F:22])[CH:3]([C:5]1[CH:6]=[C:7]([C:19]([NH:31][C@@H:29]([C:27]2[O:26][N:25]=[C:24]([CH3:23])[N:28]=2)[CH3:30])=[O:20])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:10]=1)[OH:4]
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)cc(C(O)C(F)F)c1
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3F)cc(C(O)C(F)F)c2)n1
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of 5-(2,2-difluoro-1-hydroxyethyl)-2′,4′-difluorobiphenyl-3-carboxylic acid (0.25 g, 0.80 mmol) in N,N-dimethylformamide (2.7 mL) were added (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (0.18 g, 0.88 mmol), EDC (0.27 g, 1.39 mmol), HOAT (51.1 mg, 0.40 mmol) and triethylamine (0.67 mL, 4.77 mmol). The mixture was stirred at 50 C. After 2 h, saturated sodium bicarbonate was added the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→85% dichloromethane/methanol). Product obtained was not pure therefore it was purified again by reverse phase chromatography (C-18, 95% water/acetonitrile→30% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (201 mg). HRMS 424.1283 (M+1). 1H NMR δ (ppm) (DMSO-d6): 9.28 (1H, d, J=7.3 Hz), 8.01 (2H, s), 7.76 (1H, s), 7.66 (1H, dd, J=15.6, 9.0 Hz), 7.43 (1H, m), 7.26 (1H, m), 6.11 (1H, dt, J=11.2, 0.7 Hz), 5.40 (1H, m), 4.93 (1H, m), 2.33 (3H, s), 1.61 (3H, d, J=7.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]=[C:5]3[N:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]4[CH2:13][O:12][C:6]3=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:16]1[N:15]2[C:5]3[C:6]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17]1)=[N:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:1][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]=1[N:4]=3
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc2nc3c(nc12)N1CCCCC1CO3
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Nc1cccc2nc3c(nc12)N1CCCCC1CO3)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 5.1 g. of 11-amino-1,2,3,4,4a,5-hexahydropyrido[1',2':4,5][1,4]oxazino[2,3-b]quinoxaline, 100 ml. of methylene chloride and 20 ml. of 1 N sodium hydroxide is stirred and 2.8 g. of benzoyl chloride is added. The reaction mixture is stirred overnight and the layers are separated. The methylene chloride layer is washed with water and concentrated and N-(1,2,3,4,4a,5-hexahydropyrido[1',2':4,5][1,4]oxazino[2,3-b] quinoxalin-11-yl)benzamide is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[N:9]2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:22])[CH:8]([C:4]1[CH:3]=[C:2]([NH:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: CN1c2ccc(C#N)cc2C(C)(C)CC1c1cccc(Br)c1
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1c2ccc(C#N)cc2C(C)(C)CC1c1cccc(NC(C)(C)C(=O)O)c1
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 2-(3-bromo-phenyl)-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (354.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyano-1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (113.4 mg, 30.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 378.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][NH:14][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)=[CH:28][CH:27]=1
Reactant: NCCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)cc1
Yield: 56.7 %

Procedure:
N-(3-(5-Chloro-1H-indol-3-yl)propyl)-4-(3-fluorobenzyl)benzamide was prepared according to method A with 3-(5-Chloro-1H-indol-3-yl)propan-1-amine (0.042 g; 0.201 mmol), 4-(3-fluorobenzyl)benzoic acid (0.049 g; 0.211 mmol), HATU (0.084 g: 0.221 mmol) and N,N-diisopropylethylamine (0.052 mL; 0.302 mmol) in DMF (3 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.048 g (57%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].Br[CH2:19][C:20]([NH2:22])=[O:21]>CC#N>[C:16]([C:8]1[C:9]([C:12]([F:15])([F:13])[F:14])=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:19][C:20]([NH2:22])=[O:21])[C:3]([CH2:1][CH3:2])=[CH:11]2)#[N:17]
Reactant: NC(=O)CBr
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Solvent: CC#N
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(N)=O
Temperature: 90 °C
Yield: 376.3 %

Procedure:
2-Ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.004 g, 0.018 mmol) Cs2CO3 (0.051 g, 0.16 mmol), and 2-bromoacetamide (0.022 g, 0.16 mmol) were combined in CH3CN (3 mL) and heated at 90° C. under N2 for 1 hr. Extraction with Et2O and washing with water and brine was followed by drying (Na2SO4), filtration, and concentration in vacuo. Purification (SiO2, EtOAc/hexanes) afforded the title compound (0.020 g): MS (ESI): m/z 296 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:13]3[CH:18]=[C:17]([CH3:19])[S:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O1CCCC1>[CH2:29]1[O:28][C:25]2[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:12]3[C:13]4[CH:18]=[C:17]([CH3:19])[S:16][C:14]=4[N:15]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=4)[N:11]=3)=[CH:23][C:24]=2[O:30]1
Reactant: COC(=O)c1ccc(-c2nc(NCc3ccc4c(c3)OCO4)c3cc(C)sc3n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(-c3ccc(C(=O)O)cc3)nc2s1
Yield: 70.5 %

Procedure:
A solution of 4-[4-(3,4-methylenedioxybenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester (1.1 g), 2N NaOH (30 ml), and tetrahydrofuran (30 ml) is heated 6hours to 100° C. After cooling and acidifing the solution with 20% HCl, the usual work up yields 4-[4-(3,4-methylenedioxybenzylamino)-6-methyl-thieno-[2,3-d-]pyrimidin-2-yl]-benzoic acid (0.75 g), Mp. >250° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:6]([F:11])[C:7]=1[N+:8]([O-])=O.C([O-])=O.[NH4+]>[Pd].C(O)C>[NH2:8][C:7]1[C:6]([F:11])=[CH:5][C:4]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][C:2]=1[F:1]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)c([N+](=O)[O-])c(F)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1cc(F)c(N)c(F)c1
Temperature: 25 °C
Yield: 41.2 %

Procedure:
Diethyl (3,5-difluoro-4-nitrophenyl)propanedioate (2.08 g, 6.56 mmol) was added to ethanol (100 ml). 10% Palladium on carbon (wet paste) (0.208 g) was then added under a flow of argon. This was treated with ammonium formate (2.07 g, 32.80 mmol) and the reaction heated to reflux for 30 minutes. Once cooled to room temperature the mixture was filtered through celite and washed with ethanol. This was evaporated to a brown oily solid. Triturating in DCM removed insoluble impurities. The liquors were evaporated and then purified by chromatography eluting with 5-40% ethyl acetate in hexane. The clean fractions were evaporated to give the title compound as a pale brown oil (0.774 g, 2.70 mmol). LC/MS: Rt=2.69, [MH]+ 288.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[OH2:14]>>[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[NH2:2][C@@H:1]1[CH2:7][C@H:4]([C:3]([OH:8])=[O:14])[CH:5]=[CH:6]1
Reactant: O
Reactant: O=C1NC2C=CC1C2
Agent: CS(=O)(=O)O
Product: N[C@H]1C=C[C@@H](C(=O)O)C1
Temperature: 35 °C
Yield: 0.6 %

Procedure:
A solution of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (97.45 g, 0.8929 mol, Enzymatix Ltd.) in tetrahydr n (500 mL) was filtered and warmed to 35° C. A solution of methanesulfonic acid (63.7 mL. 0.9817 mol) in water (24.1 mL, 1.34 mol) was added over the course of 1.5 hours such that the ensuing exotherm did not exceed 45° C. The resulting slurry was heated at 60° C. for three hours, then allowed to cool to room temperature over the course of 15 hours. The slurry was filtered and the cake washed twice with anhydrous tetrahydrofuran (200 mL). An analytical sample of the wet cake was removed and dried to give the title compound as a white solid (1.264 g); m.p. 167°-169.2° C.; 1H-NMR (DMSO-d6) δ: 12.6 (br s, 1H, CO2H), 8.04 (br s, 3H, NH3+), 6.10(dt, J=5.6,2.0,2.0 Hz, 1H, vinyl), 5.85 (dt, J=5.3,2.3,2.3 Hz, 1H, vinyl), 4.19 (br s, w1/2=20 Hz, 1H, allylic H), 3.61 (m, w1/2=22 Hz, 1H, allylic H), 2.53 (quintet, J=5.3 Hz (overlapping with DMSO peak), 1/2CH2), 2.39(s, 3H, CH3SO3H), 1.93 (dt, J=6.7,6.7,13.7 Hz, 1H, 1/2CH2); [α]20589 -83.8°, [α]20578 -87.4°, [α]20546 -101.2°, [α]20436 -186.7°, [α]20365 -316.2° (C=1.42, methanol); Cl-MS (CH4): 128(M+1); El-MS: 127(M).