Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=3)[CH:15]=2)[CH2:9][CH2:8]1.[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=2)=[N:41][CH:42]=1>>[ClH:35].[ClH:35].[ClH:35].[CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]4[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=4)[CH:15]=3)[CH2:11][CH2:12]2)[CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=3)=[N:41][CH:42]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(-c2ccc(CCl)cn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN3CCC(Nc4cccc(SC)c4)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2ccc(CN(c3cccc(SC)c3)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)cn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(3-Methylthioanilino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (143 mg) and 5-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a trihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)C2C=CC=CC=2)=[CH:14][C:3]=1[C:4]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH3:13])=[O:5].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.C(=O)(O)[O-].[Na+].[C:54]1(C)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][S:36][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:14][C:3]=1[C:4]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH3:13])=[O:5]
Reactant: Cc1ccccc1
Reactant: CC1CCCCC1OC(=O)c1cc(NC(=O)c2ccccc2)ccc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1CCCCC1OC(=O)c1cc(NCSc2ccccc2)ccc1Cl
Temperature: 25 °C

Procedure:
To a solution of 2-methylcyclohexyl 2-chloro-5-(benzoylamino)benzoate (1.8 g, 0.0048 mole) in toluene (100 ml) was added Lawesson's Reagent (2.5 g), sodium bicarbonate (1.0 g) to produce the reaction mixture. The reaction mixture was stirred and refluxed for 4 hours. The reaction mixture was then cooled to ambient temperature which resulted in the formation of a white solid precipitate. The white solid was filtered off. The filtrate was then passed through a short column of aluminum oxide (neutral) using ether/hexane as eluent to give a yellow solution. The yellow solution was concentrated and a yellow solid crystallized. The yellow solid was filtered to give 2-methylcyclohexyl 2-chloro-5[(phenylthiomethyl)amino]benzoate as a yellow solid (1.3 g, m.p. 143°-144° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=O)[C:12]([OH:23])=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([NH2:30])([CH3:29])([CH3:28])[CH3:27]>>[ClH:21].[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C:12]([OH:23])=[C:11]([CH2:24][NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(OCc2ccccc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: CC(C)(C)N
Product: CC(C)(C)NCc1cc(OCc2ccccc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: Cl

Procedure:
5-(Benzyloxy)-3-((tert-butylamino)methyl)-3′,4′-dichloro-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 5-(benzyloxy)-3′,4′-dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[N:21]S(C(C)(C)C)=O)[CH2:17][CH2:16]2)OCC1>>[NH2:21][C:18]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:19][CH2:20][C:15](=[O:11])[CH2:16][CH2:17]1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CC(C)(C)S(=O)N=C1CCC2(CC1)OCCO2
Product: COc1ccc(C2(N)CCC(=O)CC2)cc1

Procedure:
The title compound was prepared as a white solid from addition of 4-methoxy-phenyl magnesium bromide (Aldrich) to 2-methyl-propane-2-sulfinic acid (1,4-dioxa-spiro[4.5]dec-8-ylidene)-amide (as prepared in Example 84, Step A) followed by the hydrolysis using the procedure described in Step B of Example 84.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1.[CH2:23]1C[O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.C(Cl)(=O)C=C>CN(C=O)C>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[CH:3][C:2]([NH:1][C:25](=[O:26])[CH:24]=[CH2:23])=[CH:11][CH:10]=2)#[N:13]
Reactant: COc1cccc(Nc2c(C#N)cnc3ccc(N)cc23)c1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(OC)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Dissolved 500 mg (1.72 mmol) 6-amino-4-[(3-methoxyphenyl)amino]-3-quinolinecarbonitrile in 2 ml hot DMF, added 6 ml THF, and chilled to 0° C. Added 264 μl (1.90 mmol) triethylamine and 158 μl (1.90 mmol) acryloyl chloride. Removed ice bath at 15 minutes. Stripped solvent at 2 hours. Washed residue with dilute sodium bicarbonate, collected solids, washed with water, and air dried. Boiled solids in ethyl acetate, collected and dried in vacuo, giving 288 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=345.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][N:38]1[CH2:43][CH2:42]C(O)[CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CN1CCC(O)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCN(C)CC4)c(C)c3C)c2cc1OC
Yield: 46 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-methyl-4-piperidinol (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (33 mg, yield 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[S:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][C:16](=[CH2:27])[C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18].[CH2:28](O)C>>[CH:26]1([NH:19][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:9][CH2:10]2)[CH2:28][CH2:21][CH2:20][CH2:24][CH2:25]1.[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([S:7][CH2:15][C@@H:16]([CH3:27])[C:17]([N:19]2[CH2:26][CH2:25][CH2:24][C@H:20]2[C:21]([OH:23])=[O:22])=[O:18])=[O:8])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: CCO
Reactant: C=C(C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NS(=O)(=O)c1cc(C(O)=S)ccc1Cl
Product: C1CCC(NC2CCCCC2)CC1
Product: C[C@H](CSC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
5 g of 4-chloro-3-sulfamoyl-thiobenzoic acid is added slowly to a stirred solution of 3.6 g of 1-(2-methyl-2-propenoyl)-L-proline in 50 ml of ethanol at room temperature. The resulting mixture is stirred overnight and then concentrated under reduced pressure. To the residue are added ethyl acetate and water. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is treated in an analogous manner of Example 4 to give dicyclohexylamine salt of 1-[3-(4-chloro-3-sulfamoylbenzoylthio)-2(S)-methylpropionyl]-L-proline as white crystalline powder, melting at 143°-146° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].NC(N)=[S:15].[CH3:17][N:18]1[C:22](Cl)=[N:21][N:20]=[N:19]1.[OH-].[Na+]>C(O)C>[CH3:17][N:18]1[C:22]([S:15][CH2:2][CH2:3][CH2:4][C:5](=[O:6])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:21][N:20]=[N:19]1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: Cn1nnnc1Cl
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nnnc1SCCCC(=O)c1ccccc1
Yield: 11.6 %

Procedure:
4-Chlorobutyrophenone (1.8 g) and thiourea (0.8 g) is dissolved in ethanol (50 ml) and the solution is refluxed for 2 hours. To the mixture are added 1-methyl-5-chloro-1,2,3,4-tetrazole (1.2 g) and 10% aqueous sodium hydroxide (5 ml) and the mixture is further refluxed for 3 hours. Ethanol is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off. The residue is purified by column chromatography (Wakogel C-200, eluatn: chloroform) and the product is recrystallized from methanol-water to obtain 1-methyl-5-(3-benzoylpropyl)thio-1,2,3,4-tetrazole (0.3 g) as colorless needles, m.p. 57.5°-58° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[NH2:29][C:28]1[CH:30]=[CH:31][C:25]([C:2]2[N:7]=[C:6]([NH:8][C@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH:5]=[N:4][CH:3]=2)=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
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: Cc1ccccc1
Solvent: O
Product: C[C@H](Nc1cncc(-c2ccc(N)cc2)n1)c1ccccc1

Procedure:
A mixture of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (1.10 g, 4.71 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.10 g, 5.02 mmol), (PPh3)4Pd (580 mg, 0.5 mmol) and a Na2CO3 solution (2.6 ml, 2M solution) in toluene (20 ml) was heated under reflux for 40 h. Upon cooling, the mixture was diluted with water (30 mL) and the product extracted with ethyl acetate (3×40 ml). The organic layers were combined, washed with brine (30 ml), dried (Na2SO4), and the solvent removed in vacuo. The residue was purified by column chromatography, eluting with a hexane-ethyl acetate (2:3) to furnish the desired product from the polar fractions (0.86 g, 63%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:14]=[C:13]([CH3:15])[O:12][C:11]=2[CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[CH3:16][C:11]1[O:12][C:13]([CH3:15])=[CH:14][C:10]=1[CH2:9][NH:8][C:6]1[C:5]([F:17])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[N:7]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1cc(CNc2nc(Cl)ncc2F)c(C)o1
Product: Cc1cc(CNc2nc(Nc3cccc(O)c3)ncc2F)c(C)o1
Yield: 51 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of (2,5-dimethyl-3-furyl)methylamine (188 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol) gave 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-4-pyrimidineamine and 3-aminophenol (200 mg, 1.83 mmol) gave N4-[(2,5-dimethyl-3-furyl)methyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (50 mg, 51%). 1H NMR (CDCl3): δ 2.22 (s, 3H), 2.23 (s, 3H), 4.39 (d, J=5.1 Hz, 2H), 5.24 (br, 1H), 5.90 (s, 1H), 6.52 (d, J=6.6 Hz, 1H), 6.99 (d, J=8.1 Hz, 1H), 7.13 (t, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.71 (m, 2H), ·F NMR (282 MHz, CDCl3): δ −167.84; LCMS: ret. time: 19.83 min.; purity: 96.32%; MS (m/e): 329.05 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][N:7]=[C:8]([C:14](=[O:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].S(Cl)([Cl:20])(=O)=O>C(O)(=O)C>[Cl:20][CH2:15][C:14](=[O:16])[C:8](=[N:7][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOCCON=C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCOCCON=C(C(=O)CCl)C(=O)OCC
Yield: 88.7 %

Procedure:
Ethyl 2-(2-ethoxyethoxyimino)-3-oxobutyrate (syn isomer 56 g.), sulfuryl chloride (32.7 g.) and acetic acid (56 ml.) were treated in a similar manner to that of Example A-(2) to give ethyl 4-chloro-2-(2-ethoxyethoxyimino)-3-oxobutyrate (syn isomer, 57.1 g.).
Reaction SMILES: ClC1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[C:25]([C:38]([OH:40])=O)=[CH:24][CH:23]=3)[N:9]=2)=[CH:4]C=1.C1C=CC2N(O)N=[N:47]C=2C=1.[CH2:51]([Cl:54])[CH2:52]Cl.N>CN(C=O)C.O>[Cl:54][C:51]1[CH:52]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:16])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:35])([F:36])[F:37])[C:25]([C:38]([NH2:47])=[O:40])=[CH:24][CH:23]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: ClCCCl
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
208 mg (0.36 mmol) of the compound from Example 141 were initially charged in 5 ml of DMF, and 62 mg (0.46 mmol) of HOBt and 88 mg (0.46 mmol) of EDC were added. After 10 min of stirring at RT, 1.0 ml (16 mmol) of ammonia solution (33% strength in water) were added, and the mixture was stirred at RT for 16 h. Under reduced pressure, the reaction solution was then freed from excess ammonia, about 3 ml of water were added and the mixture was extracted three times with in each case 5 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 85 mg (39% of theory) of the target compound.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([C:3]1[N:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])[CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: CCOC(=O)Cl
Reactant: Nn1cccc1C(=O)c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1cccc1C(=O)c1ccccc1F
Yield: 91.9 %

Procedure:
1-Amino-2-(2-fluorobenzoyl)pyrrole (41 g, 0.20 mol) and sodium bicarbonate (39 g, 0.46 mol) were combined in 400 ml of dichloromethane. To this stirred slurry was added ethyl chloroformate (24 g, 0.22 mol) over 3 minutes and the reaction mixture was refluxed for 5 hours, whereupon it was quenched with 200 ml of H2O and the organic layer separated. The organic extract was washed with H2O and brine, dried (MgSO4), filtered, and evaporated to an oil which crystallized upon trituration with hexane. Filtration yielded 50.8 g (92%) of crystals, m.p. 78°-80°.
Reaction SMILES: C(OC(=O)C)(=[O:3])C.ClCC(OC(=O)CCl)=O.ClCC(NCCCCCCC(OCC)=O)=O.C([O:36][CH:37]([CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:38][CH2:39][CH2:40][N:41]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([O:54]CC)=[O:53])[C:42](=[O:45])[CH:43]=C)(=O)C.OC(CCCCC)CCCN(CCCCCCC(O)=O)C(=O)C=C>>[OH:36][CH:37]([CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:38][CH2:39][CH2:40][N:41]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([OH:54])=[O:53])[C:42](=[O:45])[CH2:43][OH:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(=O)N(CCCCCCC(=O)OCC)CCCC(CCCCC)OC(C)=O
Agent: C=CC(=O)N(CCCCCCC(=O)O)CCCC(O)CCCCC
Agent: CCOC(=O)CCCCCCNC(=O)CCl
Agent: O=C(CCl)OC(=O)CCl
Product: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(=O)CO

Procedure:
The synthesis of this compound is carried out as described in Example 2 except that, in Step A, the acetic anhydride is replaced by an equimolar amount of chloroacetic anhydride. The product of Step A is ethyl 7-(2-chloroacetamido)heptanoate. Subsequent steps yield: ethyl 7-[N-(4-acetoxynonyl)-2-chloroacetamido] heptanoate (B); and 7-[N-(4-hydroxynonyl-2-hydroxyacetamido]-heptanoic acid (C); (the basic hydrolytic conditions cause the replacement of the chlorine atom by hydroxy in this step).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([N:20]=[C:19]([NH2:21])[CH:18]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([Cl:28])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.[F:41][C:42]1[C:47](B(O)O)=[CH:46][CH:45]=[CH:44][N:43]=1>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.O>[Cl:28][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C@@:15]4([N:20]=[C:19]([NH2:21])[C@H:18]([CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)[O:17][CH2:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:47]1[C:42]([F:41])=[N:43][CH:44]=[CH:45][CH:46]=1)=[CH:7][CH:6]=3.[Cl:28][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C@:15]4([N:20]=[C:19]([NH2:21])[C@H:18]([CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)[O:17][CH2:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:47]1[C:42]([F:41])=[N:43][CH:44]=[CH:45][CH:46]=1)=[CH:7][CH:6]=3
Reactant: NC1=NC2(COC1C1CCCCC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Reactant: OB(O)c1cccnc1F
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: C1COCCO1
Product: NC1=N[C@@]2(CO[C@H]1C1CCCCC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Product: NC1=N[C@]2(CO[C@H]1C1CCCCC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 7-bromo-3-chloro-6′-cyclohexyl-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.075 g, 0.162 mmol), 2 M aqueous sodium carbonate (0.8 mL, 1.600 mmol), and dioxane (1.6 mL). The vessel was capped and the solution was degassed by bubbling nitrogen gas through the solution for 10 minutes. Next, Pd(PPh3)4 (7.49 mg, 6.48 μmol) and (2-fluoropyridin-3-yl)boronic acid (0.027 g, 0.194 mmol) were added and the vessel was sealed. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 minutes. The reaction was poured into water and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:20 MeOH in DCM, to provide the product as a racemic mixture of diastereomers. The diastereomers were seperated by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 20 min to provide racemic (3′R, 6′S)-3-chloro-6′-cyclohexyl-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine and racemic (3′S, 6′S)-3-chloro-6′-cyclohexyl-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine each as a white solid after isolating the free base by partitoning between DCM and 1 N NaOH. [M+H]+=479.1 for each racemic diastereomer pair.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1C=CC=CC=1>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]=[N:16][C:17]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C=Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution containing 1-Boc-piperidine-4-carboxaldehyde (3.0 g, ca. 14 mmol), 2-amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (3.7 g, 14 mmol), and pyridinium p-toluenesulfonate (0.3 g, 1.4 mmol) in benzene (250 mL) was heated at reflux for 24 h with azeotropic removal of water. The solution was allowed to cool to room temperature; then the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (300 mL) and water (150 mL). The organic phase was separated and washed again with water (150 mL) and then brine (150 mL); then dried with MgSO4, filtered and concentrated in vacuo to give 6.0 g (93%) of the title compound as an orange foam which was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([O-])=[O:5].C[NH2:13].C1COCC1>>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: O=C([O-])c1c(O)cccc1O
Reactant: CN
Solvent: C1CCOC1
Product: NC(=O)c1c(O)cccc1O
Temperature: 100 °C

Procedure:
The mixture of 2,6-dihydroxybenzoate (168 mg, 1.0 mmol) and 2M methylamine in THF (3 mL, 6.0 mmol) in a sealed tube was heated at 100° C. overnight. The reaction mixture was then concentrated under reduced pressure and purified by flash chromatography on silica gel with hexane/ethyl acetate (1:1) to provide the titled compound (67 mg) as white solid. MS (ESI(+)) m/e 168 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 12.57(bs, 2H), 8.82 (bs, 1H), 7.14 (t, J=8.1 Hz 1H), 6.35 (d, J=8.5 Hz, 2H), 2.85(d, J=4.7 Hz, 3H).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[C:5]([O:14][CH2:15][CH3:16])(=[O:13])/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C1C=CC=CC=1>[C:8]([O:10][CH2:11][CH3:12])(=[O:9])[C@@H:7]1[CH2:4][CH:3]=[CH:2][CH2:1][C@H:6]1[C:5]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Reactant: C=CC=C
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1CC=CC[C@H]1C(=O)OCC
Temperature: 50 °C

Procedure:
One hundred (100) parts by weight of a butadiene is dissolved into a solution of 153 parts of diethyl fumarate in 650 parts of benzene at 0° C. The reaction solution is then heated in a bomb at 50° C. for 24 hours. The solvent is removed by a distillation and the liquid crude product is purified by a fractional distillation under vacuum (b.p.: 102-105° C. at 2 mm);