Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16])[CH2:31]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Reactant: COc1cccc2c1CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)c(NCCO)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 46.4 %

Procedure:
205 mg of 1-cyclopropyl-5-(2-hydroxyethylamino)-6,7,8- trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 150 mg of 4-methoxyisoindoline, 182 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 131 mg of the target compound.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[CH2:20][CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH2:30][C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[O:27][N:26]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>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>[F:38][C:32]1[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=1[CH2:30][C:28]1[O:27][N:26]=[C:25]([C:23]([NH:22][CH2:21][CH2:20][C:14]2[C:13]3[C:17](=[CH:18][CH:19]=[C:11]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:12]=3)[NH:16][CH:15]=2)=[O:24])[CH:29]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(NCCc1c[nH]c2ccc(Br)cc12)c1cc(Cc2cc(F)ccc2F)on1
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: O=C(NCCc1c[nH]c2ccc(-c3ccccc3)cc12)c1cc(Cc2cc(F)ccc2F)on1
Yield: 6 %

Procedure:
A mixture of benzene boronic acid (0.023 g; 0.191 mmol), N-(2-(5-bromo-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide (0.080 g; 0.174 mmol), tetrakis(triphenylphosphine)palladium(0) (0.020; 0.017 mmol) and sodium carbonate (0.037 g; 0.347 mmol) in DME (3 mL) and water (1 mL) was irradiated in the microwave oven at 130° C. for 20 minutes, the resulting solution was partitioned between water and EA, the organic layer was concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.0048 g (6%) of 5-(2,5-difluorobenzyl)-N-(2-(5-phenyl-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide as a white solid.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:14][C:15]([C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=1[OH:24])=[O:16].O>N1C=CC=CC=1>[C:1]12([C:11]([O:23][C:21]3[CH:22]=[C:17]4[C:18](=[CH:19][CH:20]=3)[O:24][C:11]([C:1]35[CH2:10][CH:5]6[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]6)[CH2:8]3)[CH2:2]5)=[CH:14][C:15]4=[O:16])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: c1ccncc1
Product: O=C(Oc1ccc2oc(C34CC5CC(CC(C5)C3)C4)cc(=O)c2c1)C12CC3CC(CC(C3)C1)C2
Reaction time: 18 h

Procedure:
4 g 1-adamantoyl chloride are added to a solution of 1.5 g 2,5-dihydroxyacetophenone in dry pyridine. The mixture is stirred for 18 hours at 40°, poured into water and extracted with ethyl acetate. The combined organic layers are washed 3 times with 1 N aqueous hydrochloric acid and subsequently with aqueous sodium carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The crude product is dissolved in dry dimethylformamide and added dropwise at 5° to a suspension of 330 mg of sodium hydride (80% in mineral oil) in dry dimethylformamide. The cooling bath is removed, and the mixture is stirred for 4 hours at room temperature. Then 1.5 ml of acetic acid and 250 ml of water are added, followed by extraction with ethyl acetate. The combined extracts are dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 6/1) to remove starting materials and major by-products. Cyclisation of the resultant 1-[5-(1-adamantoyloxy)-2-hydroxyphenyl]-3-(1-adamantyl)-1,3-propandione is achieved by treatment with 20 ml of 32% aqueous hydrochloric acid in methanol/dioxane. 6-(1-adamantoyloxy)-2-(1-adamantyl)-4H-chromen-4-one is obtained:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:31])=[C:5]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[OH:23])[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].Cl>>[Cl:1][C:2]1[S:3][C:4]([Cl:31])=[C:5]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[OH:23])[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Cl)sc(Cl)c2C(O)c2cccc(Cl)c2)cc1
Agent: Cl
Product: C[C@H](NC(=O)c1c(Cl)sc(Cl)c1C(O)c1cccc(Cl)c1)c1ccc(C(=O)O)cc1

Procedure:
Methyl 4-{(1S)-1-[({2,5-dichloro-4-[(3-chlorophenyl)(hydroxy)methyl]-3-thienyl}carbonyl)amino]ethyl}benzoate from Example 9, Step 1 (49.0 mg, 0.0982 mmol) was reacted under conditions similar to Example 1, Step 11. The reaction mixture was neutralized with 25% aq. NH4OAc (instead of an acidification with 1N HCl). The desired product was obtained as an off-white foam that was not further purified. MS (−ESI): m/z 482 (M−1)−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22].Cl.N1C=CC=CC=1>CC(O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Nc1ccc(F)c(Cl)c1
Yield: 74.9 %

Procedure:
A stirred mixture of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile (10.7 g, 40 mmol), 3-chloro-4-fluoroaniline (7.0 g, 48 mmol), pyridine hydrochloride (4.6 g, 40 mmol), and 200 ml of 2-propanol was heated to reflux temperature and maintained for 1 h. The 2-propanol was evaporated off, and the residue was stirred in water with potassium bicarbonate (pH˜8). The resulting solid was filtered, washed with water and 5:1 hexane-DCM, and dried. Recrystallization from EtOH gave 11.3 g of yellow solid, mp 259-263°; ms 377.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])=[N:4][N:3]=[N:2]1.[C:14](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C=O)C.O1CCOCC1>[CH3:14][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH:8]=[O:9])=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccccc1-c1nnn[nH]1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CI
Product: Cn1nnc(-c2ccccc2C=O)n1
Temperature: 0 °C

Procedure:
With the exclusion of air, 8.0 g (45.9 mmol) of 2-(tetrazol-5-yl)-benzaldehyde are added to 19 g (138 mmol) of potassium carbonate in 100 ml of DMF/dioxane (1:1) in an ice bath. 4.25 ml (68 mmol) of methyl iodide are added dropwise thereto and the reaction mixture is stirred in the ice bath for 1 hour and at RT for 1.5 hours. The mixture is stirred into 1 liter of icewater and 0.6 liter of ethyl acetate and the aqueous phase is separated off and extracted twice more with ethyl acetate. The organic phases are washed four times with water and with brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/ethyl acetate=3:1) and stirring in hexane yield 2-(2-methyl-tetrazol-5-yl)-benzaldehyde; TLC: Rf=0.41 (hexanelethyl acetate=3:1); FAB-MS: (M+H)+=189.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:8][C:2]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)([CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)N1CCC(=O)CC1
Reaction time: 20 h

Procedure:
A mixture of ethyl 2-bromo-2-methylpropanoate (48.3 ml, 5 equiv), 4-piperidone hydrochloride monohydrate (100 g, 1 equiv), acetonitrile (1216 ml) and potassium carbonate (353 g, 4 equiv) was heated at reflux under nitrogen with mechanical stirring for 20 h then cooled in an ice bath before adding diethyl ether (approx. 1400 ml). The mixture was filtered through celite, evaporated in vacuo, then excess bromoester distilled off (50° C. still head temperature/10 Torr). Flash chromatography (silica, 5-30% ethyl acetate in hexane) and evaporation of the product fractions gave the crude product as a yellow oil. To remove some remaining bromoester contaminant this was partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The organic layer was discarded and the aqueous layer was basified with sodium carbonate, saturated with sodium chloride and extracted with ethyl acetate. Drying and evaporation of the organic extracts gave the desired product as a yellow oil (54.7 g).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[NH:36]1[CH2:43][CH2:42][CH2:41][C@H:37]1[C:38]([OH:40])=[O:39]>>[C:38]([C@@H:37]1[CH2:41][CH2:42][CH2:43][N:36]1[C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13])([OH:40])=[O:39]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Product: NCCSC(=O)N1CCC[C@H]1C(=O)O
Yield: 159.8 %

Procedure:
N-triphenylmethyl-2-paranitrophenoxycabonylthioethylamine (300 mg) and L-proline (356 mg) were subjected to similar reactions to those described in References 2 and 4 to give 2-((S)-2-carboxypyrrolidino)carbonylthioethylamine (crude formate: 216 mg). The product was dissolved in anhydrous methanol (5 ml). Triethylamine (573 μl) and mitomycin A (287 mg: 1.0 molar equivalent) were added to the reaction solution which was then treated in a similar manner to that described in Example 1 to obtain Compound 31 (112 mg) in the form of grayish blue powders with a yield of 51%.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CC1(C)OC(=O)[C:37](=[C:41]([OH:49])[CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:36](=O)[O:35]1>C(Cl)Cl.CO>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:36](=[O:35])[CH2:37][C:41](=[O:49])[CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CCOC(=O)CCC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)CC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Yield: 37.1 %

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmol), 7 mL of toluene and 70 mg of ethyl 4-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-4-hydroxybutanoate (1.1 molar equivalent) were refluxed for 6 hours. After cooling, the solvent was evaporated under reduced pressure and the residue was submitted to a flash chromatography on silica (eluent: CH2Cl2/methanol in a 97:3 volume ratio) to provide 48 mg yield=29% of the desired product (formula below) as a red powder.
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[C:23]1([CH2:29][C:30]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+].OO>C(OCC)C.O>[C:23]1([CH2:29][C@H:30]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[OH:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cc1ccccc1)c1nccs1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O[C@H](Cc1ccccc1)c1nccs1
Temperature: 0 °C
Reaction time: 6 h
Yield: 71.3 %

Procedure:
Following the method of Itako et al. (Irako, N.; Hamada, Y.; Shioiri, T. Tetrahedron 48(35), 1992, 7251-7264), to a 0° C. (ice-water bath) solution of (+)-B -chlorodiisopinocamphenylborane (+-DIP-Chloride, 3.9 g, 12 mmol) in diethyl ether (3 mL) is added dropwise a solution of 2-phenyl-1-(1,3-thiazol-2-yl)ethanone (0.83 g, 4.1 mmol, from Reference Example 2) in diethyl ether (17 mL). The mixture is stirred for 6 hours at 0° C. and then is allowed to sit in a −5° C. freezer overnight. The next day, 10% aqueous sodium hydroxide solution (10 mL) is added at 0° C. with stirring. Aqueous hydrogen peroxide solution (30%, 1.5 mL) is then added and the mixture is allowed to stir at room temperature for 2 hours. The biphasic mixture is diluted with water (50 mL). The two layers are partitioned and the aqueous phase is saturated with potassium carbonate and then extracted thrice with diethyl ether. The combined extracts are washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a bright golden oil, which is purified by flash chromatography (silica gel, hexanes/ethyl acetate). A light yellow solid (0.60 g, 72%) is provided. MS (ES+): (M+H)=206.0
Reaction SMILES: C(=O)(OC)[O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]([CH:12]2[O:17][C:16]3[CH:18]=[CH:19][C:20]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:21][C:15]=3[NH:14][CH2:13]2)=[O:11])[C:6]([C:27]#[C:28][CH2:29]O)=[CH:5][C:4]=1[CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[CH2:39]([N:41](CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.CN>ClCCl>[CH:31]1([C:4]2[C:3]([OH:2])=[CH:8][C:7]([NH:9][C:10]([CH:12]3[O:17][C:16]4[CH:18]=[CH:19][C:20]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:21][C:15]=4[NH:14][CH2:13]3)=[O:11])=[C:6]([C:27]#[C:28][CH2:29][NH:41][CH3:39])[CH:5]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCN(CC)CC
Reactant: COC(=O)Oc1cc(NC(=O)C2CNc3cc(OC(F)(F)F)ccc3O2)c(C#CCO)cc1C1CCCC1
Agent: CN
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Product: CNCC#Cc1cc(C2CCCC2)c(O)cc1NC(=O)C1CNc2cc(OC(F)(F)F)ccc2O1
Temperature: 25 °C
Reaction time: 10 h
Yield: 116 %

Procedure:
2-Cyclopentyl-4-(3-hydroxyprop-1-ynyl)-5-(6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)phenyl methyl carbonate (20 mg, 0.037 mmol) was dissolved in dichloromethane (1 mL) and triethylamine (20 μL, 0.14 mmol) and cooled to 0° C. Methanesulfonyl chloride (4.3 mg, 2.9 μL, 0.04 mmol) in 1 mL of dichloromethane was slowly added to the reaction. Conversion to the mesylate was complete after 10 min. MeNH2 (100 μL of 2 M in THF, 0.20 mmol) was then added and the reaction stirred at room temperature for 10 h. The solution was concentrated in vacuo and purified by HPLC (10-99% CH3CN/0.035% TFA) to provide N-(4-cyclopentyl-5-hydroxy-2-(3-(methylamino)prop-1-ynyl)phenyl)-6-(trifluoromethoxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (21 mg, 97% yield). LC/MS m/z 490.4 [M+H]+. 1H NMR (400.0 MHz, MeOD) δ 7.65 (s, 1H), 7.28 (s, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.60 (s, 1H), 6.54 (dd, J=1.8, 8.7 Hz, 1H), 4.78 (dd, J=3.0, 7.0 Hz, 1H), 4.14 (dd, J=16.6, 27.1 Hz, 2H), 3.67 (dd, J=3.0, 12.1 Hz, 1H), 3.49-3.44 (m, 1H), 3.24 (m, 1H), 2.79 (s, 3H), 2.05-1.92 (m, 2H), 1.81-1.77 (m, 2H), 1.71-1.68 (m, 2H), 1.54-1.51 (m, 2H).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[CH2:14][OH:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:25][C:26](OC(C)=O)=[O:27]>C(Cl)Cl.O>[OH:15][CH2:14][C:9]1[CH2:10][N:11]([C:26](=[O:27])[CH3:25])[CH2:12][CH2:13][C:8]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCC1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2ccccc2)=C(CO)C1
Yield: 77.6 %

Procedure:
To a solution of (4-phenyl-1,2,5,6-tetrahydropyridin-3-yl)methanol hydrochloride (110 mg, 0.49 mmol) in DCM (2 mL) was added DIPEA (0.17 mL, 0.98 mmol) and Ac2O (0.05 g, 0.49 mmol), 15 min later, it was diluted with water and extracted with DCM. Organic layers were combined, dried and concentrated, the resulting crude oil was purified by column (EtOAc followed by DCM/MeOH=9:1) to give 1-(5-(hydroxymethyl)-4-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (88 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=2[O:10][N:9]=1>C(O)CCC>[CH3:17][C:16]1[C:11]2[O:10][N:9]=[C:8]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc2c(Cl)noc12
Reactant: C1CNCCN1
Solvent: CCCCO
Product: Cc1cccc2c(N3CCNCC3)noc12
Reaction time: 6 h
Yield: 71.5 %

Procedure:
To a stirred and heated (90° C.) mixture of 120 parts of piperazine and 400 parts of 1-butanol were added dropwise 60 parts of 3-chloro-7-methyl-1,2-benzisoxazole. Upon complete addition, stirring was continued for 6 hours at reflux temperature. After cooling, the reaction mixture was filtered and the filtrate was evaporated. The residue was taken up in water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was solidified on standing, yielding 56 parts (71.5%) of 7-methyl-3-(1-piperazinyl)-1,2-benzisoxazole as a residue (int. 2).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7](Cl)=[O:8]>O1CCCC1>[CH3:1][NH:2][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:12]([CH3:13])=[C:4]([CH3:3])[CH:5]=1
Reactant: CN
Reactant: Cc1ccc(C(=O)Cl)cc1C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
108 ml of a 40% strength aqueous solution of methylamine were dissolved in 300 ml of tetrahydrofuran. 53 g of 3,4-dimethylbenzoyl chloride were added dropwise to this solution with ice cooling. The reaction mixture was subsequently stirred at room temperature for 1 hour. Then the reaction mixture was concentrated to half its volume under reduced pressure, saturated sodium chloride solution was added, and the mixture was acidified with concentrated hydrochloric acid. The product which then precipitated was filtered out with suction and dried at 40° C. over potassium hydroxide in a drying cabinet. 47 g of N-methyl-3,4-dimethylbenzamide were obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C:16](=O)[C:4]=2[CH:3]=1)=[CH:14][C:13]([C:18]1[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=1)=[CH:12][CH:11]=3.[CH3:25][Mg]Br.Cl>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C:16](=[CH2:25])[C:4]=2[CH:3]=1)=[CH:14][C:13]([C:18]1[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=1)=[CH:12][CH:11]=3
Reactant: O=c1c2cc(-c3cccnc3F)ccc2oc2c(F)nc(Br)cc12
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=C1c2cc(-c3cccnc3F)ccc2Oc2c1cc(Br)nc2F
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
3-Bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5H-chromeno[2,3-c]pyridin-5-one (3.75 g, 9.64 mmol) was suspended in dry THF (100 mL) and cooled in an ice bath under nitrogen. Methylmagnesium bromide (3.0 M in diethyl ether, 10 mL, 30.0 mmol) was added dropwise and the mixture stirred for an additional 10 min before removing from the ice bath. Additional THF (300 mL) and methylmagnesium bromide (15 mL, 4.5 eq) was added slowly. Once the solids had completely dissolved the reaction was stirred for 5 min. It was quenched by careful addition of 5 N HCl. Water (600 mL) and EtOAc (500 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude alcohol was dissolved in dry THF (200 mL) and treated with hydrogen chloride (4.0 M solution in 1,4-dioxane, 7 mL, 28.0 mmol). The solution was heated to 40° C. for 1 h. The solution was evaporated to dryness under reduced pressure and further dried under high vacuo. The crude 3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5-methylene-5H-chromeno[2,3-c]pyridine (2.20 g, 5.68 mmol, 59.0% yield) was used without purification. It was dissolved in dry THF (80 mL) and cooled in an ice bath under nitrogen. Silver cyanate (2.5 g, 16.68 mmol) was added and the mixture stirred. A solution of iodine (1.45 g, 5.71 mmol) in dry THF (20 mL) was added dropwise. After 30 min the colour of iodine had been consumed and the supernatant was clear. Diethyl ether (200 mL) was added and the mixture filtered through a pad of celite. The filtrate was treated with ammonia (2.0 M solution in methanol, 80 mL, 160 mmol) and the flask sealed. It was stirred overnight. The solution was evaporated to dryness under reduced pressure. The crude solids were triturated with diethyl ether and filtered through a sintered glass frit. The solids were dried under high vacuo to give the desired 3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (2.25 g, 5.05 mmol, 89% yield). MS m/z=445.0, 446.9 [M+H]+. Calculated for C19H11BrF2N4O2: 444.0. Separation of the stereoisomers using SCF gave optically pure (5R)-3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (MS m/z=445.0, 447.0 [M+H]) and (5S)-3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine
Reaction SMILES: C1[C:5]2([CH2:10][CH2:9][N:8](C(=O)[C@H](NC(=O)C3C=C(Cl)C=C(Cl)C=3)CCC(O)=O)[CH2:7][CH2:6]2)CCC1.Cl[C:31]([O:33]CC)=[O:32].C(N(CC)CC)C>C1COCC1>[NH:8]1[CH2:7][CH2:6][CH2:5][CH:10]([C:31]([OH:33])=[O:32])[CH2:9]1
Reactant: CCOC(=O)Cl
Reactant: O=C(O)CC[C@@H](NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)N1CCC2(CCCC2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)C1CCCNC1
Yield: 123.9 %

Procedure:
The method described in Example 1 was again used in this case, first of all by reacting 60 g (0.136 moles) of (R)-5-(8-azaspiro[4.5]decan-8-yl)-4-(3,5-dichloro-benzoylamino)-5-oxopentanoic acid (CR 2194) with 14 ml of ethyl chloroformate (0.1469 moles) in the presence of 20 ml of triethylamine (0.1435 moles) in THF and then by reacting the mixed anhydride thus formed with 19.2 g (0.1685 moles) of piperidine-3-carboxylic acid dissolved in THF/H2O. Upon completion of the reaction the reaction mixture was treated as described in Example 1. The crude oily residue thus obtained was precipitated by treatment with ligroin. The crude product was crystallized by acetonitrile. After cooling, the precipitate was filtered and dried at 60° C. under vacuum, producing 47.3 g (0.086 moles) of the pure product with a yield of 63% (C27H35Cl2N3O5).