Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][O:39][C:40]3[C:45]([Cl:46])=[CH:44][C:43]([CH3:47])=[CH:42][C:41]=3[Cl:48])=[CH:32][CH:31]=2)[CH2:20][NH:21]C(=O)OC(C)(C)C)=[C:15]([CH3:49])[CH:14]=1)(=[O:3])[CH3:2].Cl>CCOCC.CCOC(C)=O>[Cl-:46].[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][O:39][C:40]3[C:41]([Cl:48])=[CH:42][C:43]([CH3:47])=[CH:44][C:45]=3[Cl:46])=[CH:32][CH:31]=2)[CH2:20][NH3+:21])=[C:15]([CH3:49])[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)NCCc1ccccc1-c1ccc(C(C[NH3+])Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1
Product: [Cl-]

Procedure:
Prepared according to the procedure described in EXAMPLE 2, step 5 using tert-butyl (2-{2′-[(acetylamino)ethyl]-3-methylbiphenyl-4-yl}-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propyl)carbamate from step 1 as starting materials. Following flash chromatography the desired material (colorless oil) was dissolved in CH2Cl2/Et2O (1/1). HCl (4M in dioxane) was added in excess and the resulting suspension was triturated with Et2O to afford after filtration the title compounds as an off white salt. 1H NMR (500 MHz, CD3OD): δ 7.46 (d, 1H), 7.32-7.25 (m, 4H), 7.20-7.18 (m, 3H), 7.06 (s, 1H), 7.00 (d, 2H), 6.82 (d, 2H), 4.35-4.31 (m, 4H), 3.57-3.52 (m, 1H), 3.42-3.32 (m, 2H), 3.17 (d, 1H), 3.16 (d, 1H), 3.02 (dd, 1H), 2.88 (dd, 1H), 2.84-2.78 (m, 2H), 2.30 (s, 3H), 2.14 (s, 3H), 1.85 (s, 3H).
Reaction SMILES: O1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.F[C:10](F)(F)[C:11](OC(=O)C(F)(F)F)=O.Cl.[NH2:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1>O1CCCC1.C(N(CC)CC)C>[C:3]1([C:6]([NH:23][C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)=[O:8])[CH:4]=[CH:5][CH:11]=[CH:10][CH:2]=1
Reactant: Nc1ncc[nH]1
Reactant: O=C(O)c1ccoc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ncc[nH]1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 3-furoic acid in 50 ml. of tetrahydrofuran, there is added 10.5 g. of trifluoroacetic anhydride. To the resulting solution, after 30 minutes and at 20°-25°C., there is added 15 ml. of triethylamine and 4.1 g. of 2-aminoimidazole hydrochloride and 20 ml. of tetrahydrofuran. The thus-obtained reaction mixture is allowed to stand overnight at 20° -25°C., followed by concentration, dilution with water, filtration and recrystallization from methanol to yield 2-(3-furylcarbonylamino)-imidazole [(III), R = 3-furyl], identical to that obtained in Example 1A.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:32])[C@H:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[NH:13]C(OCC1C=CC=CC=1)=O.[NH2:33][C@H:34]([C:39]([OH:41])=[O:40])[C@H:35]([CH2:37][CH3:38])[CH3:36].CN(C)C=O.CN1CCOCC1>O>[NH2:13][C@H:12]([C:11]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[C@H:35]([CH2:37][CH3:38])[CH3:36])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Carbobenzoxytyrosine 2,4,5-trichlorophenyl ester (544 parts) is added to a suspension of 131 parts of isoleucine in 2000 parts by volume of dimethylformamide. After adding 101 parts of N-methylmorpholine, the mixture is stirred 48 hours at room temperature. Unreacted isoleucine is still present. Water (500 parts by volume) is added and stirring is continued for another 48 hours. The mixture is concentrated to dryness under high vacuum at 40°. The residue is dissolved in 2000 parts by volume of ethyl acetate, the ethyl acetate is washed with four 2000 parts by volume portions of 0.2 M potassium bisulfate, dried over sodium sulfate and stripped under reduced pressure. The residue is dissolved in 1 l. of chloroform and the solution added dropwise with violent stirring to 20 l. of ether. The resulting white powder, carbobenzoxy=tyrosylisoleucine, (42.8 parts) 0.1 mole, is dissolved in 500 parts by volume of 90% acetic acid and hydrogenated at 60 psi at room temperature over 4.3 parts of palladium black. Hydrogen uptake stopped after 2 hours. The catalyst is filtered off and the filtrate concentrated to dryness under vacuum. The residue is rubbed with ether yielding tyrosylisoleucine, Tyr-Ile.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]#N)=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]([F:12])[F:11])[CH:7]=1.[OH-:15].[Na+].[OH2:17]>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:13]([OH:17])=[O:15])=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]([F:12])[F:11])[CH:7]=1
Reactant: [OH-]
Reactant: O
Reactant: N#Cc1ncc(OCC(F)F)cc1Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1ncc(OCC(F)F)cc1Cl
Temperature: 85 °C
Reaction time: 28 h

Procedure:
To a solution of 3-Chloro-5-(2,2-difluoro-ethoxy)-pyridine-2-carbonitrile (0.202 g, 0.878 mmol) in dioxane (4 ml) was added 4N NaOH (2.2 ml, 8.8 mmol) and the resulting reaction mixture was stirred for 28 h at 85° C. The reaction mixture was diluted with water and extracted with EtOAc. The aqueous phase was acidified with 4N HCl and evaporated to dryness. The title compound was extracted with DCM/MeOH (9/1), pushed through a plug of Celite and was obtained after evaporation as a light yellow solid.
Reaction SMILES: C([O:4][C:5]([C:7]1([NH:10][C:11]([C:13]2[N:17]3[C@:18]([CH3:42])([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([N:37]5[CH:41]=[N:40][CH:39]=[N:38]5)=[CH:33][CH:32]=4)[C:19](=[O:29])[N:20]([C:21]4[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=4)[C:16]3=[N:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1)=[O:6])C=C.N1CCOCC1>C1COCC1.CCOC(C)=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:27][C:25]1[CH:26]=[C:21]([N:20]2[C:16]3=[N:15][CH:14]=[C:13]([C:11]([NH:10][C:7]4([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]4)=[O:12])[N:17]3[C@:18]([CH3:42])([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH:41]=[N:40][CH:39]=[N:38]4)=[CH:33][CH:32]=3)[C:19]2=[O:29])[CH:22]=[C:23]([Cl:28])[CH:24]=1
Reactant: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(-n4cncn4)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@]1(Cc2ccc(-n3cncn3)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.8 %

Procedure:
To a solution of 1-{[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-1,2,4-triazol-1-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid allyl ester (109 mg, 0.18 mmol) and morpholine (0.157 mL, 1.80 mmol) in 1 mL of THF was added Pd(Ph3P)4 (10 mg, 0.009 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with 30 mL of EtOAc and washed with 10 mL each of 10% HCl solution, water, and brine, dried over Na2SO4, filtered, and concentrated to afford 114 mg of 1-{[(R)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-5-(4-1,2,4-triazol-1-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid as an orange oily solid that was carried to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][CH2:21][C:22](O)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1.[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:29][CH2:28]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][CH2:21][C:22]([N:36]2[CH2:35][CH2:34][N:33]([CH:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH2:38][CH2:37]2)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:25])[CH:4]=1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)O)c(C)c1
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COCC(=O)N2CCN(C3CCN(C)CC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (114 mg, 0.706 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid (250 mg, 0.673 mmol) in dichloromethane (15 ml), and the mixture was stirred for 1 h at room temperature. A solution of 1-(1-methylpiperidin-4-yl)piperazine (123 mg, 0.673 mmol) in dichloromethane (5 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. The reaction mixture was then extracted with water (20 ml) and saturated sodium chloride solution (20 ml), and the organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using dichloromethane/methanol (97:3→90:10).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([O:18][CH3:19])[CH:4]=1)=O.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27]>CN(C=O)C>[S:27]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:1]1[C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([O:18][CH3:19])[CH:4]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1OC
Reactant: Nc1ccccc1S
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2nc3ccccc3s2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.8 %

Procedure:
In a DMF (3 mL) solvent in the presence of Na2S2O5 (136.1 mg, 0.71 mmol), a solution including Compound 122a (188.7 mg, 0.71 mmol) and 2-aminothiophenol (0.08 mL, 0.71 mmol) was stirred at room temperature for 2 days. After DMF was evaporated, the residual was distributed between ethyl acetate and water. An organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (EtOAc) (7:1) to obtain Compound 122b (244.8 mg, 93%).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH2:69])[CH:64]=1>CN(C=O)C>[CH3:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=1[C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([NH:69][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:64]=1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: COc1ccc(OC)c(-c2cccc(N)c2)c1
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: COc1ccc(OC)c(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.4 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.018 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,5′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and lyophilized for 48 hours to give 0.02 g of product in 64% yield: LCMS (ESI) m/z 486 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+]([O-])=O)[CH:10]=2)[N:5]=[CH:4][N:3]=1.NC1C=C(F)C=CC=1C(O)=[O:20].C(N)=N.C(O)(=O)C>COCCO>[F:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[O:20])[NH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Agent: N=CN
Solvent: CC(=O)O
Solvent: COCCO
Product: O=c1[nH]cnc2cc(F)ccc12

Procedure:
4-Chloro-7-fluoro-6-nitroquinazoline (7) can be prepared by methods similar to those described in J. Med. Chem. 1996, 39, 918-928. Generally, 2-amino-4-fluoro-benzoic acid (1) can be reacted with formamidine (2) and acetic acid (3) in the presence of 2-methoxyethanol to provide 7-Fluoro-3H-quinazolin-4-one (4). The 7-fluoro-3H-quinazolin-4-one (4) can then be nitrated to 7-fluoro-6-nitro-3H-quinazolin-4-one (5), which can be treated with thionyl chloride to yield 4-chloro-6-nitro-7-fluoro-3H-quinazoline (6). The 4-chloro-quinazoline compound (6) can be combined with a desirably substituted aniline, represented above by 4-fluoro-3-chloro-aniline, in the presence of a tertiary amine and isopropanol to provide the 4-anilino-6-nitro-7-fluoro-quinazoline (7).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:18]1[CH:19]=[N:20][C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34][CH3:35])[CH:29]=2)=[C:22]([CH:26]=1)[C:23]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1)=[O:24]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: N[C@H]1CC[C@H](CO)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](CO)CC2)c1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
(trans-4-Amino-cyclohexyl)-methanol (73 mg, 0.56 mmol) and triethylamine (225□l, 1.61 mmol) were dissolved in dimethylformamide (225 μl) and a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (150 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (113 mg, 0.59 mmol) and 1-hydroxybenzotriazole (80 mg, 0.59 mmol) in dimethylformamide (5 ml) was added. The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between 0.5N HCl (10 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (2×10 ml). The combined organic phases were washed with brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (97.5:2.5:0.25, by volume). The product was triturated with ethyl acetate (3 ml) to give 5-Fluoro-N-(trans-4-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (60 mg) as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Cl.[CH:7]1([CH:13]2[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][NH:14]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:7]1([CH:13]2[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][N:14]2[C:2]([O:4][CH3:5])=[O:3])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)C1CCNC(C2CCCCC2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCN(C(=O)OC)C(C2CCCCC2)C1
Reaction time: 3 h
Yield: 129.5 %

Procedure:
Methyl chloroformate (1.344 mL, 17.36 mmol) in DCM (50 mL) was added to a solution of methyl 2-cyclohexylpiperidine-4-carboxylate hydrochloride (3.50 g, 13.35 mmol) and DIPEA (1.88 mL, 10.76 mmol) in DCM (100 mL). The reaction solution was stirred for 3 h. 1.88 mL DIPEA and 1.345 mL methyl chloroformate was added and the reaction continued overnight (16 h). The organic phase was washed with satd NaHCO3. The phases were separated and the organic phase dried using a phase separator to give crude dimethyl 2-cyclohexylpiperidine-1,4-dicarboxylate (4.90 g). MS m/z 284 (M+H)+
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH:11]([Cl:13])[CH3:12])=[O:9].[C:14]([O:19][CH2:20][CH2:21][OH:22])(=[O:18])[C:15]([CH3:17])=[CH2:16]>ClCCl>[C:8](=[O:9])([O:22][CH2:21][CH2:20][O:19][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])[O:10][CH:11]([Cl:13])[CH3:12]
Reactant: C=C(C)C(=O)OCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOC(=O)OC(C)Cl
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of 1-chloroethyl chloroformate (1.20 ml, 11.00 mmol) and 2-hydroxyethyl methacrylate (1.22 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. under a dry N2 atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2×10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure to give 1.76 g (74%) of the title product. 1H NMR (60 MHz, CDCl3): δ1.85 (3H, d, J=6 Hz, CH3 --CH), 1.96 (3H, d, J=2 Hz, CH3 --C=), 5.55 (1H, m, CH=), 6.10 (1H, m, CH=), 6.38 (1H, k, J=6 Hz, CH--CH3).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C:11](=[O:17])[NH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][Cl:34])=[CH:31][CH:30]=1>O>[OH2:17].[ClH:34].[ClH:34].[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[CH2:9][CH2:10][C:11](=[O:17])[NH:12]4)[CH2:2][CH2:3]2)=[CH:31][CH:30]=1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: Nc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cl
Product: Nc1ccc(CN2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 40.8 %

Procedure:
To a mixture of 1.2 g of 5-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium carbonate and 20 ml of dimethyl sulfoxide was added 650 mg of 4-aminobenzyl chloride and the mixture was stirred at 80° C. for 2.5 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography. After conversion to hydrochloric acid salt with methanol-hydrochloric acid, the product was recrystallized from methanol-ether to give 0.4 g of 5-[4-(4-aminobenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril dihydrochloride monohydrate, m.p. 224°-227° C. (decomp.), yellow granules.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=2[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:26][OH:27].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=2[F:23])=[N:26][OH:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1cccc(C(=NO)C2CCN(C(=O)OC(C)(C)C)CC2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of 4-(2-Fluoro-3-methoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (11.6 g, 34.4 mmol), hydroxylamine hydrochloride (2.87 g, 41.3 mmol) and pyridine (50 mL) was stirred at room temperature under nitrogen overnight. The yellow reaction solution was poured into cold water (500 mL) and the mixture aged at 0° C. for 15 min. The product was collected by filtration, washed with water, and dried under vacuum at 50° C. to afford 11.6 g (96%) of the desired product as a white powder. Proton NMR showed product to be a 2:1 mixture of Z- to E-isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][C@@H:29](O)[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.CCN(S(F)(F)[F:40])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][C@H:29]([F:40])[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Solvent: ClCCl
Product: C[C@@H]1C[C@H](F)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 40.3 %

Procedure:
A solution of tert-butyl 5-chloro-1-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.010 g, 0.021 mmol) in DCM (0.3 mL) was cooled to about −20° C. The solution was treated with DAST (0.0084 ml, 0.064 mmol) and stirred at about −20° C. for 1.5 hours. The reaction was quenched with ice then warmed to ambient temperature. The mixture was diluted with saturated aqueous NH4Cl solution. The organic layer was separated. The aqueous phase was extracted with DCM. The combined organics were dried over MgSO4, filtered and concentrated. The crude residue was purified by column chromatography (30-50% EtOAc/Hexane) to yield tert-butyl 5-chloro-1-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (0.004 g, 40%). LCMS (APCI+) m/z 473, 475 [M+H]+; Rt=3.98 min.
Reaction SMILES: B(Br)(Br)Br.CC(C)(C)C([NH:9][NH:10][C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][C:17]([O:25]C)=[C:18]([O:23]C)[CH:19]=2)[CH:14]=1)=[O:12])=O.O.CCOCC>ClCCl>[OH:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[OH:25])[CH:14]=[C:13]([C:11]([NH:10][NH2:9])=[O:12])[CH:22]=[CH:21]2
Reactant: COc1cc2ccc(C(=O)NNC(=O)C(C)(C)C)cc2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: NNC(=O)c1ccc2cc(O)c(O)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
At -78° C., 3.5 g (14.2 mmol) of boron tribromide (0.5M in dichloromethane) was added dropwise to a solution of 1.59 g (4.7 mmol) of 6,7-dimethoxy-2-naphthalenecarboxylic acid, 2-(2,2-dimethyl-1-oxopropyl)hydrazide in 40 ml of dry dichloromethane. The solution was allowed to warm to room temperature and was stirred overnight. 30 ml of water and 115 ml of ether were added and the resulting precipitate filtered, washed and dried in vacuo to give 0.42 g of the title compound as its hydrobromide salt. The salt was dissolved in water and treated with one equivalent of sodium bicarbonate solution to give, after precipitation and collection by filtration, 0.22 g of the desired title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=O)[CH2:4][CH2:3]1.[CH2:13]([OH:16])[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOCC>[CH2:13]1[O:16][C:8]([CH:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)([O:10][CH2:11][CH3:12])[O:15][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC1(C2CCC(=O)CC2)OCCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96 %

Procedure:
Ethyl 4-oxocyclohexanecarboxylate (15.01 g, 88.16 mmol) was combined with ethylene glycol (21 mL, 4.27 equiv.) and p-toluenesulfonic acid monohydrate (0.2 g, 0.012 equiv.) in anhydrous toluene (50 mL), and the mixture was stirred 14 h at room temperature. The reaction was diluted with ether (200 mL) and was washed with H2O (2×200 mL), saturated sodium bicarbonate (100 mL) and brine (80 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to yield 18.15 g ethyl 4-oxocyclohexanecarboxylate ethylene ketal (96% yield). LCMS (m/z): 214.8 (MH+), 0.74 min.