Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=4)[N:15]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:16]3=[O:19])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl>[Cl:33][C:29]1[CH:28]=[C:27]([C:14]2[N:15]([CH2:20][C:21]([NH:23][CH:24]([CH3:25])[CH3:26])=[O:22])[C:16](=[O:19])[C:17]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:4]=2)[CH:18]=3)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)NC(=O)Cn1c(-c2cccc(Cl)c2)cc2ccc(-c3cccc(CCl)c3)cc2c1=O
Reactant: C1CCNCC1
Solvent: ClCCl
Product: CC(C)NC(=O)Cn1c(-c2cccc(Cl)c2)cc2ccc(-c3cccc(CN4CCCCC4)c3)cc2c1=O
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To 2-[7-(3-chloromethylphenyl)-3-(3-chlorophenyl)-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (19 mg, 0.04 mmol) in DCM (5 mL) was added piperidine (0.5 mL) and this was stirred at 23° C. for 18 h. The mixture was concentrated in vacuo, and the crude residue purified by preparative HPLC to yield the HCl salt of 2-[3-(3-chlorophenyl)-1-oxo-7-(3-piperidin-1-ylmethylphenyl)-1H-isoquinolin-2-yl]-N-isopropylacetamide (EXAMPLE 35) hydrochloride salt (7 mg, 0.013 mmol, 33%) as pale beige solid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH2:16][NH:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:24]([N:27]1[CH:35]=[N:34][C:33]2[C:28]1=[N:29][C:30](Cl)=[N:31][C:32]=2Cl)[CH:25]=[CH2:26].ClC1N=[C:46]2[C:42](NC=N2)=[CH:41][N:40]=1.C(N)C=C>C(O)C.C(O)CCC>[CH2:24]([N:27]1[CH:35]=[N:34][C:33]2[C:28]1=[N:29][C:30]([NH:40][CH2:41][CH:42]=[CH2:46])=[N:31][C:32]=2[N:21]1[CH2:22][CH2:23][CH:18]([NH:17][CH2:16][CH:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)[CH2:19][CH2:20]1)[CH:25]=[CH2:26]
Reactant: C=CCn1cnc2c(Cl)nc(Cl)nc21
Reactant: c1ccc2c(c1)CCc1ccccc1C2CNC1CCNCC1
Reactant: Clc1ncc2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCO
Solvent: C=CCN
Product: C=CCNc1nc(N2CCC(NCC3c4ccccc4CCc4ccccc43)CC2)c2ncn(CC=C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.8 %

Procedure:
3 g of 4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidine are added to a solution of 1.15 g of 9-allyl-2,6-dichloropurine in 20 ml of ethanol and the mixture is stirred for 3 hours at room temperature and then for 30 minutes at 50° C. The mixture is then treated as described in Example 1. The residue obtained is recrystallised from ether. 1.8 g of white crystals melting (cap) at 146°-148° C. are obtained. By proceeding as in Example 1, starting from 1.8 g of the 2-chloropurine compound so obtained dissolved in 20 ml of butanol and heated to 150° C. in the presence of 0.6 ml of allylamine, 0.7 g of 9-allyl-2-allylamino-6-{4-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)methylamino]piperidino}purine is obtained in the form of a resinous product of which the difumarate, recrystallised from ethanol, melts (cap) at 191°-194° C.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][NH:18][C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:26]I.Cl.[C:29](=[S:31])=[S:30]>CS(C)=O.O>[CH2:1]([N:8]1[C:20]2[CH2:19][N:18]([C:29]([S:31][CH3:26])=[S:30])[C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=C=S
Reactant: O=C(O)[C@H]1Cc2c(n(Cc3ccccc3)c3ccccc23)CN1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CSC(=S)N1Cc2c(c3ccccc3n2Cc2ccccc2)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
(3R)-9-Benzyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (1.225 g) is dissolved in dimethylsulfoxide (20 ml) and thereto are added 10N NaOH (0.8 ml) and carbon disulfide (0.24 ml). The mixture is stirred at room temperature for 10 minutes and thereto is added dropwise methyl iodide (0.29 ml). The mixture is stirred at room temperature for 20 minutes and thereto is added water (100 ml). The mixture is acidified with 10% HCl and extracted with ethyl acetate. The extract is washed with water, dried and distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, chloroform:methanol:acetic acid=90:5:1) to give the title compound (0.89 g, 52%) as pale yellow powder.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]([C:7]1[C:12]([NH2:13])=[CH:11][C:10]([O:14][CH3:15])=[C:9]([O:16][CH3:17])[CH:8]=1)=[O:6].[CH:18](OCC)=O.Cl>O.O1CCCC1>[CH3:17][O:16][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[O:14][CH3:15])[N:13]=[CH:18][CH2:4][C:5]2=[O:6]
Reactant: CCOC=O
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)CC=N2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
Tetrahydrofuran (THF) (5.3 L) and sodium methoxide (313 g) were added to 2-amino-4,5-dimethoxyacetophenone (337 g), and the mixture was stirred at 20° C. for 30 min. Ethyl formate (858 g) was added to the reaction solution at 0° C., and the mixture was stirred at 20° C. for one hr. Water (480 mL) was added thereto at 0° C., and the mixture was neutralized with 1 N hydrochloric acid. The resultant precipitate was collected by filtration, and the filtered product was slurried in water (2 L) for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give 6,7-dimethoxy-4-quinolone (352 g, yield 81.50%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[CH3:14])#[N:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:36]1([CH3:54])[CH:41]=[CH:40][CH:39]=[C:38]([C:42]2[C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=[C:44]([C:50]([F:53])([F:52])[F:51])[N:43]=2)[CH:37]=1.C(N(CC)CC)C>C(#N)C.C(OC(=O)C)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([NH:49][CH2:48][C:47]2[C:42]([C:38]3[CH:37]=[C:36]([CH3:54])[CH:41]=[CH:40][CH:39]=3)=[N:43][C:44]([C:50]([F:53])([F:51])[F:52])=[CH:45][CH:46]=2)=[O:12])=[CH:5][C:4]=1[CH3:14])#[N:2]
Reactant: Cc1cc(C(C)C(=O)O)ccc1C#N
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(C#N)c(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a stirred solution of 2-(4-cyano-3-methylphenyl)propanoic acid (100 mg, 0.53 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (152 mg, 0.80 mmol), 1-hydroxybenzotriazole (107 mg, 0.80 mmol), (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (155 mg, 0.58 mmol) and triethylamine (0.18 mL, 1.33 mmol). The reaction mixture was stirred for overnight at room temperature. The mixture was diluted with ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-Cyano-3-methylphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (152 mg) was obtained as 86% yield.
Reaction SMILES: [H-].[Na+].C(O)C=C.[S:7]([CH2:16][CH2:17][C:18]([O:20]CC=C)=[O:19])[CH2:8][CH2:9][C:10]([O:12]CC=C)=O>CCOCC>[S:7]1[CH2:8][CH2:9][C:10](=[O:12])[CH:17]([C:18]([OH:20])=[O:19])[CH2:16]1
Reactant: C=CCOC(=O)CCSCCC(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C=CCO
Product: O=C(O)C1CSCCC1=O
Temperature: 25 °C
Yield: 83.1 %

Procedure:
To a mixture of sodium hydride (60% in oil, 1.6 g, 38.7 mmol) in 10 mL of dry ether at room temperature was added allyl alcohol (2.25g, 38.7 mmol) in a dropwise manner. The resultant mixture was stirred for 15 min. A solution-of 3,3′-thiodipropionic acid, diallyl ester (5.0 g, 19.3 mmol) in 10 mL ether was slowly added and the mixture refluxed for 5 h. The reaction was cooled to room temperature and then quenched with water and the pH adjusted to 4 with IN HCl. The ether layer was separated and the aqueous layer was extracted with ether (2×100 mL). The combined etheral layer was washed with sautrated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue purified by flash column chromatography on silica gel eluted with hexane: ether (9 :1) to give 2.57 g of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]1[CH2:15][C:14](=[O:16])[CH2:13]1)=O.[CH3:17]C(O)=O>CC#N>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:10]([CH:12]3[CH2:15][C:14](=[O:16])[CH2:13]3)[N:1]([CH3:17])[C:2]=2[CH:7]=1
Reactant: CC(=O)O
Reactant: Nc1cc(Br)ccc1NC(=O)C1CC(=O)C1
Solvent: CC#N
Product: Cn1c(C2CC(=O)C2)nc2ccc(Br)cc21

Procedure:
To a stirred solution of N-(2-amino-4-bromophenyl)-3-oxocyclobutanecarboxamide (2.7 g) in CH3CN (20 ml) was added AcOH (2 ml), and the mixture was heated under reflux for 3 h. The mixture was concentrated in vacuo, and poured into saturated NaHCO3 solution. The mixture was extracted with EtOAc, washed with water and brine successively, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (hexane/EtOAc) to afford the title compound (2.0 g) as an off-white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C-:13]#[N:14].[Na+]>C(O)C>[N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][C:13]#[N:14])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCc1ccc2ncccc2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc2ncccc2c1
Temperature: 50 °C
Yield: 18.3 %

Procedure:
To a solution of crude 6-bromomethylquinoline (1.8 g) in 95% ethanol (30 mL) was added NaCN (2.0 g, 40.8 mmol) at room temperature. The mixture was heated at 50° C. for 3 hours and then concentrated under vacuum. Water (50 mL) and ethyl acetate (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4 and concentrated under vacuum. The combined crude product was purified by column (Petroleum Ether/EtOAc 5:1) to give 2-(quinolin-6-yl)acetonitrile (0.25 g, 8% over two steps). 1H NMR (300 MHz, CDCl3) δ 8.95 (dd, J=1.5, 4.2 Hz, 1H), 8.12-8.19 (m, 2H), 7.85 (s, 1H), 7.62 (dd, J=2.1, 8.7 Hz, 1H), 7.46 (q, J=4.2 Hz, 1H), 3.96 (s, 2H). MS (ESI) m/e (M+H)+ 169.0.
Reaction SMILES: [H-].[Na+].O=C1CCCN1.Cl[CH2:10][CH2:11][CH2:12][C:13]([NH:15][C:16]1[C:21]([C:22](=[O:28])[C:23]2[S:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:14].O>C1(C)C=CC=CC=1>[O:14]=[C:13]1[CH2:12][CH2:11][CH2:10][N:15]1[C:16]1[C:21]([C:22](=[O:28])[C:23]2[S:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(CCCCl)Nc1ncccc1C(=O)c1cccs1
Agent: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(c1cccs1)c1cccnc1N1CCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 20 ml of toluene is suspended 0.6 g of 60% sodium hydride, whereto 3 ml of 2-oxopyrrolidine is added. Under ice-cooling, 2.7 g of 2-(4-chlorobutyrylamino)-3-(2-thenoyl)pyridine is added thereto, and the mixture is stirred at room temperature for 1 hour. The mixture is poured into water, and the solvent of the toluene layer is distilled off. The residue is recrystallized from toluene-isopropyl ether to give 2-(2-oxopyrrolidin-1-yl)-3-(2-thenoyl)pyridine, m.p. 148°-150° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]P(=O)(OCC)OCC)[N:6]=1.[H-].[Na+].[CH3:18][O:19][CH2:20][O:21][C:22]1[C:26]([CH:27]=O)=[CH:25][N:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:23]=1.O>O1CCCC1>[CH3:1][C:2]1[S:3][CH:4]=[C:5](/[CH:7]=[CH:27]/[C:26]2[C:22]([O:21][CH2:20][O:19][CH3:18])=[N:23][N:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=2)[N:6]=1
Reactant: CCOP(=O)(Cc1csc(C)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C)n1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of diethyl [(2-methyl-1,3-thiazol-4-yl)methyl]phosphonate (2.32 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.32 g) was added to the reaction mixture, and the mixture was heated under reflux for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (4:1, v/v) to give 2-methyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as a pale-yellow oil (2.72 g, yield 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(F)c(N2CCNCC2)cc1Cl
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A solution of 19.3 g (0.08 mol) of 2-chloro-4,5-difluoronitrobenzene in 100 g of toluene are introduced into a 200 ml three-necked flask fitted with dropping funnel, precision-ground glass stirrer and reflux condenser. 18.1 g (0.21 mol) of piperazine are added dropwise to this solution at room temperature and with stirring over the course of one hour. The mixture is then stirred at room temperature for a further 2 hours. The reaction solution formed during the reaction is washed three times with 20 ml of water in each case and dried. The solvent is removed to give 18.5 g (0.071 mmol) of 2-chloro-5-fluoro-4-piperazinonitrobenzene. This corresponds to a yield of 95%, based on 2-chloro-4,5-difluoronitrobenzene used. 2-Chloro-5-fluoro-4-piperazinonitrobenzene of the following formula ##STR5## has a melting point of 91.5° C. (purity: 92.9%, determined by HPLC).
Reaction SMILES: B(Cl)(Cl)Cl.[CH2:5]([NH:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[C:13]([C:28]2[CH:33]=[C:32]([Cl:34])[C:31]([O:35]CC3C=CC=CC=3)=[CH:30][C:29]=2[O:43]CC2C=CC=CC=2)[O:12][N:11]=1)=[O:9])[CH3:6].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:5]([NH:7][C:8]([C:10]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:19][CH:20]=2)=[C:13]([C:28]2[CH:33]=[C:32]([Cl:34])[C:31]([OH:35])=[CH:30][C:29]=2[OH:43])[O:12][N:11]=1)=[O:9])[CH3:6]
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(CN2CCOCC2)cc1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)c1noc(-c2cc(Cl)c(O)cc2O)c1-c1ccc(CN2CCOCC2)cc1
Yield: 64.3 %

Procedure:
BCl3 (1M sol. in CH2Cl2, 3.87 ml, 3.87 mmol) was added dropwise to a solution of the crude 5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (810 mg, ˜1.29 mmol) in CH2Cl2 (30 ml) at 0° C. The reaction was then allowed to reach RT. Saturated aqueous NaHCO3 (40 ml) was then added slowly and the resultant mixture concentrated in vacuo. This was then partitioned between EtOAc (3×50 ml) and water (50 ml). The combined, dried (Na2SO4) organics were evaporated in vacuo. Flash chromatography eluting with CH2Cl2-10% MeOH/1% NH3/CH2Cl2 afforded 5-(5-Chloro-2,4-dihydroxy-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (380 mg, 64% over 2 steps) as a yellow foam, LC/MS: RT=1.751 min. 458.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][N:16]([C:27]([NH:26][C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[O:28])[CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
7-Chloro-2-methyl-4-(piperazin-1-yl)quinoline (0.26 g), 4-fluorophenyl isocyanate (114 μL, 1.0 mmol), and DMAP (2 mg) in THF (10 mL) are reacted according to method C yielding the product as a colorless solid after column chromatography with hexane-EtOAc. 1H NMR ([D]6-DMSO), δ 2.58 (s, 3H), 3.17 (m, 4H), 3.71 (m, 4H), 6.94 (s, 1H), 7.06 (t, 2H), 7.46 (m, 3H), 7.87 (d, 1H), 8.01 (d, 1H), 8.68 (br. s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:24][CH:21]1[CH2:22][CH2:23][N:19]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:20]1
Reactant: OC1CCNC1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC(O)C3)n2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (160 mg, 0.53 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 3-Pyrrolidinol (Fluka) (55.4 mg; 0.64 mmol; 1.20 eq.) and triethylamine (0.22 ml; 1.59 mmol; 3 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (43) as a white-off powder (40.1 mg; 21.5%). 1H NMR (DMSO-d6, 300 MHz) δ 1.75-2.12 (m, 3H), 2.12 (s, 3H), 2.48 (s, 3H), 3.45-3.70 (m, 2H), 3.90-4.25 (m, 2H), 4.31-4.40 (m, 1H), 7.97 (s, 1H), 12.13 (s, 1H). M− (ESI): 353.07; M+ (ESI): 351.09. HPLC(method A), Rt: 2.21 min (purity: 99.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:16])[CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:16])[CH2:14][CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: O
Solvent: CC(=O)O
Product: CC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
(S)-3-(1-Hydroxypropyl)pyrrolidine-1-carboxylic acid t-butyl ester (1.5 g, 6.5 mmol) was purified by preparative HPLC. The residue was dissolved in 50% AcOH/H2O and the diastereomers were separated using a gradient of 10-50% AcOH/H2O (0.05% TFA) over 80 minutes on a 2″ column at 40 mL/min. The collected fractions were lyophilized to yield each diastcrcomcr as an oil (565 mg, SS, 1st eluting peak; 565 mg, SR, 2nd eluting peak). Each diastereomer was dissolved in DCM (4 mL) and HCO3 resin (1 gΠ1.95 mmol/g) was added to recover residual TFA. The mixture was stirred for 1 hour. The product was filtered off and solvent was removed to yield the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1>CN(C)C=O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]2[O:14][N:13]=[C:12]([O:1][CH:2]3[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)[C:16]=2[CH:17]=1
Reactant: Clc1ccc2onc(Cl)c2c1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2noc3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A solution of 1.53 g (13.3 mmole) of 4-hydroxy-1-methylpiperidine in 25 ml of dimethylformamide was cooled to 5° C. in an atmosphere of nitrogen. 0.58 g (13.3 mmole) of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to the solution, and then the solution was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 5° C., and then 2.50 g (13.3 mmole) of 3,5-dichloro-1,2-benzisoxazole were added to it; the resulting mixture was then stirred at 5° C. for 30 minutes and then at room temperature for 1 hour. At the end of this time, the mixture was poured into 50 ml of ice-water and then extracted twice, each time with 50 ml of ethyl acetate. The ethyl acetate layer was separated and washed with 100 ml of a 10% w/v aqueous solution of sodium chloride; it was then dried over anhydrous magnesium sulfate, and the drying agent was removed by filtration. The solvent was removed from the filtrate by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel using ethyl acetate as the eluent to afford 2.38 g (yield 67.00%) of the title compound as a colorless powder, melting at 55°-56° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[Cl-].[NH4+:37]>CO>[NH2:32][C:31](=[NH:37])[C:27]1[CH:26]=[C:25]([O:24][C:18]2[CH:17]=[C:16]3[C:21]([CH2:22][CH2:23][CH:14]([C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=4)=[O:13])[CH2:15]3)=[CH:20][CH:19]=2)[CH:30]=[CH:29][N:28]=1
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(C#N)c4)cc3C2)c1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(C(=N)N)c4)cc3C2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-(3-tert-butylphenyl)-7-[(2-cyanopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (1.5 g, 3.5 mmol) in MeOH (20 mL) was added sodium methoxide (28 mg, 0.52 mmol). The solution was allowed to stir at rt for 3 days and then ammonium chloride (0.28 g, 5.3 mmol) was added. The reaction mixture was allowed to stir overnight and then concentrated to give 7-({2-[amino(imino)methyl]pyridin-4-yl}oxy)-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide I-422 as a white solid, which was directly used into the next step. LCMS: (FA) ES+ 443.3.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]([OH:39])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([C@H:46]3[CH2:51][CH2:50][C@H:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)[N:34]=1.[CH2:57](O)[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]>O1CCCC1>[F:32][C:33]1[C:38]([O:39][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[CH:37][CH:36]=[C:35]([C:40]2[CH:45]=[CH:44][C:43]([C@H:46]3[CH2:51][CH2:50][C@H:49]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)[N:34]=1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(O)c(F)n3)cc2)CC1
Reactant: CCCCCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCCCC)CC3)cc2)nc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.26 g (1.50 mmol) of diethyl azodicarboxylate is added dropwise at 0° C. to 0.39 g (1.50 mmol) of triphenylphosphine in 10 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 0.31 g (0.91 mmol) of 2-fluoro-3-hydroxy-6-[4-(trans-4-pentylcyclohexyl)phenyl]pyridine and 0.19 g (1.50 mmol) of 1-octanol are then added. After a reaction time of 2hours at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 9:1 hexane/ethyl acetate) and by recrystallization from acetonitrile, giving 0.20 g of 2-fluoro-3-octyloxy-6-[4-(trans-4-pentylcyclohexyl)phenyl]pyridine. ##STR52##