Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][C:16]=1[F:27])[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].Br[CH2:29][CH2:30][S:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[F:39].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:1]=[C:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][C:16]=1[F:27])[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:29][CH2:30][S:31][C:32]2[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=2[F:39])[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Reactant: Fc1ccc(F)c(SCCBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCSc2cc(F)ccc2F)CC[C@H]1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Temperature: 75 °C
Reaction time: 20 h
Yield: 48.1 %

Procedure:
A mixture of 0.57 g of methyl (3R,4R)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate obtained as described in example 1, 0.462 g of 2-(2-bromoethylsulfanyl)-1,4-difluorobenzene, 0.253 g of potassium iodide and 1.05 g of potassium carbonate in 25 cm3 of acetonitrile is heated with stirring and under an inert atmosphere for 20 hours at a temperature in the region of 75° C. After cooling to a temperature in the region of 20° C., the reaction medium is filtered and the insoluble material is washed with 2 times 10 cm3 of acetonitrile. The filtrate is evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue is taken up with 50 cm3 of distilled water and 100 cm3 of ethyl acetate. The organic phase is washed with 3 times 30 cm3 of distilled water and 2 times 50 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated according to the conditions mentioned above. The oil obtained is purified by chromatography on a column of silica gel (particle size 70–200 μm; diameter 2.5 cm), eluting with a mixture of dichloromethane-methanol (9/10 by volume) and collecting fractions of 10 cm3. The fractions containing the expected product are pooled and then evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.4 g of methyl (3R,4R)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylsulfanyl)ethyl]-piperidine-3-carboxylate, in the form of an orange-colored viscous oil, is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH3:32][NH:33][CH3:34]>>[CH3:32][N:33]([CH3:34])[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: CNC
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCN(C)C)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (+)-2-(2-Bromo-ethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 24a) and dimethylamine as starting materials.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1)[CH3:15]>>[CH2:14]([C:16]1[CH:17]=[CH:18][C:19]([N:22]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:20][CH:21]=1)[CH3:15]
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CCc1ccc(NCCN2CCCCC2)cc1
Product: CCc1ccc(N(CCN2CCCCC2)C(=O)C2CCCc3ccccc32)cc1
Yield: 86.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.34 g) and (4-ethylphenyl)(2-piperidinoethyl)amine (0.47 g) as starting materials, N-(4-ethylphenyl)-N-(2-piperidinoethyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.65 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[O:4].C(Cl)(Cl)Cl.CC(C)=O>B([O-])([O-])[O-]>[F:1][C:2]([F:15])([F:16])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:4]
Reactant: COC(=O)CCCCCNC(=O)C(F)(F)F
Agent: [O-]B([O-])[O-]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCNC(=O)C(F)(F)F
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Next, after dissolving Methyl 6-trifluoroacetamidohexanoate (3.7 g, 15.4 mmol) in 10 mM of a borate buffer pH8.0 (3000 ml), a porcine liver derived carboxylesterase (2160U, 1.2 ml) was added, and a reaction performed at 30° C. After 72 hours had passed since the start of the reaction, after boiling for 10 minutes at 100° C. and stopping the reaction, the reaction solution was concentrated and applied to a silica gel column chromatography (2.0×30 cm) equilibrated (10 ml/min) with chloroform:acetone=8:2. After fractionating into 20 ml per tube, the product was confirmed using a phosphomolybdic acid color reaction using TLC (development solution chloroform:acetone=8:2). After concentrating a fraction which is No. 5-15 (100-300 ml) including the desired product, the product was freeze dried and 6-Trifluoroacetamidohexanoic acid was obtained (weight: 3.1 g yield: 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]2[CH:14]=[CH:15][S:16][C:12]=2[CH:11]=[C:10]([C:17]([OH:19])=O)[N:9]=1.[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:20]([N:22]([CH2:23][CH3:24])[C:17]([C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:13]2[CH:14]=[CH:15][S:16][C:12]=2[CH:11]=1)=[O:19])[CH3:21]
Reactant: O=C(O)c1cc2sccc2c(-c2ccccc2Cl)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: CCNCC
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc2sccc2c(-c2ccccc2Cl)n1
Yield: 60.8 %

Procedure:
Operations are carried out as for example 7, starting from 2.9 g of 4-(2-chloro phenyl) thieno[3,2-c]pyridine 6-carboxylic acid, 1.17 g of triethylamine, 1.25 g of ethyl chloroformate and 0.94 g of diethylamine in 100 ml of chloroform. 2.1 g of N,N-diethyl 4-(2-chloro phenyl) thieno[3,2-c]pyridine 6-carboxamide, melting at 119° C., are obtained.
Reaction SMILES: [Br:1]Br.Cl[C:4]1[S:12][C:11]2[S:10](=[O:14])(=[O:13])[N:9]=[C:8]([NH:15][CH:16]([CH3:18])[CH3:17])[NH:7][C:6]=2[CH:5]=1>C(O)(=O)C>[Br:1][C:4]1[S:12][C:11]2[S:10](=[O:14])(=[O:13])[N:9]=[C:8]([NH:15][CH:16]([CH3:18])[CH3:17])[NH:7][C:6]=2[CH:5]=1
Reactant: CC(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)NC1=NS(=O)(=O)c2sc(Br)cc2N1
Temperature: 100 °C
Reaction time: 24 h
Yield: 36.4 %

Procedure:
Bromine (0.12 ml, 2.3 mmol) was added dropwise to a solution of 6-chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (280 mg, 1.0 mmol) in 10 ml of acetic acid and the mixture was stirred for 24 h at 100° C. in a sealed flask. The cooled mixture was evaporated to dryness and the residue was triturated with water to give a solid, which was recrystallised from ethanol/water (1:1) affording 118 mg (39%) of the title compound contaminated with 10% of the starting material; mp ca. 279° C. (aqueous ethanol); 1H-NMR (DMSO-d6): δ1.16 (d, 6H, 2×CH3), 3.86 (m, 1H, CH), 7.14 (s, 1H, H-5), 7.18 (br, 1H, NH), 10.74 (s, 1H, NH); MS: m/e 323/325 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:19]([CH3:21])[CH3:20])[C:7]([N:9]1[C@H:14]([C:15](O)=[O:16])[CH:13]2[CH2:18][CH:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].C([N:25](C(C)C)CC)(C)C.[OH-].[NH4+]>C(#N)C.O>[C:15]([C@@H:14]1[CH:13]2[CH2:18][CH:10]([CH2:11][CH2:12]2)[N:9]1[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:19]([CH3:21])[CH3:20])(=[O:16])[NH2:25]
Reactant: COC(=O)N[C@H](C(=O)N1C2CCC(C2)[C@H]1C(=O)O)C(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C2CCC(C2)[C@H]1C(N)=O)C(C)C
Reaction time: 1 h

Procedure:
(3S)-2-((S)-2-(Methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.78 g, 5.97 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (2.49 g, 5.56 mmol), and diisopropylethylamine (2.61 mL, 14.92 mmol) were dissolved in acetonitrile (30 mL) at ambient temperature and treated by dropwise addition with 28% ammonium hydroxide solution (2.49 g, 17.98 mmol). The resulting mixture was stirred for 1 hour and then diluted with water and extracted into dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give methyl (2S)-1-((3S)-3-carbamoyl-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a white waxy solid.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][C:29](Cl)=[O:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:28][C:29]([NH:12][C:10]2[S:11][C:7]([C:4]3[N:5]=[N:6][N:2]([CH3:1])[N:3]=3)=[C:8]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[N:9]=2)=[O:30])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Cn1nnc(-c2sc(N)nc2-c2cccs2)n1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Product: COc1ccc(CC(=O)Nc2nc(-c3cccs3)c(-c3nnn(C)n3)s2)cc1OC

Procedure:
Prepared from 5-(2-methyl-2H-tetrazol-5-yl)-4-thiophen-2-yl-thiazol-2-ylamine and (3,4-dimethoxy-phenyl)-acetyl chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([O:4][CH2:5][C:6](O)=[O:7])[CH3:3].C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([O:4][CH2:5][C:6]([Cl:13])=[O:7])[CH3:3]
Reactant: CC(C)(C)OCC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OCC(=O)Cl
Yield: 52.9 %

Procedure:
To a 3-neck 500 ml round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added (1,1-dimethylethoxy)acetic acid (24.00 g, 0.182 moles) and 300 ml of toluene under nitrogen. Oxalyl chloride (46.10 g, 0.363 moles) was then added dropwise and to this mixture was added N,N-dimethylformamide (0.25 g, 0.003 moles). This solution was heated at 30°-40° C. for 5 hours and then concentrated in vacuo to give 14.5 g of the product as a brown oil.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][N:7]([CH3:37])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:34][C@@:32]3([CH3:33])[C@@H:28]([CH2:29][CH2:30][C:31]3=[O:35])[C@H:27]3[C:18]2=[C:19]2[C:24]([CH2:25][CH2:26]3)=[CH:23][C:22](=[O:36])[CH2:21][CH2:20]2)=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>ClCCl.N1C=CC=CC=1>[Cl:4][C:23]1[C:22](=[O:36])[CH2:21][CH2:20][C:19]2[C:24]=1[CH2:25][CH2:26][C@@H:27]1[C:18]=2[C@@H:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][N:7]([CH3:6])[CH3:37])=[CH:16][CH:15]=2)[CH2:34][C@@:32]2([CH3:33])[C@H:28]1[CH2:29][CH2:30][C:31]2=[O:35]
Reactant: O=S(=O)(Cl)Cl
Reactant: CN(C)CCOc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)CCOc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=C(Cl)C(=O)CCC4=C32)cc1
Reaction time: 0.5 h

Procedure:
6 ml of sulphuryl chloride at 10% in dichloromethane is added under an inert atmosphere, at ambient temperature to a solution of 1.08 g of 11β-[4-(2-(dimethylamino)ethoxy)phenyl]-estra-4,9-diene-3,17-dione in 11 ml of pyridine and agitation is carried out for 30 minutes at approximately −36° C. The reaction medium is poured into sodium bicarbonate, followed by extraction, washing, drying and evaporating under reduced pressure until 1.84 g of crude product is obtained, which is purified by chromatography, eluting with an ethyl acetate/triethylamine mixture 80/20. 616 mg of expected pure product is obtained. (Rf AcOEt/TEA 8/2=0.35).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[O:38][N:37]=[C:36]([C:39]2[N:40]=[C:41]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[S:42][CH:43]=2)[CH2:35]1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]1[O:38][N:37]=[C:36]([C:39]2[N:40]=[C:41]([CH:44]3[CH2:49][CH2:48][N:47]([C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[CH2:46][CH2:45]3)[S:42][CH:43]=2)[CH2:35]1
Reactant: C#CCCC(=O)O
Reactant: Fc1ccccc1C1CC(c2csc(C3CCNCC3)n2)=NO1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4F)C3)cs2)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 4-pentynoic acid (64 mg, 0.408 mmol) in dichloromethane (3 mL) was added 1-propanephosphonic acid cyclic anhydride solution (50% in ethyl acetate, 0.5 mL). After stirring for 5 minutes, 4-[4-[5-(2-fluorophenyl)-4,5-dihydro-3-isoxazolyl)-2-thiazolyl]piperidine hydrochloride (i.e. the product of Step C, Example 6) (150 mg, 0.408 mmol), triethylamine (0.1 mL) and 4-dimethylaminopyridine (5 mg) were sequentially added. The reaction mixture was stirred for 3 h and then concentrated under reduced pressure. The resulting material was purified by column chromatography on silica gel to provide the title compound, a compound of the present invention, as an oil (142 mg).
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[C:19]1([NH:25][C:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:19]1([NH:25][C:26]([CH:28]2[CH2:29][CH2:30][N:31]([CH2:2][C:3]3[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]4[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=4[CH:4]=3)[CH2:32][CH2:33]2)=[O:27])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Nc1ccccc1)C1CCNCC1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2CCC(C(=O)Nc3ccccc3)CC2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.4 %

Procedure:
To a solution of 100 mg (0.32 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and 230 mg (0.96 mmoles) of piperidine-4-carboxylic acid phenylamide in 5 ml of DMF, 130 mg (0.96 mmoles) of K2CO3 is added at ambient temperature. The reaction mixture is stirred for 18 hours at ambient temperature. The reaction mixture is quenched with H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 130 mg of disired 1-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-piperidine-4-carboxylic acid phenylamide in 95% yield.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH3:11])(=[O:20])=[O:19]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Brc1cccc2[nH]ccc12
Product: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Yield: 87 %

Procedure:
The compound was prepared from 4-bromoindole (1.02 g, 5.25 mmol) and o-methylbenzenesulfonyl chloride (a 9:1 mixture of ortho and para methyl isomers) (1.29 g, 6.78 mmol) according to method 4. Purification by column chromatography (SiO2, CH2Cl2:heptane) gave 1.6 g (87%) of the title compound which contains ca 10% of the p-methyl isomer) as a light purple viscous oil: 1H NMR (CD3OD) δ 7.94–6.68 (m, 9H), 2.52 (s, 3H); MS (ESI) 352.3 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: O.O.C[O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([NH2:16])=[NH:15])=[CH:8][CH:7]=1.CN(/[CH:21]=[CH:22]/[C:23]([C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1)=O)C.C[O-].[Na+].[OH-].[Na+]>CO.O>[N:26]1[CH:27]=[CH:28][N:29]=[CH:30][C:25]=1[C:23]1[CH:22]=[CH:21][N:16]=[C:14]([NH:13][CH2:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]([OH:4])=[O:17])=[CH:7][CH:8]=2)[N:15]=1
Reactant: CN(C)/C=C/C(=O)c1cnccn1
Reactant: COC(=O)c1ccc(CNC(=N)N)cc1
Agent: C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Yield: 87.6 %

Procedure:
A suspension of 24 (6.2 g, 25.4 mmol) and 23a (3.0 g, 16.9 mmol) in anhydrous methanol (40 mL) was stirred and heated to reflux for 10 min, then a solution of sodium methoxide 95% (3.65 g, 67.6 mmol) in methanol (40 mL) was slowly added. After refluxing for 24 h, 20 mL of 2.5N NaOH in water were added and the refluxing was maintained for additional 24 h. The mixture was allowed to cool to the room temperature methanol was removed under reduced pressure, 100 mL of water were added and the resultant mixture was extracted with AcOEt. The aqueous phase was separated and acidified to pH 5-6 with 2N HCl to form a precipitate which was collected by filtration, rinsed with water and dried to afford the desired carboxylic acid 25a (4.55 g, 14.8 mmol, 87%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:18]3[N:23]=[C:22]4[S:24][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=5[F:35])=[N:26][C:21]4=[CH:20][CH:19]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:37]1[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:18]3[N:23]=[C:22]4[S:24][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH2:31][N:37]6[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]6)=[CH:29][C:28]=5[F:35])=[N:26][C:21]4=[CH:20][CH:19]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccc(OCc6ccccc6)cc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccc(OCc7ccccc7)cc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Synthesized from 4-(5-(1-(4-(benzyloxy)phenyl)cyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzaldehyde (0.224 g, 0.466 mmol) and methyl azetidine-3-carboxylate hydrochloride (0.177 g, 1.17 mmol) according to the general procedure for reductive amination to give methyl 1-(4-(5-(1-(4-(benzyloxy)phenyl)cyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)-3-fluorobenzyl)azetidine-3-carboxylate as a yellow solid. MS (ESI) m/z: calculated: 579.2; Observed: 580.1 (M++1).
Reaction SMILES: [C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])([O:3][CH2:4][CH3:5])=[O:2].[CH3:29]NC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2CC)[C@H](O)[C@@H]1O.ClCCC(OCC)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH2:25][CH3:29])[C@H:12]([OH:26])[C@@H:11]1[OH:27])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CNC)[C@@H](O)[C@H]1O
Reactant: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Agent: CCOC(=O)CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(CC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 13b was prepared by the same procedure as described for the preparation of 13a using 4b (260 mg, 0.84 mmol), ethyl 3-chloropropionate (138 mg, 1.0 mmol), DIEA (53 mg, 0.07 mL, 0.41 mmol), and DMF (4 mL). After column chromatography (elution with 7:1:0.1 chloroform:methanol:NH4OH), a glassy sticky solid was obtained: yield 153 mg (44%), MS: m/z 409 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.10 (bs, 2H, 6-NH2), 5.71 (d, 1H, H-1′, J1′,2′=5.5 Hz), 5.32 (bd, 1H, OH-2′, J2′-2′OH=5.0 Hz), 5.16 (bd, 1H, OH-3′, J3′-3′OH=5.1 Hz), 5.12 (ddd, 1H, H-2′, J1′,2′=5.5 Hz, J2′,3′=5.7 Hz, J2′-2′OH=5.0 Hz), 4.14 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.1 Hz, J3′-3′OH=5.1 Hz), 4.01 (q, 2H, OCH2CH3), 3.91-3.98 (m, 1H, H-4′), 2.87 (q, 2H, CH2 of 8-Et), 2.71-2.79 (m, 1H, 5′-CH2), 2.51-2.65 (m, 3H, 5′-CH2, CO—CH2), 2.38 (t, 2H, N(CH3)—CH2), 2.16 (bs, 3H, N—CH3), 1.30 (t, 3H, CH3 of 8-Et), 1.15 (t, 3H, OCH2CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:35][C:36]#[CH:37])[CH3:34]>O1CCCC1.C(N(CC)CC)C.[Cu]I.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>[CH3:32][N:33]([CH3:34])[CH2:35][C:36]#[C:37][C:28]1[CH:29]=[CH:30][C:25](/[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:26][CH:27]=1
Reactant: C#CCN(C)C
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(C#CCN(C)C)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.75 mmol; example 10 was dissolved in a mixture of anhydrous tetrahydrofuran (10 mL) and anhydrous triethylamine (20 mL). The solution was degassed and a solution of N,N-dimethylpropargylamine (125 mg, 1.50 mmol) in anhydrous tetrahydrofuran (2 mL) was added under inert atmosphere. The resulting solution was degassed once more, copper(I) iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added and the mixture was degassed again. The reaction mixture was stirred at ambient temperature overnight and the resulting suspension was filtered through a paddle of silica gel. Silica gel was washed thoroughly with ethyl acetate; the filtrate was evaporated in vacuo and the residue was dissolved in dichloromethane (50 mL). The solution was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1) yielding methyl (E)-[4-[3-[4-[3-(dimethylamino)propynyl)phenyl]-3-(4-fluorophenyl)allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[C:7]1([CH:17]=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.Cl>CCOCC>[C:7]1([CH:17]([OH:18])[CH3:5])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CI
Agent: C[Mg]I
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a solution of methylmagnesium iodide in ether which was prepared from magnesium turning (1.08 g, 44.4 mmol) and methyl iodide (2.75 ml, 44.2 mmol) in 100 ml of ether, were added a solution of 1-naphthaldehyde (1) (5.75 g, 36.8 mmol) in 10 ml of ether with cooling in an ice-water bath, then the resulting reaction mixture was stirred for 2 hours at room temperature. To this mixture was added 25 ml of 2N hydrochloric acid and then the organic layer was separated from the aqueous layer. The organic layer was washed with 50 ml of brine and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 6.20 g (97%) of 2 as a viscous oil.