Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([CH2:9][OH:10])[C@H:7]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@@H:4]1[CH2:5][CH2:6]2.CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:10][CH2:9][CH:8]1[CH:3]([CH2:2][O:1][S:30]([CH3:29])(=[O:32])=[O:31])[C@H:4]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[C@@H:7]1[CH2:6][CH2:5]2)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1[C@@H]2CC[C@H]1C(CO)C2CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1C(COS(C)(=O)=O)[C@@H]2CC[C@H]1N2C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of (1R,4S)-benzyl 2,3-bis(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (LI) (1.85 g, 6.35 mmol) and Et3N (2.65 mL, 19.05 mmol) in DCM (70 mL) at −30° C. was added a solution of MsCl (1.47 mL, 19.05 mmol) in DCM (15 mL) dropwise. The reaction mixture was stirred for 15 min at −10° C. then for 1.5 h at 0° C. The reaction mixture was dilluted with DCM, washed with 1 M HCl, 1 M K2CO3, brine and then dried over MgSO4. The solvent was removed under vacuum to give (1R,4S)-benzyl 2,3-bis((methylsulfonyloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (LII) as a very thick, light yellow oil (2.70 g, 6.03 mmol, 95% yield). 1H NMR (CDCl3) δ ppm 1.74 (brs, 4H), 1.88 (brs, 1H), 2.16 (brs, 1H), 2.97 (brs, 2H), 3.03 (brs, 3H), 3.97-4.09 (m, 1H), 4.10-4.18 (m, 1H), 4.22 (brs, 1H), 4.26-4.34 (m, 1H), 4.40 (brs, 1H), 5.11 (brs, 2H), 7.35 (brs, 5H); ESIMS found for C18H25NO8S2 m/z 448 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][O:12][CH2:13][CH2:14]I.CC(C)=O.C([O-])([O-])=O.[K+].[K+].COCCI>C1(C)C=CC=CC=1.CC(C)=O>[CH3:11][O:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: COCCI
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COCCOc1ccc2[nH]ccc2c1
Yield: 86.2 %

Procedure:
To a solution of 5-hydroxy-indole (15.2 g, 114 mmol) in 250 ml of dry acetone 2-methoxyethyl iodide (15 ml, 141 mmol, 1.25 equiv) and anhydrous K2CO3 (46.7 g, 338 mmol, 3 equiv) are added and the mixture is refluxed. Additional amounts of 0.5 equiv of 2-methoxyethyl iodide and K2CO3 are added each day. After 6 days TLC (toluene-acetone, 9:1) indicates the absence of starting material. The solid is removed by filtration, and the solvent is evaporated. The residue is taken up in dichloromethane (800 ml) and the solution is washed with 2 M aqueous HCl, 10% aqueous NaHCO3, and water. The organic layer is dried and concentrated. Column chromatography (toluene-acetone, 9:1) provides 5-(2-methoxyethoxy)-1H-indole (18.8 g, 86%). M.p. 58-60° C. (from ethyl acetate-light petroleum).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([CH2:21][OH:22])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][O:26][CH3:27].Cl>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]([CH2:21][O:22][CH2:24][CH2:25][O:26][CH3:27])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: O=C(O)c1cc(CO)nn1Cc1cc(-c2ccc(Cl)s2)on1
Agent: Cl
Solvent: CN(C)C=O
Product: COCCOCc1cc(C(=O)O)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Temperature: 80 °C

Procedure:
To a solution of 500 mg of 2-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-hydroxymethyl-2H-pyrazole-3-carboxylic acid in 5 ml DMF 480 mg Cs2CO3 and 204 mg 1-Bromo-2-methoxy-ethane were added and the mixture was heated to 80° C. for 5 h. Then the mixture was acidified to pH 4 with aqueous HCl and filtered through a chem elut® cartridge by elution with ethyl acetate. After concentration the crude product was directly subjected to the next reaction step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:11]#[C:10][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:7]=1
Reactant: COc1ccnc(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccnc(C#C[Si](C)(C)C)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 2-chloro-4-methoxypyrimidine (2.60 g, 17.99 mmol), ethynyltrimethylsilane (3.05 mL, 21.58 mmol), tetrahydrofuran (24 mL) and triethylamine (12.53 mL, 89.90 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and then copper(I) iodide (0.14 g, 0.72 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.51 g, 0.72 mmol) were added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath at 90° C. After 16 hours, the mixture was filtered and the solvent was removed under reduced pressure. The residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated, washed with 4% aqueous sodium hydrogencarbonate solution, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (9:1 hexane/ethyl acetate) gave the title compound (2.85 g, 77%) as an oil.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH2:27][CH2:28]O)[CH:24]=[CH:25][CH:26]=1>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: OCCc1cccc(C(F)(F)F)c1
Product: O=C(O)CNC(=O)c1ccc(OCCc2cccc(C(F)(F)F)c2)cc1
Yield: 50.1 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (502 mg, 2.00 mmol) prepared in Example 1 (1a) and 2-[3-(trifluoromethyl)phenyl]ethanol (330 μL, 2.20 mmol) to give 368 mg of the title compound (white powder, yield: 80%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1>C(=S)=S>[C:5]([CH:9]1[CH2:14][CH2:13][CH:12]([C:9]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:14][CH3:13])=[CH:11][CH:10]=2)[CH2:11][CH2:10]1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: C1=CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCc1ccc(C2CCC(C(C)=O)CC2)cc1
Temperature: 25 °C

Procedure:
To a suspension of 66.6 g. of anhydrous aluminum chloride in 200 ml. of carbon disulphide there are added at -15° C., with stirring, 39 g. of acetyl chloride and thereafter 41 g. of cyclohexene. The reaction mixture is stirred for 30 minutes at -15° C. and then the upper carbon disulphide layer is removed and replaced by 400 ml. of n-pentylbenzene. After the addition of a further 33 g. of aluminum chloride, while stirring, the reaction mixture is warmed up to ambient temperature and further stirred until the evolution of hydrogen chloride ceases. Thereafter, the reaction mixture is poured onto ice water, the separated aluminum hydroxide is brought into solution with hydrochloric acid and the organic phase is separated off, dried and distilled. After stripping off excess n-pentylbenzene, the 4-acetyl-1-(4-pentylphenyl)-cyclohexane thus obtained is distilled off under reduced pressure; yield 48 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[C:31]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:43]2[CH:44]=[CH:45][C:40]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:41][CH:42]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(-c3ccccc3)cc2)sc1C(=O)OCC

Procedure:
Prepared from 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester, example 81(b), and 1,1′-biphenyl-4-yl-boronic acid under conditions analogous to experimental example 81(c). MS: (+) m/z 575.0 (M+1).
Reaction SMILES: [OH-].[Na+].S(OC)(O[CH3:7])(=O)=O.[OH:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([C:15](=[O:24])[CH2:16][C:17]([CH3:23])([CH3:22])[O:18]2)=[CH:13][CH:12]=1>O>[CH3:7][O:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([C:15](=[O:24])[CH2:16][C:17]([CH3:22])([CH3:23])[O:18]2)=[CH:13][CH:12]=1
Reactant: Cc1c(O)ccc2c1OC(C)(C)CC2=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(c1C)OC(C)(C)CC2=O
Reaction time: 2 h
Yield: 78 %

Procedure:
The reaction is carried out under nitrogen. In 50 ml of a 10% sodium hydroxide solution 4.9 g (20 millimoles) of 7-hydroxy-2,2,8-trimethyl-4-chromanone are dissolved, 2.6 g (2 ml, 21 millimoles) of dimethyl sulfate are added and the reaction mixture is vigorously stirred for 2 hours. The reaction mixture is diluted with 100 ml of icecold water and extracted three times with 50 ml of carbon tetrachloride each. The organic phase is washed twice with 50 ml of water each, dried over sodium sulfate, the solvent is removed and the residue crystallized from 90% methanol. Thus 3.4 g of the desired compound are obtained, yield 78%. Mp.: 105°-107° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([Cl:27])[N:20]=[C:19]2[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=1)(=[O:4])=[O:3].[C:32](Cl)(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH2:32]([NH:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([Cl:27])[N:20]=[C:19]2[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15][CH:16]=1)(=[O:4])=[O:3])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCCc1nc(Cl)c(C(=O)OC)n1Cc1ccc(-c2ccccc2S(=O)(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
To a stirred solution of 1-((2'-(aminosulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid, methyl ester (67.0 mg, 0.145 mmol) in pyridine (1.0 ml) under nitrogen at room temperature was added benzoyl chloride (168 μl, 1.45 mmol) dropwise. The pale orange solution was stirred at room temperature for 12 hours then saturated sodium bicarbonate solution added. The mixture was extracted four times with ethyl acetate. The compound organic phase was washed with water, twice with saturated copper sulfate solution, water, brine and dried (magnesium sulfate). The solvent was removed in vacuo and the residue chromatographed (silica gel, 2% methanolmethylene chloride) to give 1-((2'-((benzylamino)sulfonyl)(1,1'-biphenyl)-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid, methyl ester (63.4 mg, 77%) as a white solid; 1H NMR (300 MHz, CD3OD) δ8.30 (dd, J=7.7, 1.7 Hz, 1H), 7.65-7.42 (m, 5H), 7.40-7.30 (m, 2H), 7.29-7.18 (m, 3H), 6.90 (d, J=8.2 Hz, 2H), 5.54 (s, 2H), 3.84 (s, 3H), 2.62 (t, J=7.8 Hz, 2H), 1.64 (quin, J=7.8 Hz, 2H), 1.32 (apparent sext, 2H), 0.87 (t, J=7.3 Hz, 3H); FAB-MS: 568 and 566 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[N:7]([C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH2:24])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)=O.[NH3:31]>>[NH2:24][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:12]3[N:13]=[C:6]4[C:5]([C:3]([NH2:31])=[O:2])=[CH:10][CH:9]=[CH:8][N:7]4[C:11]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: N
Reactant: COC(=O)c1cccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Product: NC(=O)c1cccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Temperature: 130 °C

Procedure:
A mixture of 2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-8-carboxylic acid methyl ester (Example 2-23, 128 mg) and ammonia (2.23 mL of a 7M aqueous solution) was heated at 130° C. under microwave irradiation for 90 minutes. On cooling, the reaction mixture was concentrated to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.Br[CH2:21]C1C=CC=CC=1C>>[CH3:14][O:13][C:10]1[C:9]([O:15][CH3:16])=[CH:8][C:7]([S:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:2][C:3]=2[CH3:21])=[CH:12][N:11]=1
Reactant: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Reactant: Cc1ccccc1CBr
Product: COc1cc(SCc2ccccc2C)cnc1OC

Procedure:
Prepared as described for 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine (Intermediate 8) but using 1-(bromomethyl)-2-methylbenzene instead of 1-(bromomethyl)-3-chlorobenzene.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12]C(=O)OC(C)(C)C)=[N:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1.[ClH:20].O1CCOCC1>C(Cl)Cl>[ClH:20].[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cnnn2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ccc(-n2cnnn2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl 5-(1H-tetrazol-1-yl)pyridin-2-ylcarbamate (300 mg, 1.14 mmol) was dissolved in DCM (2 mL), followed by addition of 4 M HCl in dioxane (2.86 mL, 11.4 mmol). The mixture was stirred at RT for 4 hours, then concentrated to give title compound. LC/MS: [(M+1)]+=163.20.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17]([OH:19])=O)=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O>O1CCCC1>[C:1]1([C:7]2[C:15]([CH2:16][C:17]([NH2:22])=[O:19])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1c(-c2ccccc2)nn2cccnc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NC(=O)Cc1c(-c2ccccc2)nn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A mixture of 3.5 g (0.013 mole) of 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 2.24 g (0.013 mole) of 1,1'-carbonyldiimidazole in 150 ml of anhydrous tetrahydrofuran was stirred for 3 hours at room temperature while nitrogen was bubbled through the mixture. The reaction mixture was cooled in a dry ice/acetone bath, and treated with 50 ml of liquid ammonia. The reaction mixture was warmed to room temperature and stirred for two days. The suspended solid which formed was collected by filtration (2.81 g, mp 204°-219° C.) combined with the residue from evaporation of the filtrate (3.1 g), and recrystallized from ethanol to give 2.1 g of product (60%), mp 217°-219° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2C(OC(C)(C)C)=O)[CH:4]=1)#[N:2].[H][H].[ClH:32]>C(O)C.O1CCOCC1.[Pd]>[ClH:32].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([O:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:4]=1)#[N:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(C#N)cc1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)CCc1ccc(C#N)cc1OC[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.0 g (7.5 mmol) of ethyl 3-[4-cyano-(2R)-2-(1-t-butoxycarbonylpyrrolidine-2-ylmethoxy)phenyl]acrylate was dissolved in 20 ml of ethanol. 600 mg of 10% palladium/carbon (50% aqueous) was added to the obtained solution, and they were stirred in the presence of hydrogen overnight. The reaction solution was filtered through Celite, and the solvent was evaporated. The obtained crude product was dissolved in 10 ml of 4 N solution of hydrogen chloride in dioxane, and the obtained solution was stirred at room temperature for 3 hours. The solvent was evaporated to obtain hydrochloride of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:53][C:54]1[CH:55]=[CH:56][C:57]([C:60](O)=[O:61])=[N:58][CH:59]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:60]([C:57]3[CH:56]=[CH:55][C:54]([Cl:53])=[CH:59][N:58]=3)=[O:61])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)cn3)cc2)COC1(C)C
Temperature: 50 °C
Yield: 91.5 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg, example 14 (b)) in THF (4 ml) were added sequentially N-methylmorpholine (0.21 ml), TBTU (301 mg) and 5-chloro-2-pyridinecarboxylic acid (111 mg, CAS 86873-60-1) and the mixture was heated at 50° C. for 18 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(2-{4-[(5-chloro-pyridine-2-carbonyl)-amino]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (197 mg, 91%) as a white solid. MS (ISP): 484.3 ([{37Cl}M+Na]+), 482.3 ([{35Cl}M+Na]+), 462.4 ([{37Cl}M+H]+), 460.5 ([{35Cl}M+H]+), 406.4 ([{37Cl}M+H—C4H8]+), 404.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:31])[CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])=[CH:9][C:8]=1[CH2:32][CH2:33][CH2:34][O:35][CH3:36])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:36][O:35][CH2:34][CH2:33][CH2:32][C:8]1[CH:9]=[C:10]([N:13]([CH3:31])[CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:30])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)COc1ccc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1CCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCc1cc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
0.280 g (0.52 mmol) of the above prepared (2-(3-methoxy-propyl)-4-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester was dissolved in 3.3 ml of THF/EtOH=1/1, treated with 1.56 ml (3 eq.) of 1N NaOH, and kept at ambient temperature for 0.5 h. The reaction mixture was then poured onto crashed ice/HCl dil., extracted twice with EtOAc, the organic layer washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Crystallization from hexane/EtOAc afforded finally 0.209 g of the title compound as off-white crystals of mp. 142-143° C., MS: 507.5 (M-H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=2)=[O:9])[C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2nccn2C)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Product: Cc1ccc(-c2nccn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(1-methyl-1H-imidazol-2-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.Br[CH2:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:24][C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])[C:8]=2[N:9]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(Cc3c(Cl)cccc3Cl)c2n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
To a suspension of NaH (60% in mineral oil, 36 mg) in 8 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (208 mg, 0.68 mmol). The mixture was heated at 70° C. for 10 minutes and then at 50° C. for 30 minutes, resulting in a clear solution. α-Bromo-2,6-dichlorotoluene (215 mg, 0.90 mmol) was added, and the reaction mixture was heated at 50° C. for 25 minutes, then poured onto ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate then dried in vacuo to provide 112 mg (35%) of 2-amino-8-(2,6-dichlorobenzyl)-6-(2,6-dichlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; mp 274°-276° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([C:22](=O)[CH3:23])[CH:10]=[CH:11][C:12]=2[S:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.CO.C([BH3-])#[N:28].[Na+].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH:22]([NH2:28])[CH3:23])[CH:10]=[CH:11][C:12]=2[S:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccc(S(=O)(=O)N2CCOCC2)c(-c2ccc(Cl)s2)c1
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1ccc(S(=O)(=O)N2CCOCC2)c(-c2ccc(Cl)s2)c1
Yield: 43.5 %

Procedure:
To a solution of the compound yielded from step 3 (2.2 g, 5.7 mmol) in MeOH (30 mL) ammonium acetate (4.39 g, 57.0 mmol) and sodium cyanoborohydride (358 mg, 5.7 mmol) were added. The reaction mixture was refluxed for 4 h. After that the mixture was acidified with trifluoroacetic acid to pH=2 and then evaporated to dryness. Purification of the crude product by prep-HPLC and lyophilization of the relevant fractions gave the desired product (0.96g, 34%).